A small number of abnormal brain connections predicts adult autism spectrum disorder

PubMed Central

Yahata, Noriaki; Morimoto, Jun; Hashimoto, Ryuichiro; Lisi, Giuseppe; Shibata, Kazuhisa; Kawakubo, Yuki; Kuwabara, Hitoshi; Kuroda, Miho; Yamada, Takashi; Megumi, Fukuda; Imamizu, Hiroshi; Náñez Sr, José E.; Takahashi, Hidehiko; Okamoto, Yasumasa; Kasai, Kiyoto; Kato, Nobumasa; Sasaki, Yuka; Watanabe, Takeo; Kawato, Mitsuo

2016-01-01

Although autism spectrum disorder (ASD) is a serious lifelong condition, its underlying neural mechanism remains unclear. Recently, neuroimaging-based classifiers for ASD and typically developed (TD) individuals were developed to identify the abnormality of functional connections (FCs). Due to over-fitting and interferential effects of varying measurement conditions and demographic distributions, no classifiers have been strictly validated for independent cohorts. Here we overcome these difficulties by developing a novel machine-learning algorithm that identifies a small number of FCs that separates ASD versus TD. The classifier achieves high accuracy for a Japanese discovery cohort and demonstrates a remarkable degree of generalization for two independent validation cohorts in the USA and Japan. The developed ASD classifier does not distinguish individuals with major depressive disorder and attention-deficit hyperactivity disorder from their controls but moderately distinguishes patients with schizophrenia from their controls. The results leave open the viable possibility of exploring neuroimaging-based dimensions quantifying the multiple-disorder spectrum. PMID:27075704

A consensus prognostic gene expression classifier for ER positive breast cancer

PubMed Central

Teschendorff, Andrew E; Naderi, Ali; Barbosa-Morais, Nuno L; Pinder, Sarah E; Ellis, Ian O; Aparicio, Sam; Brenton, James D; Caldas, Carlos

2006-01-01

Background A consensus prognostic gene expression classifier is still elusive in heterogeneous diseases such as breast cancer. Results Here we perform a combined analysis of three major breast cancer microarray data sets to hone in on a universally valid prognostic molecular classifier in estrogen receptor (ER) positive tumors. Using a recently developed robust measure of prognostic separation, we further validate the prognostic classifier in three external independent cohorts, confirming the validity of our molecular classifier in a total of 877 ER positive samples. Furthermore, we find that molecular classifiers may not outperform classical prognostic indices but that they can be used in hybrid molecular-pathological classification schemes to improve prognostic separation. Conclusion The prognostic molecular classifier presented here is the first to be valid in over 877 ER positive breast cancer samples and across three different microarray platforms. Larger multi-institutional studies will be needed to fully determine the added prognostic value of molecular classifiers when combined with standard prognostic factors. PMID:17076897

Predicting the Individual Risk of Acute Severe Colitis at Diagnosis

PubMed Central

Cesarini, Monica; Collins, Gary S.; Rönnblom, Anders; Santos, Antonieta; Wang, Lai Mun; Sjöberg, Daniel; Parkes, Miles; Keshav, Satish

2017-01-01

Abstract Background and Aims: Acute severe colitis [ASC] is associated with major morbidity. We aimed to develop and externally validate an index that predicted ASC within 3 years of diagnosis. Methods: The development cohort included patients aged 16–89 years, diagnosed with ulcerative colitis [UC] in Oxford and followed for 3 years. Primary outcome was hospitalization for ASC, excluding patients admitted within 1 month of diagnosis. Multivariable logistic regression examined the adjusted association of seven risk factors with ASC. Backwards elimination produced a parsimonious model that was simplified to create an easy-to-use index. External validation occurred in separate cohorts from Cambridge, UK, and Uppsala, Sweden. Results: The development cohort [Oxford] included 34/111 patients who developed ASC within a median 14 months [range 1–29]. The final model applied the sum of 1 point each for extensive disease, C-reactive protein [CRP] > 10mg/l, or haemoglobin < 12g/dl F or < 14g/dl M at diagnosis, to give a score from 0/3 to 3/3. This predicted a 70% risk of developing ASC within 3 years [score 3/3]. Validation cohorts included different proportions with ASC [Cambridge = 25/96; Uppsala = 18/298]. Of those scoring 3/3 at diagnosis, 18/18 [Cambridge] and 12/13 [Uppsala] subsequently developed ASC. Discriminant ability [c-index, where 1.0 = perfect discrimination] was 0.81 [Oxford], 0.95 [Cambridge], 0.97 [Uppsala]. Internal validation using bootstrapping showed good calibration, with similar predicted risk across all cohorts. A nomogram predicted individual risk. Conclusions: An index applied at diagnosis reliably predicts the risk of ASC within 3 years in different populations. Patients with a score 3/3 at diagnosis may merit early immunomodulator therapy. PMID:27647858

The Student Perception of University Support and Structure Scale: Development and Validation

ERIC Educational Resources Information Center

Wintre, Maxine G.; Gates, Shawn K. E.; Pancer, W. Mark; Pratt, Michael S.; Polivy, Janet; Birnie-Lefcovitch, S.; Adams, Gerald

2009-01-01

A new scale, the Student Perception of University Support and Structure Scale (SPUSS), was developed for research on the transition to university. The scale was based on concepts derived from Baumrind's (1971) theory of parenting styles. Data were obtained from two separate cohorts of freshmen (n=759 and 397) attending six Canadian universities of…

Genetic risk prediction and neurobiological understanding of alcoholism

PubMed Central

Levey, D F; Le-Niculescu, H; Frank, J; Ayalew, M; Jain, N; Kirlin, B; Learman, R; Winiger, E; Rodd, Z; Shekhar, A; Schork, N; Kiefe, F; Wodarz, N; Müller-Myhsok, B; Dahmen, N; Nöthen, M; Sherva, R; Farrer, L; Smith, A H; Kranzler, H R; Rietschel, M; Gelernter, J; Niculescu, A B

2014-01-01

We have used a translational Convergent Functional Genomics (CFG) approach to discover genes involved in alcoholism, by gene-level integration of genome-wide association study (GWAS) data from a German alcohol dependence cohort with other genetic and gene expression data, from human and animal model studies, similar to our previous work in bipolar disorder and schizophrenia. A panel of all the nominally significant P-value SNPs in the top candidate genes discovered by CFG  (n=135 genes, 713 SNPs) was used to generate a genetic  risk prediction score (GRPS), which showed a trend towards significance (P=0.053) in separating  alcohol dependent individuals from controls in an independent German test cohort. We then validated and prioritized our top findings from this discovery work, and subsequently tested them in three independent cohorts, from two continents. In order to validate and prioritize the key genes that drive behavior without some of the pleiotropic environmental confounds present in humans, we used a stress-reactive animal model of alcoholism developed by our group, the D-box binding protein (DBP) knockout mouse, consistent with the surfeit of stress theory of addiction proposed by Koob and colleagues. A much smaller panel (n=11 genes, 66 SNPs) of the top CFG-discovered genes for alcoholism, cross-validated and prioritized by this stress-reactive animal model showed better predictive ability in the independent German test cohort (P=0.041). The top CFG scoring gene for alcoholism from the initial discovery step, synuclein alpha (SNCA) remained the top gene after the stress-reactive animal model cross-validation. We also tested this small panel of genes in two other independent test cohorts from the United States, one with alcohol dependence (P=0.00012) and one with alcohol abuse (a less severe form of alcoholism; P=0.0094). SNCA by itself was able to separate alcoholics from controls in the alcohol-dependent cohort (P=0.000013) and the alcohol abuse cohort (P=0.023). So did eight other genes from the panel of 11 genes taken individually, albeit to a lesser extent and/or less broadly across cohorts. SNCA, GRM3 and MBP survived strict Bonferroni correction for multiple comparisons. Taken together, these results suggest that our stress-reactive DBP animal model helped to validate and prioritize from the CFG-discovered genes some of the key behaviorally relevant genes for alcoholism. These genes fall into a series of biological pathways involved in signal transduction, transmission of nerve impulse (including myelination) and cocaine addiction. Overall, our work provides leads towards a better understanding of illness, diagnostics and therapeutics, including treatment with omega-3 fatty acids. We also examined the overlap between the top candidate genes for alcoholism from this work and the top candidate genes for bipolar disorder, schizophrenia, anxiety from previous CFG analyses conducted by us, as well as cross-tested genetic risk predictions. This revealed the significant genetic overlap with other major psychiatric disorder domains, providing a basis for comorbidity and dual diagnosis, and placing alcohol use in the broader context of modulating the mental landscape. PMID:24844177

Development and validation of a predictive risk model for all-cause mortality in type 2 diabetes.

PubMed

Robinson, Tom E; Elley, C Raina; Kenealy, Tim; Drury, Paul L

2015-06-01

Type 2 diabetes is common and is associated with an approximate 80% increase in the rate of mortality. Management decisions may be assisted by an estimate of the patient's absolute risk of adverse outcomes, including death. This study aimed to derive a predictive risk model for all-cause mortality in type 2 diabetes. We used primary care data from a large national multi-ethnic cohort of patients with type 2 diabetes in New Zealand and linked mortality records to develop a predictive risk model for 5-year risk of mortality. We then validated this model using information from a separate cohort of patients with type 2 diabetes. 26,864 people were included in the development cohort with a median follow up time of 9.1 years. We developed three models initially using demographic information and then progressively more clinical detail. The final model, which also included markers of renal disease, proved to give best prediction of all-cause mortality with a C-statistic of 0.80 in the development cohort and 0.79 in the validation cohort (7610 people) and was well calibrated. Ethnicity was a major factor with hazard ratios of 1.37 for indigenous Maori, 0.41 for East Asian and 0.55 for Indo Asian compared with European (P<0.001). We have developed a model using information usually available in primary care that provides good assessment of patient's risk of death. Results are similar to models previously published from smaller cohorts in other countries and apply to a wider range of patient ethnic groups. Copyright © 2015. Published by Elsevier Ireland Ltd.

Derivation and Validation of a Renal Risk Score for People With Type 2 Diabetes

PubMed Central

Elley, C. Raina; Robinson, Tom; Moyes, Simon A.; Kenealy, Tim; Collins, John; Robinson, Elizabeth; Orr-Walker, Brandon; Drury, Paul L.

2013-01-01

OBJECTIVE Diabetes has become the leading cause of end-stage renal disease (ESRD). Renal risk stratification could assist in earlier identification and targeted prevention. This study aimed to derive risk models to predict ESRD events in type 2 diabetes in primary care. RESEARCH DESIGN AND METHODS The nationwide derivation cohort included adults with type 2 diabetes from the New Zealand Diabetes Cohort Study initially assessed during 2000–2006 and followed until December 2010, excluding those with pre-existing ESRD. The outcome was fatal or nonfatal ESRD event (peritoneal dialysis or hemodialysis for ESRD, renal transplantation, or death from ESRD). Risk models were developed using Cox proportional hazards models, and their performance was assessed in a separate validation cohort. RESULTS The derivation cohort included 25,736 individuals followed for up to 11 years (180,497 person-years; 86% followed for ≥5 years). At baseline, mean age was 62 years, median diabetes duration 5 years, and median HbA1c 7.2% (55 mmol/mol); 37% had albuminuria; and median estimated glomerular filtration rate (eGFR) was 77 mL/min/1.73 m2. There were 637 ESRD events (2.5%) during follow-up. Models that included sex, ethnicity, age, diabetes duration, albuminuria, serum creatinine, systolic blood pressure, HbA1c, smoking status, and previous cardiovascular disease status performed well with good discrimination and calibration in the derivation cohort and the validation cohort (n = 5,877) (C-statistics 0.89–0.92), improving predictive performance compared with previous models. CONCLUSIONS These 5-year renal risk models performed very well in two large primary care populations with type 2 diabetes. More accurate risk stratification could facilitate earlier intervention than using eGFR and/or albuminuria alone. PMID:23801726

Development and validation of risk prediction equations to estimate future risk of blindness and lower limb amputation in patients with diabetes: cohort study

PubMed Central

Coupland, Carol

2015-01-01

Study question Is it possible to develop and externally validate risk prediction equations to estimate the 10 year risk of blindness and lower limb amputation in patients with diabetes aged 25-84 years? Methods This was a prospective cohort study using routinely collected data from general practices in England contributing to the QResearch and Clinical Practice Research Datalink (CPRD) databases during the study period 1998-2014. The equations were developed using 763 QResearch practices (n=454 575 patients with diabetes) and validated in 254 different QResearch practices (n=142 419) and 357 CPRD practices (n=206 050). Cox proportional hazards models were used to derive separate risk equations for blindness and amputation in men and women that could be evaluated at 10 years. Measures of calibration and discrimination were calculated in the two validation cohorts. Study answer and limitations Risk prediction equations to quantify absolute risk of blindness and amputation in men and women with diabetes have been developed and externally validated. In the QResearch derivation cohort, 4822 new cases of lower limb amputation and 8063 new cases of blindness occurred during follow-up. The risk equations were well calibrated in both validation cohorts. Discrimination was good in men in the external CPRD cohort for amputation (D statistic 1.69, Harrell’s C statistic 0.77) and blindness (D statistic 1.40, Harrell’s C statistic 0.73), with similar results in women and in the QResearch validation cohort. The algorithms are based on variables that patients are likely to know or that are routinely recorded in general practice computer systems. They can be used to identify patients at high risk for prevention or further assessment. Limitations include lack of formally adjudicated outcomes, information bias, and missing data. What this study adds Patients with type 1 or type 2 diabetes are at increased risk of blindness and amputation but generally do not have accurate assessments of the magnitude of their individual risks. The new algorithms calculate the absolute risk of developing these complications over a 10 year period in patients with diabetes, taking account of their individual risk factors. Funding, competing interests, data sharing JH-C is co-director of QResearch, a not for profit organisation which is a joint partnership between the University of Nottingham and Egton Medical Information Systems, and is also a paid director of ClinRisk Ltd. CC is a paid consultant statistician for ClinRisk Ltd. PMID:26560308

Development and validation of risk prediction equations to estimate future risk of blindness and lower limb amputation in patients with diabetes: cohort study.

PubMed

Hippisley-Cox, Julia; Coupland, Carol

2015-11-11

Is it possible to develop and externally validate risk prediction equations to estimate the 10 year risk of blindness and lower limb amputation in patients with diabetes aged 25-84 years? This was a prospective cohort study using routinely collected data from general practices in England contributing to the QResearch and Clinical Practice Research Datalink (CPRD) databases during the study period 1998-2014. The equations were developed using 763 QResearch practices (n=454,575 patients with diabetes) and validated in 254 different QResearch practices (n=142,419) and 357 CPRD practices (n=206,050). Cox proportional hazards models were used to derive separate risk equations for blindness and amputation in men and women that could be evaluated at 10 years. Measures of calibration and discrimination were calculated in the two validation cohorts. Risk prediction equations to quantify absolute risk of blindness and amputation in men and women with diabetes have been developed and externally validated. In the QResearch derivation cohort, 4822 new cases of lower limb amputation and 8063 new cases of blindness occurred during follow-up. The risk equations were well calibrated in both validation cohorts. Discrimination was good in men in the external CPRD cohort for amputation (D statistic 1.69, Harrell's C statistic 0.77) and blindness (D statistic 1.40, Harrell's C statistic 0.73), with similar results in women and in the QResearch validation cohort. The algorithms are based on variables that patients are likely to know or that are routinely recorded in general practice computer systems. They can be used to identify patients at high risk for prevention or further assessment. Limitations include lack of formally adjudicated outcomes, information bias, and missing data. Patients with type 1 or type 2 diabetes are at increased risk of blindness and amputation but generally do not have accurate assessments of the magnitude of their individual risks. The new algorithms calculate the absolute risk of developing these complications over a 10 year period in patients with diabetes, taking account of their individual risk factors. JH-C is co-director of QResearch, a not for profit organisation which is a joint partnership between the University of Nottingham and Egton Medical Information Systems, and is also a paid director of ClinRisk Ltd. CC is a paid consultant statistician for ClinRisk Ltd. © Hippisley-Cox et al 2015.

Development and external validation of a prostate health index-based nomogram for predicting prostate cancer

PubMed Central

Zhu, Yao; Han, Cheng-Tao; Zhang, Gui-Ming; Liu, Fang; Ding, Qiang; Xu, Jian-Feng; Vidal, Adriana C.; Freedland, Stephen J.; Ng, Chi-Fai; Ye, Ding-Wei

2015-01-01

To develop and externally validate a prostate health index (PHI)-based nomogram for predicting the presence of prostate cancer (PCa) at biopsy in Chinese men with prostate-specific antigen 4–10 ng/mL and normal digital rectal examination (DRE). 347 men were recruited from two hospitals between 2012 and 2014 to develop a PHI-based nomogram to predict PCa. To validate these results, we used a separate cohort of 230 men recruited at another center between 2008 and 2013. Receiver operator curves (ROC) were used to assess the ability to predict PCa. A nomogram was derived from the multivariable logistic regression model and its accuracy was assessed by the area under the ROC (AUC). PHI achieved the highest AUC of 0.839 in the development cohort compared to the other predictors (p < 0.001). Including age and prostate volume, a PHI-based nomogram was constructed and rendered an AUC of 0.877 (95% CI 0.813–0.938). The AUC of the nomogram in the validation cohort was 0.786 (95% CI 0.678–0.894). In clinical effectiveness analyses, the PHI-based nomogram reduced unnecessary biopsies from 42.6% to 27% using a 5% threshold risk of PCa to avoid biopsy with no increase in the number of missed cases relative to conventional biopsy decision. PMID:26471350

Assessment of heart rate, acidosis, consciousness, oxygenation, and respiratory rate to predict noninvasive ventilation failure in hypoxemic patients.

PubMed

Duan, Jun; Han, Xiaoli; Bai, Linfu; Zhou, Lintong; Huang, Shicong

2017-02-01

To develop and validate a scale using variables easily obtained at the bedside for prediction of failure of noninvasive ventilation (NIV) in hypoxemic patients. The test cohort comprised 449 patients with hypoxemia who were receiving NIV. This cohort was used to develop a scale that considers heart rate, acidosis, consciousness, oxygenation, and respiratory rate (referred to as the HACOR scale) to predict NIV failure, defined as need for intubation after NIV intervention. The highest possible score was 25 points. To validate the scale, a separate group of 358 hypoxemic patients were enrolled in the validation cohort. The failure rate of NIV was 47.8 and 39.4% in the test and validation cohorts, respectively. In the test cohort, patients with NIV failure had higher HACOR scores at initiation and after 1, 12, 24, and 48 h of NIV than those with successful NIV. At 1 h of NIV the area under the receiver operating characteristic curve was 0.88, showing good predictive power for NIV failure. Using 5 points as the cutoff value, the sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy for NIV failure were 72.6, 90.2, 87.2, 78.1, and 81.8%, respectively. These results were confirmed in the validation cohort. Moreover, the diagnostic accuracy for NIV failure exceeded 80% in subgroups classified by diagnosis, age, or disease severity and also at 1, 12, 24, and 48 h of NIV. Among patients with NIV failure with a HACOR score of >5 at 1 h of NIV, hospital mortality was lower in those who received intubation at ≤12 h of NIV than in those intubated later [58/88 (66%) vs. 138/175 (79%); p = 0.03). The HACOR scale variables are easily obtained at the bedside. The scale appears to be an effective way of predicting NIV failure in hypoxemic patients. Early intubation in high-risk patients may reduce hospital mortality.

The heterogeneity of systemic inflammation in bronchiectasis.

PubMed

Saleh, Aarash D; Chalmers, James D; De Soyza, Anthony; Fardon, Thomas C; Koustas, Spiro O; Scott, Jonathan; Simpson, A John; Brown, Jeremy S; Hurst, John R

2017-06-01

Systemic inflammation in bronchiectasis is poorly studied in relation to aetiology and severity. We hypothesized that molecular patterns of inflammation may define particular aetiology and severity groups in bronchiectasis. We assayed blood concentrations of 31 proteins from 90 bronchiectasis patients (derivation cohort) and conducted PCA to examine relationships between these markers, disease aetiology and severity. Key results were validated in two separate cohorts of 97 and 79 patients from other centres. There was significant heterogeneity in protein concentrations across the derivation population. Increasing severity of bronchiectasis (BSI) was associated with increasing fibrinogen (rho = 0.34, p = 0.001 -validated in a second cohort), and higher fibrinogen was associated with worse lung function, Pseudomonas colonisation and impaired health-status. There were generally similar patterns of inflammation in patients with idiopathic and post-infectious disease. However, patients with primary immunodeficiency had exaggerated IL-17 responses, validated in a second cohort (n = 79, immunodeficient 12.82 pg/ml versus idiopathic/post-infectious 4.95 pg/ml, p = 0.001), and thus IL-17 discriminated primary immunodeficiency from other aetiologies (AUC 0.769 (95%CI 0.661-0.877)). Bronchiectasis is associated with heterogeneity of systemic inflammatory proteins not adequately explained by differences in disease aetiology or severity. More severe disease is associated with enhanced acute-phase responses. Plasma fibrinogen was associated with bronchiectasis severity in two cohorts, Pseudomonas colonisation and health status, and offers potential as a useful biomarker. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

Prospective validation of pathologic complete response models in rectal cancer: Transferability and reproducibility.

PubMed

van Soest, Johan; Meldolesi, Elisa; van Stiphout, Ruud; Gatta, Roberto; Damiani, Andrea; Valentini, Vincenzo; Lambin, Philippe; Dekker, Andre

2017-09-01

Multiple models have been developed to predict pathologic complete response (pCR) in locally advanced rectal cancer patients. Unfortunately, validation of these models normally omit the implications of cohort differences on prediction model performance. In this work, we will perform a prospective validation of three pCR models, including information whether this validation will target transferability or reproducibility (cohort differences) of the given models. We applied a novel methodology, the cohort differences model, to predict whether a patient belongs to the training or to the validation cohort. If the cohort differences model performs well, it would suggest a large difference in cohort characteristics meaning we would validate the transferability of the model rather than reproducibility. We tested our method in a prospective validation of three existing models for pCR prediction in 154 patients. Our results showed a large difference between training and validation cohort for one of the three tested models [Area under the Receiver Operating Curve (AUC) cohort differences model: 0.85], signaling the validation leans towards transferability. Two out of three models had a lower AUC for validation (0.66 and 0.58), one model showed a higher AUC in the validation cohort (0.70). We have successfully applied a new methodology in the validation of three prediction models, which allows us to indicate if a validation targeted transferability (large differences between training/validation cohort) or reproducibility (small cohort differences). © 2017 American Association of Physicists in Medicine.

PRRT genomic signature in blood for prediction of 177Lu-octreotate efficacy.

PubMed

Bodei, Lisa; Kidd, Mark S; Singh, Aviral; van der Zwan, Wouter A; Severi, Stefano; Drozdov, Ignat A; Cwikla, Jaroslaw; Baum, Richard P; Kwekkeboom, Dik J; Paganelli, Giovanni; Krenning, Eric P; Modlin, Irvin M

2018-07-01

Peptide receptor radionuclide therapy (PRRT) utilizes somatostatin receptor (SSR) overexpression on neuroendocrine tumors (NET) to deliver targeted radiotherapy. Intensity of uptake at imaging is considered related to efficacy but has low sensitivity. A pretreatment strategy to determine individual PRRT response remains a key unmet need. NET transcript expression in blood integrated with tumor grade provides a PRRT predictive quotient (PPQ) which stratifies PRRT "responders" from "non-responders". This study clinically validates the utility of the PPQ in NETs. The development and validation of the PPQ was undertaken in three independent 177 Lu-PRRT treated cohorts. Specificity was tested in two separate somatostatin analog-treated cohorts. Prognostic value of the marker was defined in a cohort of untreated patients. The developmental cohort included lung and gastroenteropancreatic [GEP] NETs (n = 72) from IRST Meldola, Italy. The majority were GEP (71%) and low grade (86% G1-G2). Prospective validation cohorts were from Zentralklinik Bad Berka, Germany (n = 44), and Erasmus Medical Center, Rotterdam, Netherlands (n = 42). Each cohort included predominantly well differentiated, low grade (86-95%) lung and GEP-NETs. The non-PRRT comparator cohorts included SSA cohort I, n = 28 (100% low grade, 100% GEP-NET); SSA cohort II, n = 51 (98% low grade; 76% GEP-NET); and an untreated cohort, n = 44 (64% low grade; 91% GEP-NET). Baseline evaluations included clinical information (disease status, grade, SSR) and biomarker (CgA). NET blood gene transcripts (n = 8: growth factor signaling and metabolism) were measured pre-therapy and integrated with tumor Ki67 using a logistic regression model. This provided a binary output: "predicted responder" (PPQ+); "predicted non-responder" (PPQ-). Treatment response was evaluated using RECIST criteria [Responder (stable, partial and complete response) vs Non-Responder)]. Sample measurement and analyses were blinded to study outcome. Statistical evaluation included Kaplan-Meier survival and standard test evaluation analyses. In the developmental cohort, 56% responded to PRRT. The PPQ predicted 100% of responders and 84% of non-responders (accuracy: 93%). In the two validation cohorts (response: 64-79%), the PPQ was 95% accurate (Bad Berka: PPQ + =97%, PPQ- = 93%; Rotterdam: PPQ + =94%, PPQ- = 100%). Overall, the median PFS was not reached in PPQ+ vs PPQ- (10-14 months; HR: 18-77, p < 0.0001). In the comparator cohorts, the predictor (PPQ) was 47-50% accurate for SSA-treatment and 50% as a prognostic. No differences in PFS were respectively noted (PPQ+: 10-12 months vs. PPQ-: 9-15 months). The PPQ derived from circulating NET specific genes and tumor grade prior to the initiation of therapy is a highly specific predictor of the efficacy of PRRT with an accuracy of 95%.

Predicting the Individual Risk of Acute Severe Colitis at Diagnosis.

PubMed

Cesarini, Monica; Collins, Gary S; Rönnblom, Anders; Santos, Antonieta; Wang, Lai Mun; Sjöberg, Daniel; Parkes, Miles; Keshav, Satish; Travis, Simon P L

2017-03-01

Acute severe colitis [ASC] is associated with major morbidity. We aimed to develop and externally validate an index that predicted ASC within 3 years of diagnosis. The development cohort included patients aged 16-89 years, diagnosed with ulcerative colitis [UC] in Oxford and followed for 3 years. Primary outcome was hospitalization for ASC, excluding patients admitted within 1 month of diagnosis. Multivariable logistic regression examined the adjusted association of seven risk factors with ASC. Backwards elimination produced a parsimonious model that was simplified to create an easy-to-use index. External validation occurred in separate cohorts from Cambridge, UK, and Uppsala, Sweden. The development cohort [Oxford] included 34/111 patients who developed ASC within a median 14 months [range 1-29]. The final model applied the sum of 1 point each for extensive disease, C-reactive protein [CRP] > 10mg/l, or haemoglobin < 12g/dl F or < 14g/dl M at diagnosis, to give a score from 0/3 to 3/3. This predicted a 70% risk of developing ASC within 3 years [score 3/3]. Validation cohorts included different proportions with ASC [Cambridge = 25/96; Uppsala = 18/298]. Of those scoring 3/3 at diagnosis, 18/18 [Cambridge] and 12/13 [Uppsala] subsequently developed ASC. Discriminant ability [c-index, where 1.0 = perfect discrimination] was 0.81 [Oxford], 0.95 [Cambridge], 0.97 [Uppsala]. Internal validation using bootstrapping showed good calibration, with similar predicted risk across all cohorts. A nomogram predicted individual risk. An index applied at diagnosis reliably predicts the risk of ASC within 3 years in different populations. Patients with a score 3/3 at diagnosis may merit early immunomodulator therapy. Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com

Risk Factors for Venous Thromboembolism in Pediatric Trauma Patients and Validation of a Novel Scoring System: The Risk of Clots in Kids with Trauma (ROCKIT score)

PubMed Central

Yen, Jennifer; Van Arendonk, Kyle J.; Streiff, Michael B.; McNamara, LeAnn; Stewart, F. Dylan; Conner G, Kim G; Thompson, Richard E.; Haut, Elliott R.; Takemoto, Clifford M.

2017-01-01

OBJECTIVES Identify risk factors for venous thromboembolism (VTE) and develop a VTE risk assessment model for pediatric trauma patients. DESIGN, SETTING, AND PATIENTS We performed a retrospective review of patients 21 years and younger who were hospitalized following traumatic injuries at the John Hopkins level 1 adult and pediatric trauma center (1987-2011). The clinical characteristics of patients with and without VTE were compared, and multivariable logistic regression analysis was used to identify independent risk factors for VTE. Weighted risk assessment scoring systems were developed based on these and previously identified factors from patients in the National Trauma Data Bank (NTDB 2008-2010); the scoring systems were validated in this cohort from Johns Hopkins as well as a cohort of pediatric admissions from the NTDB (2011-2012). MAIN RESULTS Forty-nine of 17,366 pediatric trauma patients (0.28%) were diagnosed with VTE after admission to our trauma center. After adjusting for potential confounders, VTE was independently associated with older age, surgery, blood transfusion, higher Injury Severity Score (ISS), and lower Glasgow Coma Scale (GCS) score. These and additional factors were identified in 402,329 pediatric patients from the NTDB from 2008-2010; independent risk factors from the logistic regression analysis of this NTDB cohort were selected and incorporated into weighted risk assessment scoring systems. Two models were developed and were cross-validated in 2 separate pediatric trauma cohorts: 1) 282,535 patients in the NTDB from 2011 to 2012 2) 17,366 patients from Johns Hopkins. The receiver operator curve using these models in the validation cohorts had area under the curves that ranged 90% to 94%. CONCLUSIONS VTE is infrequent after trauma in pediatric patients. We developed weighted scoring systems to stratify pediatric trauma patients at risk for VTE. These systems may have potential to guide risk-appropriate VTE prophylaxis in children after trauma. PMID:26963757

Development and external validation of nomograms to predict the risk of skeletal metastasis at the time of diagnosis and skeletal metastasis-free survival in nasopharyngeal carcinoma.

PubMed

Yang, Lin; Xia, Liangping; Wang, Yan; He, Shasha; Chen, Haiyang; Liang, Shaobo; Peng, Peijian; Hong, Shaodong; Chen, Yong

2017-09-06

The skeletal system is the most common site of distant metastasis in nasopharyngeal carcinoma (NPC); various prognostic factors have been reported for skeletal metastasis, though most studies have focused on a single factor. We aimed to establish nomograms to effectively predict skeletal metastasis at initial diagnosis (SMAD) and skeletal metastasis-free survival (SMFS) in NPC. A total of 2685 patients with NPC who received bone scintigraphy (BS) and/or 18F-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and 2496 patients without skeletal metastasis were retrospectively assessed to develop individual nomograms for SMAD and SMFS. The models were validated externally using separate cohorts of 1329 and 1231 patients treated at two other institutions. Five independent prognostic factors were included in each nomogram. The SMAD nomogram had a significantly higher c-index than the TNM staging system (training cohort, P = 0.005; validation cohort, P < 0.001). The SMFS nomogram had significantly higher c-index values in the training and validation sets than the TNM staging system (P < 0.001 and P = 0.005, respectively). Three proposed risk stratification groups were created using the nomograms, and enabled significant discrimination of SMFS for each risk group. The prognostic nomograms established in this study enable accurate stratification of distinct risk groups for skeletal metastasis, which may improve counseling and facilitate individualized management of patients with NPC.

Development and Validation of a qRT-PCR Classifier for Lung Cancer Prognosis

PubMed Central

Chen, Guoan; Kim, Sinae; Taylor, Jeremy MG; Wang, Zhuwen; Lee, Oliver; Ramnath, Nithya; Reddy, Rishindra M; Lin, Jules; Chang, Andrew C; Orringer, Mark B; Beer, David G

2011-01-01

Purpose This prospective study aimed to develop a robust and clinically-applicable method to identify high-risk early stage lung cancer patients and then to validate this method for use in future translational studies. Patients and Methods Three published Affymetrix microarray data sets representing 680 primary tumors were used in the survival-related gene selection procedure using clustering, Cox model and random survival forest (RSF) analysis. A final set of 91 genes was selected and tested as a predictor of survival using a qRT-PCR-based assay utilizing an independent cohort of 101 lung adenocarcinomas. Results The RSF model built from 91 genes in the training set predicted patient survival in an independent cohort of 101 lung adenocarcinomas, with a prediction error rate of 26.6%. The mortality risk index (MRI) was significantly related to survival (Cox model p < 0.00001) and separated all patients into low, medium, and high-risk groups (HR = 1.00, 2.82, 4.42). The MRI was also related to survival in stage 1 patients (Cox model p = 0.001), separating patients into low, medium, and high-risk groups (HR = 1.00, 3.29, 3.77). Conclusions The development and validation of this robust qRT-PCR platform allows prediction of patient survival with early stage lung cancer. Utilization will now allow investigators to evaluate it prospectively by incorporation into new clinical trials with the goal of personalized treatment of lung cancer patients and improving patient survival. PMID:21792073

Validation of microRNA pathway polymorphisms in esophageal adenocarcinoma survival.

PubMed

Faluyi, Olusola O; Eng, Lawson; Qiu, Xin; Che, Jiahua; Zhang, Qihuang; Cheng, Dangxiao; Ying, Nanjiao; Tse, Alvina; Kuang, Qin; Dodbiba, Lorin; Renouf, Daniel J; Marsh, Sharon; Savas, Sevtap; Mackay, Helen J; Knox, Jennifer J; Darling, Gail E; Wong, Rebecca K S; Xu, Wei; Azad, Abul Kalam; Liu, Geoffrey

2017-02-01

Polymorphisms in miRNA and miRNA pathway genes have been previously associated with cancer risk and outcome, but have not been studied in esophageal adenocarcinoma outcomes. Here, we evaluate candidate miRNA pathway polymorphisms in esophageal adenocarcinoma prognosis and attempt to validate them in an independent cohort of esophageal adenocarcinoma patients. Among 231 esophageal adenocarcinoma patients of all stages/treatment plans, 38 candidate genetic polymorphisms (17 biogenesis, 9 miRNA targets, 5 pri-miRNA, 7 pre-miRNA) were genotyped and analyzed. Cox proportional hazard models adjusted for sociodemographic and clinicopathological covariates helped assess the association of genetic polymorphisms with overall survival (OS) and progression-free survival (PFS). Significantly associated polymorphisms were then evaluated in an independent cohort of 137 esophageal adenocarcinoma patients. Among the 231 discovery cohort patients, 86% were male, median diagnosis age was 64 years, 34% were metastatic at diagnosis, and median OS and PFS were 20 and 12 months, respectively. GEMIN3 rs197412 (aHR = 1.37, 95%CI: [1.04-1.80]; P = 0.02), hsa-mir-124-1 rs531564 (aHR = 0.60, 95% CI: [0.53-0.90]; P = 0.05), and KIAA0423 rs1053667 (aHR = 0.51, 95% CI: [0.28-0.96]; P = 0.04) were found associated with OS. Furthermore, GEMIN3 rs197412 (aHR = 1.33, 95% CI: [1.03-1.74]; P = 0.03) and KRT81 rs3660 (aHR = 1.29, 95% CI: [1.01-1.64]; P = 0.04) were found associated with PFS. Although none of these polymorphisms were significant in the second cohort, hsa-mir-124-1 rs531564 and KIAA0423 rs1053667 had trends in the same direction; when both cohorts were combined together, GEMIN3 rs197412, hsa-mir-124-1 rs531564, and KIAA0423 rs1053667 remained significantly associated with OS. We demonstrate the association of multiple miRNA pathway polymorphisms with esophageal adenocarcinoma prognosis in a discovery cohort of patients, which did not validate in a separate cohort but had consistent associations in the pooled cohort. Larger studies are required to confirm/validate the prognostic value of these polymorphisms in esophageal adenocarcinoma. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Development and validation of a brief screening instrument for psychosocial risk associated with genetic testing: a pan-Canadian cohort study

PubMed Central

Esplen, Mary Jane; Cappelli, Mario; Wong, Jiahui; Bottorff, Joan L; Hunter, Jon; Carroll, June; Dorval, Michel; Wilson, Brenda; Allanson, Judith; Semotiuk, Kara; Aronson, Melyssa; Bordeleau, Louise; Charlemagne, Nicole; Meschino, Wendy

2013-01-01

Objectives To develop a brief, reliable and valid instrument to screen psychosocial risk among those who are undergoing genetic testing for Adult-Onset Hereditary Disease (AOHD). Design A prospective two-phase cohort study. Setting 5 genetic testing centres for AOHD, such as cancer, Huntington's disease or haemochromatosis, in ambulatory clinics of tertiary hospitals across Canada. Participants 141 individuals undergoing genetic testing were approached and consented to the instrument development phase of the study (Phase I). The Genetic Psychosocial Risk Instrument (GPRI) developed in Phase I was tested in Phase II for item refinement and validation. A separate cohort of 722 individuals consented to the study, 712 completed the baseline package and 463 completed all follow-up assessments. Most participants were female, at the mid-life stage. Individuals in advanced stages of the illness or with cognitive impairment or a language barrier were excluded. Interventions Phase I: GPRI items were generated from (1) a review of the literature, (2) input from genetic counsellors and (3) phase I participants. Phase II: further item refinement and validation were conducted with a second cohort of participants who completed the GPRI at baseline and were followed for psychological distress 1-month postgenetic testing results. Primary and secondary outcome measures GPRI, Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A), Brief Symptom Inventory (BSI) and Impact of Event Scale (IES). Results The final 20-item GPRI had a high reliability—Cronbach's α at 0.81. The construct validity was supported by high correlations between GPRI and BSI and IES. The predictive value was demonstrated by a receiver operating characteristic curve of 0.78 plotting GPRI against follow-up assessments using HAM-D and HAM-A. Conclusions With a cut-off score of 50, GPRI identified 84% of participants who displayed distress postgenetic testing results, supporting its potential usefulness in a clinical setting. PMID:23485718

Risk score to predict hospital-acquired pneumonia after spontaneous intracerebral hemorrhage.

PubMed

Ji, Ruijun; Shen, Haipeng; Pan, Yuesong; Du, Wanliang; Wang, Penglian; Liu, Gaifen; Wang, Yilong; Li, Hao; Zhao, Xingquan; Wang, Yongjun

2014-09-01

We aimed to develop a risk score (intracerebral hemorrhage-associated pneumonia score, ICH-APS) for predicting hospital-acquired stroke-associated pneumonia (SAP) after ICH. The ICH-APS was developed based on the China National Stroke Registry (CNSR), in which eligible patients were randomly divided into derivation (60%) and validation (40%) cohorts. Variables routinely collected at presentation were used for predicting SAP after ICH. For testing the added value of hematoma volume measure, we separately developed 2 models with (ICH-APS-B) and without (ICH-APS-A) hematoma volume included. Multivariable logistic regression was performed to identify independent predictors. The area under the receiver operating characteristic curve (AUROC), Hosmer-Lemeshow goodness-of-fit test, and integrated discrimination index were used to assess model discrimination, calibration, and reclassification, respectively. The SAP was 16.4% and 17.7% in the overall derivation (n=2998) and validation (n=2000) cohorts, respectively. A 23-point ICH-APS-A was developed based on a set of predictors and showed good discrimination in the overall derivation (AUROC, 0.75; 95% confidence interval, 0.72-0.77) and validation (AUROC, 0.76; 95% confidence interval, 0.71-0.79) cohorts. The ICH-APS-A was more sensitive for patients with length of stay >48 hours (AUROC, 0.78; 95% confidence interval, 0.75-0.81) than those with length of stay <48 hours (AUROC, 0.64; 95% confidence interval, 0.55-0.73). The ICH-APS-A was well calibrated (Hosmer-Lemeshow test) in the derivation (P=0.20) and validation (P=0.66) cohorts. Similarly, a 26-point ICH-APS-B was established. The ICH-APS-A and ICH-APS-B were not significantly different in discrimination and reclassification for SAP after ICH. The ICH-APSs are valid risk scores for predicting SAP after ICH, especially for patients with length of stay >48 hours. © 2014 American Heart Association, Inc.

Validation of the NCCN-IPI for diffuse large B-cell lymphoma (DLBCL): the addition of β2 -microglobulin yields a more accurate GELTAMO-IPI.

PubMed

Montalbán, Carlos; Díaz-López, Antonio; Dlouhy, Ivan; Rovira, Jordina; Lopez-Guillermo, Armando; Alonso, Sara; Martín, Alejandro; Sancho, Juan M; García, Olga; Sánchez, Jose M; Rodríguez, Mario; Novelli, Silvana; Salar, Antonio; Gutiérrez, Antonio; Rodríguez-Salazar, Maria J; Bastos, Mariana; Domínguez, Juan F; Fernández, Rubén; Gonzalez de Villambrosia, Sonia; Queizan, José A; Córdoba, Raul; de Oña, Raquel; López-Hernandez, Andrés; Freue, Julian M; Garrote, Heidys; López, Lourdes; Martin-Moreno, Ana M; Rodriguez, Jose; Abraira, Víctor; García, Juan F

2017-03-01

The study included 1848 diffuse large B-cell lymphoma (DLBCL)patients treated with chemotherapy/rituximab. The aims were to validate the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) and explore the effect of adding high Beta-2 microglobulin (β2M), primary extranodal presentation and intense treatment to the NCCN-IPI variables in order to develop an improved index. Comparing survival curves, NCCN-IPI discriminated better than IPI, separating four risk groups with 5-year overall survival rates of 93%, 83%, 67% and 49%, but failing to identify a true high-risk population. For the second aim the series was split into training and validation cohorts: in the former the multivariate model identified age, lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, Stage III-IV, and β2M as independently significant, whereas the NCCN-IPI-selected extranodal sites, primary extranodal presentation and intense treatments were not. These results were confirmed in the validation cohort. The Grupo Español de Linfomas/Trasplante de Médula ósea (GELTAMO)-IPI developed here, with 7 points, significantly separated four risk groups (0, 1-3, 4 or ≥5 points) with 11%, 58%, 17% and 14% of patients, and 5-year overall survival rates of 93%, 79%, 66% and 39%, respectively. In the comparison GELTAMO IPI discriminated better than the NCCN-IPI. In conclusion, GELTAMO-IPI is more accurate than the NCCN-IPI and has statistical and practical advantages in that the better discrimination identifies an authentic high-risk group and is not influenced by primary extranodal presentation or treatments of different intensity. © 2017 John Wiley & Sons Ltd.

Differential expression of microRNA-675, microRNA-139-3p and microRNA-335 in benign and malignant adrenocortical tumours

PubMed Central

Helwig, J; Bertram, S; Sheu, S Y; Suttorp, A C; Seggewiß, J; Willscher, E; Walz, M K; Worm, K; Schmid, K W

2011-01-01

Background For the clinical management of adrenocortical neoplasms it is crucial to correctly distinguish between benign and malignant tumours. Even histomorphologically based scoring systems do not allow precise separation in single lesions, thus novel parameters are desired which offer a more accurate differentiation. The tremendous potential of microRNAs (miRNAs) as diagnostic biomarkers in surgical pathology has recently been shown in a broad variety of tumours. Methods In order to elucidate the diagnostic impact of miRNA expression in adrenocortical neoplasms, a cohort of 20 adrenocortical specimens including normal adrenal tissue (n=4), adrenocortical adenomas (ACAs) (n=9), adrenocortical carcinomas (ACCs) (n=4) and metastases (n=3) was analysed using TaqMan low density arrays to identify specific miRNA profiles in order to distinguish between benign and malignant adrenocortical lesions. Results were validated in a validation cohort (n=16). Results Concerning the differential diagnosis of ACAs and ACCs, 159 out of 667 miRNAs were up- and 89 were down-regulated in ACAs. Using real-time PCR analysis of three of the most significantly expressed single key miRNAs allowed separation of ACAs from ACCs. ACCs exhibited significantly lower levels of miR-139-3p (up to 8.49-fold, p<0.001), miR-675 (up to 23.25-fold, p<0.001) and miR-335 (up to 5.25-fold, p<0.001). A validation cohort of 16 specimen with known Weiss score showed up-regulation of miR-335 and miR-675 in the majority of cases with probable malignant course, although overlapping values exist. Conclusion miRNA profiling of miR-675 and miR-335 helps in discriminating ACCs from ACAs. miRNA analysis may indicate malignant behaviour in cases with indeterminate malignant potential. PMID:21471143

Quantification of the heterogeneity of prognostic cellular biomarkers in ewing sarcoma using automated image and random survival forest analysis.

PubMed

Bühnemann, Claudia; Li, Simon; Yu, Haiyue; Branford White, Harriet; Schäfer, Karl L; Llombart-Bosch, Antonio; Machado, Isidro; Picci, Piero; Hogendoorn, Pancras C W; Athanasou, Nicholas A; Noble, J Alison; Hassan, A Bassim

2014-01-01

Driven by genomic somatic variation, tumour tissues are typically heterogeneous, yet unbiased quantitative methods are rarely used to analyse heterogeneity at the protein level. Motivated by this problem, we developed automated image segmentation of images of multiple biomarkers in Ewing sarcoma to generate distributions of biomarkers between and within tumour cells. We further integrate high dimensional data with patient clinical outcomes utilising random survival forest (RSF) machine learning. Using material from cohorts of genetically diagnosed Ewing sarcoma with EWSR1 chromosomal translocations, confocal images of tissue microarrays were segmented with level sets and watershed algorithms. Each cell nucleus and cytoplasm were identified in relation to DAPI and CD99, respectively, and protein biomarkers (e.g. Ki67, pS6, Foxo3a, EGR1, MAPK) localised relative to nuclear and cytoplasmic regions of each cell in order to generate image feature distributions. The image distribution features were analysed with RSF in relation to known overall patient survival from three separate cohorts (185 informative cases). Variation in pre-analytical processing resulted in elimination of a high number of non-informative images that had poor DAPI localisation or biomarker preservation (67 cases, 36%). The distribution of image features for biomarkers in the remaining high quality material (118 cases, 104 features per case) were analysed by RSF with feature selection, and performance assessed using internal cross-validation, rather than a separate validation cohort. A prognostic classifier for Ewing sarcoma with low cross-validation error rates (0.36) was comprised of multiple features, including the Ki67 proliferative marker and a sub-population of cells with low cytoplasmic/nuclear ratio of CD99. Through elimination of bias, the evaluation of high-dimensionality biomarker distribution within cell populations of a tumour using random forest analysis in quality controlled tumour material could be achieved. Such an automated and integrated methodology has potential application in the identification of prognostic classifiers based on tumour cell heterogeneity.

Customizing national models for a medical center's population to rapidly identify patients at high risk of 30-day all-cause hospital readmission following a heart failure hospitalization.

PubMed

Cox, Zachary L; Lai, Pikki; Lewis, Connie M; Lindenfeld, JoAnn; Collins, Sean P; Lenihan, Daniel J

2018-05-28

Nationally-derived models predicting 30-day readmissions following heart failure (HF) hospitalizations yield insufficient discrimination for institutional use. Develop a customized readmission risk model from Medicare-employed and institutionally-customized risk factors and compare the performance against national models in a medical center. Medicare patients age ≥ 65 years hospitalized for HF (n = 1,454) were studied in a derivation cohort and in a separate validation cohort (n = 243). All 30-day hospital readmissions were documented. The primary outcome was risk discrimination (c-statistic) compared to national models. A customized model demonstrated improved discrimination (c-statistic 0.72; 95% CI 0.69 - 0.74) compared to national models (c-statistics of 0.60 and 0.61) with a c-statistic of 0.63 in the validation cohort. Compared to national models, a customized model demonstrated superior readmission risk profiling by distinguishing a high-risk (38.3%) from a low-risk (9.4%) quartile. A customized model improved readmission risk discrimination from HF hospitalizations compared to national models. Copyright © 2018 Elsevier Inc. All rights reserved.

Classification and regression tree analysis of acute-on-chronic hepatitis B liver failure: Seeing the forest for the trees.

PubMed

Shi, K-Q; Zhou, Y-Y; Yan, H-D; Li, H; Wu, F-L; Xie, Y-Y; Braddock, M; Lin, X-Y; Zheng, M-H

2017-02-01

At present, there is no ideal model for predicting the short-term outcome of patients with acute-on-chronic hepatitis B liver failure (ACHBLF). This study aimed to establish and validate a prognostic model by using the classification and regression tree (CART) analysis. A total of 1047 patients from two separate medical centres with suspected ACHBLF were screened in the study, which were recognized as derivation cohort and validation cohort, respectively. CART analysis was applied to predict the 3-month mortality of patients with ACHBLF. The accuracy of the CART model was tested using the area under the receiver operating characteristic curve, which was compared with the model for end-stage liver disease (MELD) score and a new logistic regression model. CART analysis identified four variables as prognostic factors of ACHBLF: total bilirubin, age, serum sodium and INR, and three distinct risk groups: low risk (4.2%), intermediate risk (30.2%-53.2%) and high risk (81.4%-96.9%). The new logistic regression model was constructed with four independent factors, including age, total bilirubin, serum sodium and prothrombin activity by multivariate logistic regression analysis. The performances of the CART model (0.896), similar to the logistic regression model (0.914, P=.382), exceeded that of MELD score (0.667, P<.001). The results were confirmed in the validation cohort. We have developed and validated a novel CART model superior to MELD for predicting three-month mortality of patients with ACHBLF. Thus, the CART model could facilitate medical decision-making and provide clinicians with a validated practical bedside tool for ACHBLF risk stratification. © 2016 John Wiley & Sons Ltd.

Predicting Blunt Cerebrovascular Injury in Pediatric Trauma: Validation of the “Utah Score”

PubMed Central

Ravindra, Vijay M.; Bollo, Robert J.; Sivakumar, Walavan; Akbari, Hassan; Naftel, Robert P.; Limbrick, David D.; Jea, Andrew; Gannon, Stephen; Shannon, Chevis; Birkas, Yekaterina; Yang, George L.; Prather, Colin T.; Kestle, John R.

2017-01-01

Abstract Risk factors for blunt cerebrovascular injury (BCVI) may differ between children and adults, suggesting that children at low risk for BCVI after trauma receive unnecessary computed tomography angiography (CTA) and high-dose radiation. We previously developed a score for predicting pediatric BCVI based on retrospective cohort analysis. Our objective is to externally validate this prediction score with a retrospective multi-institutional cohort. We included patients who underwent CTA for traumatic cranial injury at four pediatric Level I trauma centers. Each patient in the validation cohort was scored using the “Utah Score” and classified as high or low risk. Before analysis, we defined a misclassification rate <25% as validating the Utah Score. Six hundred forty-five patients (mean age 8.6 ± 5.4 years; 63.4% males) underwent screening for BCVI via CTA. The validation cohort was 411 patients from three sites compared with the training cohort of 234 patients. Twenty-two BCVIs (5.4%) were identified in the validation cohort. The Utah Score was significantly associated with BCVIs in the validation cohort (odds ratio 8.1 [3.3, 19.8], p < 0.001) and discriminated well in the validation cohort (area under the curve 72%). When the Utah Score was applied to the validation cohort, the sensitivity was 59%, specificity was 85%, positive predictive value was 18%, and negative predictive value was 97%. The Utah Score misclassified 16.6% of patients in the validation cohort. The Utah Score for predicting BCVI in pediatric trauma patients was validated with a low misclassification rate using a large, independent, multicenter cohort. Its implementation in the clinical setting may reduce the use of CTA in low-risk patients. PMID:27297774

Diagnosis of TIA (DOT) score--design and validation of a new clinical diagnostic tool for transient ischaemic attack.

PubMed

Dutta, Dipankar

2016-02-09

The diagnosis of Transient Ischaemic Attack (TIA) can be difficult and 50-60% of patients seen in TIA clinics turn out to be mimics. Many of these mimics have high ABCD2 scores and fill urgent TIA clinic slots inappropriately. A TIA diagnostic tool may help non-specialists make the diagnosis with greater accuracy and improve TIA clinic triage. The only available diagnostic score (Dawson et al) is limited in scope and not widely used. The Diagnosis of TIA (DOT) Score is a new and internally validated web and mobile app based diagnostic tool which encompasses both brain and retinal TIA. The score was derived retrospectively from a single centre TIA clinic database using stepwise logistic regression by backwards elimination to find the best model. An optimum cutpoint was obtained for the score. The derivation and validation cohorts were separate samples drawn from the years 2010/12 and 2013 respectively. Receiver Operating Characteristic (ROC) curves and area under the curve (AUC) were calculated and the diagnostic accuracy of DOT was compared to the Dawson score. A web and smartphone calculator were designed subsequently. The derivation cohort had 879 patients and the validation cohort 525. The final model had seventeen predictors and had an AUC of 0.91 (95% CI: 0.89-0.93). When tested on the validation cohort, the AUC for DOTS was 0.89 (0.86-0.92) while that of the Dawson score was 0.77 (0.73-0.81). The sensitivity and specificity of the DOT score were 89% (CI: 84%-93%) and 76% (70%-81%) respectively while those of the Dawson score were 83% (78%-88%) and 51% (45%-57%). Other diagnostic accuracy measures (DOT vs. Dawson) include positive predictive values (75% vs. 58%), negative predictive values (89% vs. 79%), positive likelihood ratios (3.67 vs. 1.70) and negative likelihood ratios (0.15 vs. 0.32). The DOT score shows promise as a diagnostic tool for TIA and requires independent external validation before it can be widely used. It could potentially improve the triage of patients assessed for suspected TIA.

The DASS-14: Improving the Construct Validity and Reliability of the Depression, Anxiety, and Stress Scale in a Cohort of Health Professionals.

PubMed

Wise, Frances M; Harris, Darren W; Olver, John H

2017-01-01

Considerable research has been undertaken in evaluating the DASS-21 in a variety of clinical populations, but studies of the instrument's psychometric adequacy in healthcare professionals is lacking. This study aimed to establish and improve the construct validity and reliability of the DASS-21 in a cohort of Australian health professionals. 343 rehabilitation health professionals completed the DASS-21, along with a demographic questionnaire. Principal components analysis was performed to identify potential factors in the DASS-21. Factors were interpreted against theoretical constructs underlying the instrument. Items loading on separate factors were then subjected to reliability analysis to determine internal consistency of subscales. Items that demonstrated poor fit, or loaded onto more than one factor, were deleted to maximise the reliability of each subscale. Principal components analysis identified three dimensions (depression, anxiety, stress) in a modified version of the DASS-21 (renamed DASS-14), with appropriate construct validity and good reliability (a=0.73 to 0.88). The three dimensions accounted for over 62% of variance between items. The modified DASS-14 scale is a more parsimonious measure of depression, anxiety, and stress, with acceptable reliability and construct validity, in rehabilitation health professionals and is appropriate for use in studies of similar populations.

The Perceived Medical Condition Self-Management Scale can be applied to patients with chronic kidney disease.

PubMed

Wild, Marcus G; Wallston, Kenneth A; Green, Jamie A; Beach, Lauren B; Umeukeje, Ebele; Wright Nunes, Julie A; Ikizler, T Alp; Steed, Julia; Cavanaugh, Kerri L

2017-10-01

Chronic Kidney Disease (CKD) is a major burden on patients and the health care system. Treatment of CKD requires dedicated involvement from both caretakers and patients. Self-efficacy, also known as perceived competence, contributes to successful maintenance of patient's CKD self-management behaviors such as medication adherence and dietary regulations. Despite a clear association between self-efficacy and improved CKD outcomes, there remains a lack of validated self-report measures of CKD self-efficacy. To address this gap, the Perceived Kidney/Dialysis Self-Management Scale (PKDSMS) was adapted from the previously validated Perceived Medical Condition Self-Management Scale. We then sought to validate this using data from two separate cohorts: a cross-sectional investigation of 146 patients with end-stage renal disease receiving maintenance hemodialysis and a longitudinal study of 237 patients with CKD not receiving dialysis. The PKDSMS was found to be positively and significantly correlated with self-management behaviors and medication adherence in both patient cohorts. The PKDSMS had acceptable reliability, was internally consistent, and exhibited predictive validity between baseline PKDSMS scores and self-management behaviors across multiple time points. Thus, the PKDSMS is a valid and reliable measure of CKD patient self-efficacy and supports the development of interventions enhancing perceived competence to improve CKD self-management. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Association Between Obesity and Discordance in Fibrosis Stage Determination by Magnetic Resonance vs Transient Elastography in Patients With Nonalcoholic Liver Disease.

PubMed

Caussy, Cyrielle; Chen, Jun; Alquiraish, Mosab H; Cepin, Sandra; Nguyen, Phirum; Hernandez, Carolyn; Yin, Meng; Bettencourt, Ricki; Cachay, Edward R; Jayakumar, Saumya; Fortney, Lynda; Hooker, Jonathan; Sy, Ethan; Valasek, Mark A; Rizo, Emily; Richards, Lisa; Brenner, David A; Sirlin, Claude B; Ehman, Richard L; Loomba, Rohit

2018-01-17

Magnetic resonance elastography (MRE) and transient elastography (TE) are noninvasive techniques used to detect liver fibrosis in nonalcoholic fatty liver disease. MRE detects fibrosis more accurately than TE, but MRE is more expensive, and the concordance between MRE and TE have not been optimally assessed in obese patients. It is important to determine under which conditions TE and MRE produce the same readings, so that some patients can simply undergo TE evaluation to detect fibrosis. We aimed to assess the association between body mass index (BMI) and discordancy between MRE and TE findings, using liver biopsy as the reference, and validated our findings in a separate cohort. We performed a cross-sectional study of 119 adults with nonalcoholic fatty liver disease who underwent MRE, TE with M and XL probe, and liver biopsy analysis from October 2011 through January 2017 (training cohort). MRE and TE results were considered to be concordant if they found patients to have the same stage fibrosis as liver biopsy analysis. We validated our findings in 75 adults with nonalcoholic fatty liver disease who underwent contemporaneous MRE, TE, and liver biopsy at a separate institution from March 2010 through May 2013. The primary outcome was rate of discordance between MRE and TE in determining stage of fibrosis (stage 2-4 vs 0-1). Secondary outcomes were the rate of discordance between MRE and TE in determining dichotomized stage of fibrosis (1-4 vs 0, 3-4 vs 0-2, and 4 vs 0-3). In the training cohort, there was 43.7% discordance in findings from MRE versus TE. BMI associated significantly with discordance in findings from MRE versus TE (odds ratio, 1.69; 95% confidence interval, 1.15-2.51; P = .008) after multivariable adjustment by age and sex. The findings were confirmed in the validation cohort: there was 45.3% discordance in findings from MRE versus TE. BMI again associated significantly with discordance in findings from MRE versus TE (odds ratio, 1.52; 95% confidence interval, 1.04-2.21; P = .029) after multivariable adjustment by age and sex. We identified and validated BMI as a factor significantly associated with discordance of findings from MRE versus TE in assessment of fibrosis stage. The degree of discordancy increases with BMI. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

Dexamethasone exerts profound immunologic interference on treatment efficacy for recurrent glioblastoma

PubMed Central

Wong, E T; Lok, E; Gautam, S; Swanson, K D

2015-01-01

Background: Patients with recurrent glioblastoma have a poor outcome. Data from the phase III registration trial comparing tumour-treating alternating electric fields (TTFields) vs chemotherapy provided a unique opportunity to study dexamethasone effects on patient outcome unencumbered by the confounding immune and myeloablative side effects of chemotherapy. Methods: Using an unsupervised binary partitioning algorithm, we segregated both cohorts of the trial based on the dexamethasone dose that yielded the greatest statistical difference in overall survival (OS). The results were validated in a separate cohort treated in a single institution with TTFields and their T lymphocytes were correlated with OS. Results: Patients who used dexamethasone doses >4.1 mg per day had a significant reduction in OS when compared with those who used ⩽4.1 mg per day, 4.8 vs 11.0 months respectively (χ2=34.6, P<0.0001) in the TTField-treated cohort and 6.0 vs 8.9 months respectively (χ2=10.0, P<0.0015) in the chemotherapy-treated cohort. In a single institution validation cohort treated with TTFields, the median OS of patients who used dexamethasone >4.1 mg per day was 3.2 months compared with those who used ⩽4.1 mg per day was 8.7 months (χ2=11.1, P=0.0009). There was a significant correlation between OS and T-lymphocyte counts. Conclusions: Dexamethasone exerted profound effects on both TTFields and chemotherapy efficacy resulting in lower patient OS. Therefore, global immunosuppression by dexamethasone likely interferes with immune functions that are necessary for the treatment of glioblastoma. PMID:26125449

Predicting high risk of exacerbations in bronchiectasis: the E-FACED score.

PubMed

Martinez-Garcia, M A; Athanazio, R A; Girón, R; Máiz-Carro, L; de la Rosa, D; Olveira, C; de Gracia, J; Vendrell, M; Prados-Sánchez, C; Gramblicka, G; Corso Pereira, M; Lundgren, F L; Fernandes De Figueiredo, M; Arancibia, F; Rached, S Z

2017-01-01

Although the FACED score has demonstrated a great prognostic capacity in bronchiectasis, it does not include the number or severity of exacerbations as a separate variable, which is important in the natural history of these patients. Construction and external validation of a new index, the E-FACED, to evaluate the predictive capacity of exacerbations and mortality. The new score was constructed on the basis of the complete cohort for the construction of the original FACED score, while the external validation was undertaken with six cohorts from three countries (Brazil, Argentina, and Chile). The main outcome was the number of annual exacerbations/hospitalizations, with all-cause and respiratory-related deaths as the secondary outcomes. A statistical evaluation comprised the relative weight and ideal cut-off point for the number or severity of the exacerbations and was incorporated into the FACED score (E-FACED). The results obtained after the application of FACED and E-FACED were compared in both the cohorts. A total of 1,470 patients with bronchiectasis (819 from the construction cohorts and 651 from the external validation cohorts) were followed up for 5 years after diagnosis. The best cut-off point was at least two exacerbations in the previous year (two additional points), meaning that the E-FACED has nine points of growing severity. E-FACED presented an excellent prognostic capacity for exacerbations (areas under the receiver operating characteristic curve: 0.82 for at least two exacerbations in 1 year and 0.87 for at least one hospitalization in 1 year) that was statistically better than that of the FACED score (0.72 and 0.78, P <0.05, respectively). The predictive capacities for all-cause and respiratory mortality were 0.87 and 0.86, respectively, with both being similar to those of the FACED. E-FACED score significantly increases the FACED capacity to predict future yearly exacerbations while maintaining the score's simplicity and prognostic capacity for death.

Predicting high risk of exacerbations in bronchiectasis: the E-FACED score

PubMed Central

Martinez-Garcia, MA; Athanazio, RA; Girón, R; Máiz-Carro, L; de la Rosa, D; Olveira, C; de Gracia, J; Vendrell, M; Prados-Sánchez, C; Gramblicka, G; Corso Pereira, M; Lundgren, FL; Fernandes De Figueiredo, M; Arancibia, F; Rached, SZ

2017-01-01

Background Although the FACED score has demonstrated a great prognostic capacity in bronchiectasis, it does not include the number or severity of exacerbations as a separate variable, which is important in the natural history of these patients. Objective Construction and external validation of a new index, the E-FACED, to evaluate the predictive capacity of exacerbations and mortality. Methods The new score was constructed on the basis of the complete cohort for the construction of the original FACED score, while the external validation was undertaken with six cohorts from three countries (Brazil, Argentina, and Chile). The main outcome was the number of annual exacerbations/hospitalizations, with all-cause and respiratory-related deaths as the secondary outcomes. A statistical evaluation comprised the relative weight and ideal cut-off point for the number or severity of the exacerbations and was incorporated into the FACED score (E-FACED). The results obtained after the application of FACED and E-FACED were compared in both the cohorts. Results A total of 1,470 patients with bronchiectasis (819 from the construction cohorts and 651 from the external validation cohorts) were followed up for 5 years after diagnosis. The best cut-off point was at least two exacerbations in the previous year (two additional points), meaning that the E-FACED has nine points of growing severity. E-FACED presented an excellent prognostic capacity for exacerbations (areas under the receiver operating characteristic curve: 0.82 for at least two exacerbations in 1 year and 0.87 for at least one hospitalization in 1 year) that was statistically better than that of the FACED score (0.72 and 0.78, P<0.05, respectively). The predictive capacities for all-cause and respiratory mortality were 0.87 and 0.86, respectively, with both being similar to those of the FACED. Conclusion E-FACED score significantly increases the FACED capacity to predict future yearly exacerbations while maintaining the score’s simplicity and prognostic capacity for death. PMID:28182132

A clinical prognostic model compared to the newly adopted UICC staging in an independent validation cohort of P16 negative/positive head and neck cancer patients.

PubMed

Rasmussen, Jacob H; Håkansson, Katrin; Rasmussen, Gregers B; Vogelius, Ivan R; Friborg, Jeppe; Fischer, Barbara M; Bentzen, Søren M; Specht, Lena

2018-06-01

A previously published prognostic model in patients with head and neck squamous cell carcinoma (HNSCC) was validated in both a p16-negative and a p16-positive independent patient cohort and the performance was compared with the newly adopted 8th edition of the UICC staging system. Consecutive patients with HNSCC treated at a single institution from 2005 to 2012 were included. The cohort was divided in three. 1.) Training cohort, patients treated from 2005 to 2009 excluding patients with p16-positive oropharyngeal squamous cell carcinomas (OPSCC); 2.) A p16-negative validation cohort and 3.) A p16-positive validation cohort. A previously published prognostic model (clinical model) with the significant covariates (smoking status, FDG uptake, and tumor volume) was refitted in the training cohort and validated in the two validation cohorts. The clinical model was used to generate four risk groups based on the predicted risk of disease recurrence after 2 years and the performance was compared with UICC staging 8th edition using concordance index. Overall 568 patients were included. Compared to UICC the clinical model had a significantly better concordance index in the p16-negative validation cohort (AUC = 0.63 for UICC and AUC = 0.73 for the clinical model; p = 0.003) and a borderline significantly better concordance index in the p16-positive cohort (AUC = 0.63 for UICC and 0.72 for the clinical model; p = 0.088). The validated clinical model provided a better prognostication of risk of disease recurrence than UICC stage in the p16-negative validation cohort, and similar prognostication as the newly adopted 8th edition of the UICC staging in the p16-positive patient cohort. Copyright © 2018 Elsevier Ltd. All rights reserved.

A predictive score to identify hospitalized patients' risk of discharge to a post-acute care facility

PubMed Central

Louis Simonet, Martine; Kossovsky, Michel P; Chopard, Pierre; Sigaud, Philippe; Perneger, Thomas V; Gaspoz, Jean-Michel

2008-01-01

Background Early identification of patients who need post-acute care (PAC) may improve discharge planning. The purposes of the study were to develop and validate a score predicting discharge to a post-acute care (PAC) facility and to determine its best assessment time. Methods We conducted a prospective study including 349 (derivation cohort) and 161 (validation cohort) consecutive patients in a general internal medicine service of a teaching hospital. We developed logistic regression models predicting discharge to a PAC facility, based on patient variables measured on admission (day 1) and on day 3. The value of each model was assessed by its area under the receiver operating characteristics curve (AUC). A simple numerical score was derived from the best model, and was validated in a separate cohort. Results Prediction of discharge to a PAC facility was as accurate on day 1 (AUC: 0.81) as on day 3 (AUC: 0.82). The day-3 model was more parsimonious, with 5 variables: patient's partner inability to provide home help (4 pts); inability to self-manage drug regimen (4 pts); number of active medical problems on admission (1 pt per problem); dependency in bathing (4 pts) and in transfers from bed to chair (4 pts) on day 3. A score ≥ 8 points predicted discharge to a PAC facility with a sensitivity of 87% and a specificity of 63%, and was significantly associated with inappropriate hospital days due to discharge delays. Internal and external validations confirmed these results. Conclusion A simple score computed on the 3rd hospital day predicted discharge to a PAC facility with good accuracy. A score > 8 points should prompt early discharge planning. PMID:18647410

Using microRNA profiling in urine samples to develop a non-invasive test for bladder cancer.

PubMed

Mengual, Lourdes; Lozano, Juan José; Ingelmo-Torres, Mercedes; Gazquez, Cristina; Ribal, María José; Alcaraz, Antonio

2013-12-01

Current standard methods used to detect and monitor bladder urothelial cell carcinoma (UCC) are invasive or have low sensitivity. The incorporation into clinical practice of a non-invasive tool for UCC assessment would enormously improve patients' quality of life and outcome. This study aimed to examine the microRNA (miRNA) expression profiles in urines of UCC patients in order to develop a non-invasive accurate and reliable tool to diagnose and provide information on the aggressiveness of the tumor. We performed a global miRNA expression profiling analysis of the urinary cells from 40 UCC patients and controls using TaqMan Human MicroRNA Array followed by validation of 22 selected potentially diagnostic and prognostic miRNAs in a separate cohort of 277 samples using a miRCURY LNA qPCR system. miRNA-based signatures were developed by multivariate logistic regression analysis and internally cross-validated. In the initial cohort of patients, we identified 40 and 30 aberrantly expressed miRNA in UCC compared with control urines and in high compared with low grade tumors, respectively. Quantification of 22 key miRNAs in an independent cohort resulted in the identification of a six miRNA diagnostic signature with a sensitivity of 84.8% and specificity of 86.5% (AUC = 0.92) and a two miRNA prognostic model with a sensitivity of 84.95% and a specificity of 74.14% (AUC = 0.83). Internal cross-validation analysis confirmed the accuracy rates of both models, reinforcing the strength of our findings. Although the data needs to be externally validated, miRNA analysis in urine appears to be a valuable tool for the non-invasive assessment of UCC. Copyright © 2013 UICC.

Maternal Separation Does Not Produce a Significant Behavioral Change in Mice

PubMed Central

Tan, Shawn; Ho, Hin San; Song, Anna Yoonsu; Low, Joey

2017-01-01

Early life adversities together with genetic predispositions have been associated with elevated risks of neuropsychiatric disorders during later life. In order to investigate the underlying mechanisms, many chronic, early-life stress paradigms in multiple animal models have been developed. Previously, studies reported that maternal separation (MS) in the early postnatal stages triggers depression-and/or anxiety-like behaviors in rats. However, similar studies using mice have reported inconsistent behavioral outcomes. In this study, we sought to assess behavioral outcomes from two different early-life stress paradigms; a conventional 3-hour MS and a maternal separation with early weaning (MSEW) paradigm using C57BL/6J male mice with independent cohorts. Our data demonstrated that both MS and MSEW paradigms did not produce reported behavioral anomalies. Therefore, MS paradigms in mice require further validation and modification. PMID:29302206

Parental Separation and Cardiometabolic Risk Factors in Late Adolescence: A Cross-Cohort Comparison

PubMed Central

Soares, Ana Luiza Gonçalves; Gonçalves, Helen; Matijasevich, Alicia; Sequeira, Maija; Smith, George Davey; Menezes, Ana M. B.; Assunção, Maria Cecília; Wehrmeister, Fernando C.; Fraser, Abigail; Howe, Laura D.

2017-01-01

Abstract The aim of this study was to explore the association between parental separation during childhood (up to 18 years of age) and cardiometabolic risk factors (body mass index, fat mass index, blood pressure, physical activity, smoking, and alcohol consumption) in late adolescence using a cross-cohort comparison and to explore whether associations differ according to the age at which the parental separation occurred and the presence or absence of parental conflict prior to separation. Data from the Avon Longitudinal Study of Parents and Children (ALSPAC, United Kingdom) (1991–2011) and the 1993 Pelotas Birth Cohort (Brazil) (1993–2011) were used. The associations of parental separation with children's cardiometabolic risk factors were largely null. Higher odds of daily smoking were observed in both cohorts for those adolescents whose parents separated (for ALSPAC, odds ratio = 1.46; for Pelotas Birth Cohort, odds ratio = 1.98). Some additional associations were observed in the Pelotas Birth Cohort but were generally in the opposite direction to our a priori hypothesis: Parental separation was associated with lower blood pressure and fat mass index, and with more physical activity. No consistent differences were observed when analyses were stratified by child's age at parental separation or parental conflict. PMID:28444145

C-reactive protein and N-terminal prohormone brain natriuretic peptide as biomarkers in acute exacerbations of COPD leading to hospitalizations.

PubMed

Chen, Yu-Wei Roy; Chen, Virginia; Hollander, Zsuzsanna; Leipsic, Jonathon A; Hague, Cameron J; DeMarco, Mari L; FitzGerald, J Mark; McManus, Bruce M; Ng, Raymond T; Sin, Don D

2017-01-01

There are currently no accepted and validated blood tests available for diagnosing acute exacerbations of chronic obstructive pulmonary disease (AECOPD). In this study, we sought to determine the discriminatory power of blood C-reactive protein (CRP) and N-terminal prohormone brain natriuretic peptide (NT-proBNP) in the diagnosis of AECOPD requiring hospitalizations. The study cohort consisted of 468 patients recruited in the COPD Rapid Transition Program who were hospitalized with a primary diagnosis of AECOPD, and 110 stable COPD patients who served as controls. Logistic regression was used to build a classification model to separate AECOPD from convalescent or stable COPD patients. Performance was assessed using an independent validation set of patients who were not included in the discovery set. Serum CRP and whole blood NT-proBNP concentrations were highest at the time of hospitalization and progressively decreased over time. Of the 3 classification models, the one with both CRP and NT-proBNP had the highest AUC in discriminating AECOPD (cross-validated AUC of 0.80). These data were replicated in a validation cohort with an AUC of 0.88. A combination of CRP and NT-proBNP can reasonably discriminate AECOPD requiring hospitalization versus clinical stability and can be used to rapidly diagnose patients requiring hospitalization for AECOPD.

External validity of two nomograms for predicting distant brain failure after radiosurgery for brain metastases in a bi-institutional independent patient cohort.

PubMed

Prabhu, Roshan S; Press, Robert H; Boselli, Danielle M; Miller, Katherine R; Lankford, Scott P; McCammon, Robert J; Moeller, Benjamin J; Heinzerling, John H; Fasola, Carolina E; Patel, Kirtesh R; Asher, Anthony L; Sumrall, Ashley L; Curran, Walter J; Shu, Hui-Kuo G; Burri, Stuart H

2018-03-01

Patients treated with stereotactic radiosurgery (SRS) for brain metastases (BM) are at increased risk of distant brain failure (DBF). Two nomograms have been recently published to predict individualized risk of DBF after SRS. The goal of this study was to assess the external validity of these nomograms in an independent patient cohort. The records of consecutive patients with BM treated with SRS at Levine Cancer Institute and Emory University between 2005 and 2013 were reviewed. Three validation cohorts were generated based on the specific nomogram or recursive partitioning analysis (RPA) entry criteria: Wake Forest nomogram (n = 281), Canadian nomogram (n = 282), and Canadian RPA (n = 303) validation cohorts. Freedom from DBF at 1-year in the Wake Forest study was 30% compared with 50% in the validation cohort. The validation c-index for both the 6-month and 9-month freedom from DBF Wake Forest nomograms was 0.55, indicating poor discrimination ability, and the goodness-of-fit test for both nomograms was highly significant (p < 0.001), indicating poor calibration. The 1-year actuarial DBF in the Canadian nomogram study was 43.9% compared with 50.9% in the validation cohort. The validation c-index for the Canadian 1-year DBF nomogram was 0.56, and the goodness-of-fit test was also highly significant (p < 0.001). The validation accuracy and c-index of the Canadian RPA classification was 53% and 0.61, respectively. The Wake Forest and Canadian nomograms for predicting risk of DBF after SRS were found to have limited predictive ability in an independent bi-institutional validation cohort. These results reinforce the importance of validating predictive models in independent patient cohorts.

Sexual epigenetic dimorphism in the human placenta: implications for susceptibility during the prenatal period.

PubMed

Martin, Elizabeth; Smeester, Lisa; Bommarito, Paige A; Grace, Matthew R; Boggess, Kim; Kuban, Karl; Karagas, Margaret R; Marsit, Carmen J; O'Shea, T Michael; Fry, Rebecca C

2017-03-01

Sex-based differences in response to adverse prenatal environments and infant outcomes have been observed, yet the underlying mechanisms for this are unclear. The placental epigenome may be a driver of these differences. Placental DNA methylation was assessed at more than 480,000 CpG sites from male and female infants enrolled in the extremely low gestational age newborns cohort (ELGAN) and validated in a separate US-based cohort. The impact of gestational age on placental DNA methylation was further examined using the New Hampshire Birth Cohort Study for a total of n = 467 placentas. A total of n = 2745 CpG sites, representing n = 587 genes, were identified as differentially methylated (p < 1 × 10 -7 ). The majority (n = 582 or 99%) of these were conserved among the New Hampshire Birth Cohort. The identified genes encode proteins related to immune function, growth/transcription factor signaling and transport across cell membranes. These data highlight sex-dependent epigenetic patterning in the placenta and provide insight into differences in infant outcomes and responses to the perinatal environment.

Parental Separation and Cardiometabolic Risk Factors in Late Adolescence: A Cross-Cohort Comparison.

PubMed

Soares, Ana Luiza Gonçalves; Gonçalves, Helen; Matijasevich, Alicia; Sequeira, Maija; Smith, George Davey; Menezes, Ana M B; Assunção, Maria Cecília; Wehrmeister, Fernando C; Fraser, Abigail; Howe, Laura D

2017-05-15

The aim of this study was to explore the association between parental separation during childhood (up to 18 years of age) and cardiometabolic risk factors (body mass index, fat mass index, blood pressure, physical activity, smoking, and alcohol consumption) in late adolescence using a cross-cohort comparison and to explore whether associations differ according to the age at which the parental separation occurred and the presence or absence of parental conflict prior to separation. Data from the Avon Longitudinal Study of Parents and Children (ALSPAC, United Kingdom) (1991-2011) and the 1993 Pelotas Birth Cohort (Brazil) (1993-2011) were used. The associations of parental separation with children's cardiometabolic risk factors were largely null. Higher odds of daily smoking were observed in both cohorts for those adolescents whose parents separated (for ALSPAC, odds ratio = 1.46; for Pelotas Birth Cohort, odds ratio = 1.98). Some additional associations were observed in the Pelotas Birth Cohort but were generally in the opposite direction to our a priori hypothesis: Parental separation was associated with lower blood pressure and fat mass index, and with more physical activity. No consistent differences were observed when analyses were stratified by child's age at parental separation or parental conflict. © The Author 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.

Prediction of prostate cancer in unscreened men: external validation of a risk calculator.

PubMed

van Vugt, Heidi A; Roobol, Monique J; Kranse, Ries; Määttänen, Liisa; Finne, Patrik; Hugosson, Jonas; Bangma, Chris H; Schröder, Fritz H; Steyerberg, Ewout W

2011-04-01

Prediction models need external validation to assess their value beyond the setting where the model was derived from. To assess the external validity of the European Randomized study of Screening for Prostate Cancer (ERSPC) risk calculator (www.prostatecancer-riskcalculator.com) for the probability of having a positive prostate biopsy (P(posb)). The ERSPC risk calculator was based on data of the initial screening round of the ERSPC section Rotterdam and validated in 1825 and 531 men biopsied at the initial screening round in the Finnish and Swedish sections of the ERSPC respectively. P(posb) was calculated using serum prostate specific antigen (PSA), outcome of digital rectal examination (DRE), transrectal ultrasound and ultrasound assessed prostate volume. The external validity was assessed for the presence of cancer at biopsy by calibration (agreement between observed and predicted outcomes), discrimination (separation of those with and without cancer), and decision curves (for clinical usefulness). Prostate cancer was detected in 469 men (26%) of the Finnish cohort and in 124 men (23%) of the Swedish cohort. Systematic miscalibration was present in both cohorts (mean predicted probability 34% versus 26% observed, and 29% versus 23% observed, both p<0.001). The areas under the curves were 0.76 and 0.78, and substantially lower for the model with PSA only (0.64 and 0.68 respectively). The model proved clinically useful for any decision threshold compared with a model with PSA only, PSA and DRE, or biopsying all men. A limitation is that the model is based on sextant biopsies results. The ERSPC risk calculator discriminated well between those with and without prostate cancer among initially screened men, but overestimated the risk of a positive biopsy. Further research is necessary to assess the performance and applicability of the ERSPC risk calculator when a clinical setting is considered rather than a screening setting. Copyright © 2010 Elsevier Ltd. All rights reserved.

Validation of the Retinal Detachment after Open Globe Injury (RD-OGI) Score as an Effective Tool for Predicting Retinal Detachment.

PubMed

Brodowska, Katarzyna; Stryjewski, Tomasz P; Papavasileiou, Evangelia; Chee, Yewlin E; Eliott, Dean

2017-05-01

The Retinal Detachment after Open Globe Injury (RD-OGI) Score is a clinical prediction model that was developed at the Massachusetts Eye and Ear Infirmary to predict the risk of retinal detachment (RD) after open globe injury (OGI). This study sought to validate the RD-OGI Score in an independent cohort of patients. Retrospective cohort study. The predictive value of the RD-OGI Score was evaluated by comparing the original RD-OGI Scores of 893 eyes with OGI that presented between 1999 and 2011 (the derivation cohort) with 184 eyes with OGI that presented from January 1, 2012, to January 31, 2014 (the validation cohort). Three risk classes (low, moderate, and high) were created and logistic regression was undertaken to evaluate the optimal predictive value of the RD-OGI Score. A Kaplan-Meier survival analysis evaluated survival experience between the risk classes. Time to RD. At 1 year after OGI, 255 eyes (29%) in the derivation cohort and 66 eyes (36%) in the validation cohort were diagnosed with an RD. At 1 year, the low risk class (RD-OGI Scores 0-2) had a 3% detachment rate in the derivation cohort and a 0% detachment rate in the validation cohort, the moderate risk class (RD-OGI Scores 2.5-4.5) had a 29% detachment rate in the derivation cohort and a 35% detachment rate in the validation cohort, and the high risk class (RD-OGI scores 5-7.5) had a 73% detachment rate in the derivation cohort and an 86% detachment rate in the validation cohort. Regression modeling revealed the RD-OGI to be highly discriminative, especially 30 days after injury, with an area under the receiver operating characteristic curve of 0.939 in the validation cohort. Survival experience was significantly different depending upon the risk class (P < 0.0001, log-rank chi-square). The RD-OGI Score can reliably predict the future risk of developing an RD based on clinical variables that are present at the time of the initial evaluation after OGI. Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

The Optimal Screening for Prediction of Referral and Outcome (OSPRO) in patients with musculoskeletal pain conditions: a longitudinal validation cohort from the USA

PubMed Central

George, Steven Z; Beneciuk, Jason M; Lentz, Trevor A; Wu, Samuel S

2017-01-01

Purpose There is an increased need for determining which patients with musculoskeletal pain benefit from additional diagnostic testing or psychologically informed intervention. The Optimal Screening for Prediction of Referral and Outcome (OSPRO) cohort studies were designed to develop and validate standard assessment tools for review of systems and yellow flags. This cohort profile paper provides a description of and future plans for the validation cohort. Participants Patients (n=440) with primary complaint of spine, shoulder or knee pain were recruited into the OSPRO validation cohort via a national Orthopaedic Physical Therapy-Investigative Network. Patients were followed up at 4 weeks, 6 months and 12 months for pain, functional status and quality of life outcomes. Healthcare utilisation outcomes were also collected at 6 and 12 months. Findings to date There are no longitudinal findings reported to date from the ongoing OSPRO validation cohort. The previously completed cross-sectional OSPRO development cohort yielded two assessment tools that were investigated in the validation cohort. Future plans Follow-up data collection was completed in January 2017. Primary analyses will investigate how accurately the OSPRO review of systems and yellow flag tools predict 12-month pain, functional status, quality of life and healthcare utilisation outcomes. Planned secondary analyses include prediction of pain interference and/or development of chronic pain, investigation of treatment expectation on patient outcomes and analysis of patient satisfaction following an episode of physical therapy. Trial registration number The OSPRO validation cohort was not registered. PMID:28600371

Early Prediction of Intensive Care Unit-Acquired Weakness: A Multicenter External Validation Study.

PubMed

Witteveen, Esther; Wieske, Luuk; Sommers, Juultje; Spijkstra, Jan-Jaap; de Waard, Monique C; Endeman, Henrik; Rijkenberg, Saskia; de Ruijter, Wouter; Sleeswijk, Mengalvio; Verhamme, Camiel; Schultz, Marcus J; van Schaik, Ivo N; Horn, Janneke

2018-01-01

An early diagnosis of intensive care unit-acquired weakness (ICU-AW) is often not possible due to impaired consciousness. To avoid a diagnostic delay, we previously developed a prediction model, based on single-center data from 212 patients (development cohort), to predict ICU-AW at 2 days after ICU admission. The objective of this study was to investigate the external validity of the original prediction model in a new, multicenter cohort and, if necessary, to update the model. Newly admitted ICU patients who were mechanically ventilated at 48 hours after ICU admission were included. Predictors were prospectively recorded, and the outcome ICU-AW was defined by an average Medical Research Council score <4. In the validation cohort, consisting of 349 patients, we analyzed performance of the original prediction model by assessment of calibration and discrimination. Additionally, we updated the model in this validation cohort. Finally, we evaluated a new prediction model based on all patients of the development and validation cohort. Of 349 analyzed patients in the validation cohort, 190 (54%) developed ICU-AW. Both model calibration and discrimination of the original model were poor in the validation cohort. The area under the receiver operating characteristics curve (AUC-ROC) was 0.60 (95% confidence interval [CI]: 0.54-0.66). Model updating methods improved calibration but not discrimination. The new prediction model, based on all patients of the development and validation cohort (total of 536 patients) had a fair discrimination, AUC-ROC: 0.70 (95% CI: 0.66-0.75). The previously developed prediction model for ICU-AW showed poor performance in a new independent multicenter validation cohort. Model updating methods improved calibration but not discrimination. The newly derived prediction model showed fair discrimination. This indicates that early prediction of ICU-AW is still challenging and needs further attention.

Validation of the Children's Eating Behavior Questionnaire in 3 year old children of a multi-ethnic Asian population: The GUSTO cohort study.

PubMed

Quah, Phaik Ling; Cheung, Yin Bun; Pang, Wei Wei; Toh, Jia Ying; Saw, Seang-Mei; Godfrey, Keith M; Yap, Fabian; Chong, Yap Seng; Mary, Chong Foong-Fong

2017-06-01

The Children's Eating Behaviour Questionnaire (CEBQ) was developed to measure eating behaviors related to obesity risk in children. However, this questionnaire has not been validated for use in South East Asia, where parenting practices are different from those in western countries and child obesity rates are increasing. The aim of this study was to examine the validity of the CEBQ administered to mothers of children aged 3 years in Singapore. Confirmatory factor analysis (CFA) was used to examine if the original 35-item, 8-factor model was supported in our cohort. Participants were 636 mother-child dyads (mean (SD) child age = 36.7 (1.6) months), from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) birth cohort in which the mothers were characterized in pregnancy and children were followed up to age 3 years. The CFA showed a poor model fit; RMSEA = 0.072 (PCLOSE<0.001), SRMR = 0.094, CFI = 0.826, and TLI = 0.805. Exploratory factor analysis revealed a 35 item, 7-factor structure (factor loadings ≥ 0.35): enjoyment of food, food fussiness, emotional overeating, desire to drink, emotional under eating, satiety responsiveness and slowness in eating. Cronbach's alpha estimates ranged from 0.70 to 0.88 for the 7 subscales. Convergent validity tests via correlation analysis revealed that emotional under eating (r = -0.14), slowness in eating (r = -0.16) and satiety responsiveness (r = -0.11) were negatively correlated with BMI z-score at 3 years, while enjoyment of food (r = 0.12) was positively correlated, p < 0.05. In conclusion, we found a revised 7-factor structure of the CEBQ more appropriate for examining eating behavior in 3 year old children in the Singapore setting. Further replication studies in a separate cohort study are warranted before further use of these factor structures generated. Copyright © 2017 Elsevier Ltd. All rights reserved.

Assessment of two different types of bias affecting the results of outcome-based evaluation in undergraduate medical education.

PubMed

Schiekirka, Sarah; Anders, Sven; Raupach, Tobias

2014-07-21

Estimating learning outcome from comparative student self-ratings is a reliable and valid method to identify specific strengths and shortcomings in undergraduate medical curricula. However, requiring students to complete two evaluation forms (i.e. one before and one after teaching) might adversely affect response rates. Alternatively, students could be asked to rate their initial performance level retrospectively. This approach might threaten the validity of results due to response shift or effort justification bias. Two consecutive cohorts of medical students enrolled in a six-week cardio-respiratory module were enrolled in this study. In both cohorts, performance gain was estimated for 33 specific learning objectives. In the first cohort, outcomes calculated from ratings provided before (pretest) and after (posttest) teaching were compared to outcomes derived from comparative self-ratings collected after teaching only (thentest and posttest). In the second cohort, only thentests and posttests were used to calculate outcomes, but data collection tools differed with regard to item presentation. In one group, thentest and posttest ratings were obtained sequentially on separate forms while in the other, both ratings were obtained simultaneously for each learning objective. Using thentest ratings to calculate performance gain produced slightly higher values than using true pretest ratings. Direct comparison of then- and posttest ratings also yielded slightly higher performance gain than sequential ratings, but this effect was negligibly small. Given the small effect sizes, using thentests appears to be equivalent to using true pretest ratings. Item presentation in the posttest does not significantly impact on results.

Assessment of two different types of bias affecting the results of outcome-based evaluation in undergraduate medical education

PubMed Central

2014-01-01

Background Estimating learning outcome from comparative student self-ratings is a reliable and valid method to identify specific strengths and shortcomings in undergraduate medical curricula. However, requiring students to complete two evaluation forms (i.e. one before and one after teaching) might adversely affect response rates. Alternatively, students could be asked to rate their initial performance level retrospectively. This approach might threaten the validity of results due to response shift or effort justification bias. Methods Two consecutive cohorts of medical students enrolled in a six-week cardio-respiratory module were enrolled in this study. In both cohorts, performance gain was estimated for 33 specific learning objectives. In the first cohort, outcomes calculated from ratings provided before (pretest) and after (posttest) teaching were compared to outcomes derived from comparative self-ratings collected after teaching only (thentest and posttest). In the second cohort, only thentests and posttests were used to calculate outcomes, but data collection tools differed with regard to item presentation. In one group, thentest and posttest ratings were obtained sequentially on separate forms while in the other, both ratings were obtained simultaneously for each learning objective. Results Using thentest ratings to calculate performance gain produced slightly higher values than using true pretest ratings. Direct comparison of then- and posttest ratings also yielded slightly higher performance gain than sequential ratings, but this effect was negligibly small. Conclusions Given the small effect sizes, using thentests appears to be equivalent to using true pretest ratings. Item presentation in the posttest does not significantly impact on results. PMID:25043503

Prediction of overall survival for metastatic pancreatic cancer: Development and validation of a prognostic nomogram with data from open clinical trial and real-world study.

PubMed

Hang, Junjie; Wu, Lixia; Zhu, Lina; Sun, Zhiqiang; Wang, Ge; Pan, Jingjing; Zheng, Suhua; Xu, Kequn; Du, Jiadi; Jiang, Hua

2018-06-01

It is necessary to develop prognostic tools of metastatic pancreatic cancer (MPC) for optimizing therapeutic strategies. Thus, we tried to develop and validate a prognostic nomogram of MPC. Data from 3 clinical trials (NCT00844649, NCT01124786, and NCT00574275) and 133 Chinese MPC patients were used for analysis. The former 2 trials were taken as the training cohort while NCT00574275 was used as the validation cohort. In addition, 133 MPC patients treated in China were taken as the testing cohort. Cox regression model was used to investigate prognostic factors in the training cohort. With these factors, we established a nomogram and verified it by Harrell's concordance index (C-index) and calibration plots. Furthermore, the nomogram was externally validated in the validation cohort and testing cohort. In the training cohort (n = 445), performance status, liver metastasis, Carbohydrate antigen 19-9 (CA19-9) log-value, absolute neutrophil count (ANC), and albumin were independent prognostic factors for overall survival (OS). A nomogram was established with these factors to predict OS and survival probabilities. The nomogram showed an acceptable discrimination ability (C-index: .683) and good calibration, and was further externally validated in the validation cohort (n = 273, C-index: .699) and testing cohort (n = 133, C-index: .653).The nomogram total points (NTP) had the potential to stratify patients into 3-risk groups with median OS of 11.7, 7.0 and 3.7 months (P < .001), respectively. In conclusion, the prognostic nomogram with NTP can predict OS for patients with MPC with considerable accuracy. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Development and Validation of Web-Based Nomograms to Precisely Predict Conditional Risk of Site-Specific Recurrence for Patients With Completely Resected Non-small Cell Lung Cancer: A Multiinstitutional Study.

PubMed

Zhang, Yang; Zheng, Difan; Xie, Juntao; Li, Yuan; Wang, Yiyang; Li, Chenguang; Xiang, Jiaqing; Zhang, Yawei; Hu, Hong; Sun, Yihua; Chen, Haiquan

2018-06-15

There is currently no consensus regarding the optimal postoperative follow-up strategy for patients with completely resected non-small cell lung cancer (NSCLC). We aimed to develop web-based nomograms to precisely predict site-specific postoperative recurrence in patients with NSCLC and to guide individual surveillance strategies including when to follow up and what diagnostic tests to perform. We investigated the pattern of recurrence in a series of 2,017 patients with NSCLC (squamous cell carcinoma and nonlepidic invasive adenocarcinoma) who underwent complete surgical resection at Fudan University Shanghai Cancer Center (development cohort), and developed web-based clinicopathologic prediction models for conditional risk of site-specific recurrence based on Cox regression. The variables used in the analysis included sex, age, smoking history, tumor size, tumor histology, lymphovascular invasion, visceral pleural invasion, and pathologic TNM stage. A separate cohort of 3,308 patients with NSCLC from Shanghai Chest Hospital was used for external validation. In the development cohort and the external validation cohort for the established nomograms to predict overall recurrence, thorax recurrence, abdomen recurrence, neck recurrence, brain recurrence, and bone recurrence, the C-statistics of Harrell et al were 0.743 and 0.748, 0.728 and 0.703, 0.760 and 0.749, 0.779 and 0.757, 0.787 and 0.784, and 0.777 and 0.739, respectively. The calibration plots showed optimal agreement between nomogram-predicted 3-year recurrence-free survival and actual 3-year recurrence-free survival. These user-friendly nomograms can precisely predict site-specific recurrence in patients with completely resected NSCLC, based on clinicopathologic features. They may help physicians to make individual postoperative follow-up plans. Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

The utility of liver function tests for mortality prediction within one year in primary care using the algorithm for liver function investigations (ALFI).

PubMed

McLernon, David J; Dillon, John F; Sullivan, Frank M; Roderick, Paul; Rosenberg, William M; Ryder, Stephen D; Donnan, Peter T

2012-01-01

Although liver function tests (LFTs) are routinely measured in primary care, raised levels in patients with no obvious liver disease may trigger a range of subsequent expensive and unnecessary management plans. The aim of this study was to develop and validate a prediction model to guide decision-making by general practitioners, which estimates risk of one year all-cause mortality in patients with no obvious liver disease. In this population-based historical cohort study, biochemistry data from patients in Tayside, Scotland, with LFTs performed in primary care were record-linked to secondary care and prescription databases to ascertain baseline characteristics, and to mortality data. Using this derivation cohort a survival model was developed to predict mortality. The model was assessed for calibration, discrimination (using the C-statistic) and performance, and validated using a separate cohort of Scottish primary care practices. From the derivation cohort (n = 95 977), 2.7% died within one year. Predictors of mortality included: age; male gender; social deprivation; history of cancer, renal disease, stroke, ischaemic heart disease or respiratory disease; statin use; and LFTs (albumin, transaminase, alkaline phosphatase, bilirubin, and gamma-glutamyltransferase). The C-statistic for the final model was 0.82 (95% CI 0.80-0.84), and was similar in the validation cohort (n = 11 653) 0.86 (0.79-0.90). As an example of performance, for a 10% predicted probability cut-off, sensitivity = 52.8%, specificity = 94.0%, PPV = 21.0%, NPV = 98.5%. For the model without LFTs the respective values were 43.8%, 92.8%, 15.6%, 98.1%. The Algorithm for Liver Function Investigations (ALFI) is the first model to successfully estimate the probability of all-cause mortality in patients with no apparent liver disease having LFTs in primary care. While LFTs added to the model's discrimination and sensitivity, the clinical utility of ALFI remains to be established since LFTs did not improve an already high NPV for short term mortality and only modestly improved a very low PPV.

Gastro-esophageal reflux disease symptoms and demographic factors as a pre-screening tool for Barrett's esophagus.

PubMed

Liu, Xinxue; Wong, Angela; Kadri, Sudarshan R; Corovic, Andrej; O'Donovan, Maria; Lao-Sirieix, Pierre; Lovat, Laurence B; Burnham, Rodney W; Fitzgerald, Rebecca C

2014-01-01

Barrett's esophagus (BE) occurs as consequence of reflux and is a risk factor for esophageal adenocarcinoma. The current "gold-standard" for diagnosing BE is endoscopy which remains prohibitively expensive and impractical as a population screening tool. We aimed to develop a pre-screening tool to aid decision making for diagnostic referrals. A prospective (training) cohort of 1603 patients attending for endoscopy was used for identification of risk factors to develop a risk prediction model. Factors associated with BE in the univariate analysis were selected to develop prediction models that were validated in an independent, external cohort of 477 non-BE patients referred for endoscopy with symptoms of reflux or dyspepsia. Two prediction models were developed separately for columnar lined epithelium (CLE) of any length and using a stricter definition of intestinal metaplasia (IM) with segments ≥ 2 cm with areas under the ROC curves (AUC) of 0.72 (95%CI: 0.67-0.77) and 0.81 (95%CI: 0.76-0.86), respectively. The two prediction models included demographics (age, sex), symptoms (heartburn, acid reflux, chest pain, abdominal pain) and medication for "stomach" symptoms. These two models were validated in the independent cohort with AUCs of 0.61 (95%CI: 0.54-0.68) and 0.64 (95%CI: 0.52-0.77) for CLE and IM ≥ 2 cm, respectively. We have identified and validated two prediction models for CLE and IM ≥ 2 cm. Both models have fair prediction accuracies and can select out around 20% of individuals unlikely to benefit from investigation for Barrett's esophagus. Such prediction models have the potential to generate useful cost-savings for BE screening among the symptomatic population.

Fall Risk Assessment Through Automatic Combination of Clinical Fall Risk Factors and Body-Worn Sensor Data.

PubMed

Greene, Barry R; Redmond, Stephen J; Caulfield, Brian

2017-05-01

Falls are the leading global cause of accidental death and disability in older adults and are the most common cause of injury and hospitalization. Accurate, early identification of patients at risk of falling, could lead to timely intervention and a reduction in the incidence of fall-related injury and associated costs. We report a statistical method for fall risk assessment using standard clinical fall risk factors (N = 748). We also report a means of improving this method by automatically combining it, with a fall risk assessment algorithm based on inertial sensor data and the timed-up-and-go test. Furthermore, we provide validation data on the sensor-based fall risk assessment method using a statistically independent dataset. Results obtained using cross-validation on a sample of 292 community dwelling older adults suggest that a combined clinical and sensor-based approach yields a classification accuracy of 76.0%, compared to either 73.6% for sensor-based assessment alone, or 68.8% for clinical risk factors alone. Increasing the cohort size by adding an additional 130 subjects from a separate recruitment wave (N = 422), and applying the same model building and validation method, resulted in a decrease in classification performance (68.5% for combined classifier, 66.8% for sensor data alone, and 58.5% for clinical data alone). This suggests that heterogeneity between cohorts may be a major challenge when attempting to develop fall risk assessment algorithms which generalize well. Independent validation of the sensor-based fall risk assessment algorithm on an independent cohort of 22 community dwelling older adults yielded a classification accuracy of 72.7%. Results suggest that the present method compares well to previously reported sensor-based fall risk assessment methods in assessing falls risk. Implementation of objective fall risk assessment methods on a large scale has the potential to improve quality of care and lead to a reduction in associated hospital costs, due to fewer admissions and reduced injuries due to falling.

Determinants of Acute Kidney Injury Duration After Cardiac Surgery: An Externally Validated Tool

PubMed Central

Brown, Jeremiah R.; Kramer, Robert S.; MacKenzie, Todd A.; Coca, Steven G.; Sint, Kyaw; Parikh, Chirag R.

2013-01-01

Background Acute kidney injury (AKI) duration following cardiac surgery is associated with poor survival in a dose-dependent manner. However, it is not known what peri-operative risk factors contribute to prolonged AKI and delayed recovery. We sought to identify peri-operative risk factors that predict duration of AKI, a complication that effects short and long term survival. Methods We studied 4,987 consecutive cardiac surgery patients from 2002 through 2007. AKI was defined as a ≥0.3 (mg/dL) or ≥50% increase in SCr from baseline. Duration of AKI was defined by the number of days AKI was present. Step-wise multivariable negative binomial regression analysis was conducted using peri-operative risk factors for AKI duration. C-index was estimated by Kendall’s tau. Results AKI developed in 39% of patients with a median duration of AKI at 3 days and ranged from 1 to 108 days. Patients without AKI had duration of zero days. Independent predictors of AKI duration included baseline patient and disease characteristics, operative and post-operative factors. Prediction for mean duration of AKI was developed using coefficients from the regression model and externally validated the model on 1,219 cardiac surgery patients in a separate cardiac surgery cohort (TRIBE-AKI). The C-index was 0.65 (p<0.001) for the derivation cohort and 0.62 (p<0.001) for the validation cohort. Conclusion We identified and externally validated peri-operative predictors of AKI duration. These risk-factors will be useful to evaluate a patient’s risk for the tempo of recovery from AKI after cardiac surgery and subsequent short and long term survival. The level of awareness created by working with these risk factors have implications regarding positive changes in processes of care that have the potential to decrease the incidence and mitigate AKI. PMID:22206952

Integration of copy number and transcriptomics provides risk stratification in prostate cancer: A discovery and validation cohort study

PubMed Central

Ross-Adams, H.; Lamb, A.D.; Dunning, M.J.; Halim, S.; Lindberg, J.; Massie, C.M.; Egevad, L.A.; Russell, R.; Ramos-Montoya, A.; Vowler, S.L.; Sharma, N.L.; Kay, J.; Whitaker, H.; Clark, J.; Hurst, R.; Gnanapragasam, V.J.; Shah, N.C.; Warren, A.Y.; Cooper, C.S.; Lynch, A.G.; Stark, R.; Mills, I.G.; Grönberg, H.; Neal, D.E.

2015-01-01

Background Understanding the heterogeneous genotypes and phenotypes of prostate cancer is fundamental to improving the way we treat this disease. As yet, there are no validated descriptions of prostate cancer subgroups derived from integrated genomics linked with clinical outcome. Methods In a study of 482 tumour, benign and germline samples from 259 men with primary prostate cancer, we used integrative analysis of copy number alterations (CNA) and array transcriptomics to identify genomic loci that affect expression levels of mRNA in an expression quantitative trait loci (eQTL) approach, to stratify patients into subgroups that we then associated with future clinical behaviour, and compared with either CNA or transcriptomics alone. Findings We identified five separate patient subgroups with distinct genomic alterations and expression profiles based on 100 discriminating genes in our separate discovery and validation sets of 125 and 103 men. These subgroups were able to consistently predict biochemical relapse (p = 0.0017 and p = 0.016 respectively) and were further validated in a third cohort with long-term follow-up (p = 0.027). We show the relative contributions of gene expression and copy number data on phenotype, and demonstrate the improved power gained from integrative analyses. We confirm alterations in six genes previously associated with prostate cancer (MAP3K7, MELK, RCBTB2, ELAC2, TPD52, ZBTB4), and also identify 94 genes not previously linked to prostate cancer progression that would not have been detected using either transcript or copy number data alone. We confirm a number of previously published molecular changes associated with high risk disease, including MYC amplification, and NKX3-1, RB1 and PTEN deletions, as well as over-expression of PCA3 and AMACR, and loss of MSMB in tumour tissue. A subset of the 100 genes outperforms established clinical predictors of poor prognosis (PSA, Gleason score), as well as previously published gene signatures (p = 0.0001). We further show how our molecular profiles can be used for the early detection of aggressive cases in a clinical setting, and inform treatment decisions. Interpretation For the first time in prostate cancer this study demonstrates the importance of integrated genomic analyses incorporating both benign and tumour tissue data in identifying molecular alterations leading to the generation of robust gene sets that are predictive of clinical outcome in independent patient cohorts. PMID:26501111

Development and validation of a risk assessment tool for gastric cancer in a general Japanese population.

PubMed

Iida, Masahiro; Ikeda, Fumie; Hata, Jun; Hirakawa, Yoichiro; Ohara, Tomoyuki; Mukai, Naoko; Yoshida, Daigo; Yonemoto, Koji; Esaki, Motohiro; Kitazono, Takanari; Kiyohara, Yutaka; Ninomiya, Toshiharu

2018-05-01

There have been very few reports of risk score models for the development of gastric cancer. The aim of this study was to develop and validate a risk assessment tool for discerning future gastric cancer risk in Japanese. A total of 2444 subjects aged 40 years or over were followed up for 14 years from 1988 (derivation cohort), and 3204 subjects of the same age group were followed up for 5 years from 2002 (validation cohort). The weighting (risk score) of each risk factor for predicting future gastric cancer in the risk assessment tool was determined based on the coefficients of a Cox proportional hazards model in the derivation cohort. The goodness of fit of the established risk assessment tool was assessed using the c-statistic and the Hosmer-Lemeshow test in the validation cohort. During the follow-up, gastric cancer developed in 90 subjects in the derivation cohort and 35 subjects in the validation cohort. In the derivation cohort, the risk prediction model for gastric cancer was established using significant risk factors: age, sex, the combination of Helicobacter pylori antibody and pepsinogen status, hemoglobin A1c level, and smoking status. The incidence of gastric cancer increased significantly as the sum of risk scores increased (P trend < 0.001). The risk assessment tool was validated internally and showed good discrimination (c-statistic = 0.76) and calibration (Hosmer-Lemeshow test P = 0.43) in the validation cohort. We developed a risk assessment tool for gastric cancer that provides a useful guide for stratifying an individual's risk of future gastric cancer.

Validation of a predictive model that identifies patients at high risk of developing febrile neutropaenia following chemotherapy for breast cancer.

PubMed

Jenkins, P; Scaife, J; Freeman, S

2012-07-01

We have previously developed a predictive model that identifies patients at increased risk of febrile neutropaenia (FN) following chemotherapy, based on pretreatment haematological indices. This study was designed to validate our earlier findings in a separate cohort of patients undergoing more myelosuppressive chemotherapy supported by growth factors. We conducted a retrospective analysis of 263 patients who had been treated with adjuvant docetaxel, adriamycin and cyclophosphamide (TAC) chemotherapy for breast cancer. All patients received prophylactic pegfilgrastim and the majority also received prophylactic antibiotics. Thirty-one patients (12%) developed FN. Using our previous model, patients in the highest risk group (pretreatment absolute neutrophil count≤3.1 10(9)/l and absolute lymphocyte count≤1.5 10(9)/l) comprised 8% of the total population and had a 33% risk of developing FN. Compared with the rest of the cohort, this group had a 3.4-fold increased risk of developing FN (P=0.001) and a 5.2-fold increased risk of cycle 1 FN (P<0.001). A simple model based on pretreatment differential white blood cell count can be applied to pegfilgrastim-supported patients to identify those who are at higher risk of FN.

Development and validation of a predictive model for excessive postpartum blood loss: A retrospective, cohort study.

PubMed

Rubio-Álvarez, Ana; Molina-Alarcón, Milagros; Arias-Arias, Ángel; Hernández-Martínez, Antonio

2018-03-01

postpartum haemorrhage is one of the leading causes of maternal morbidity and mortality worldwide. Despite the use of uterotonics agents as preventive measure, it remains a challenge to identify those women who are at increased risk of postpartum bleeding. to develop and to validate a predictive model to assess the risk of excessive bleeding in women with vaginal birth. retrospective cohorts study. "Mancha-Centro Hospital" (Spain). the elaboration of the predictive model was based on a derivation cohort consisting of 2336 women between 2009 and 2011. For validation purposes, a prospective cohort of 953 women between 2013 and 2014 were employed. Women with antenatal fetal demise, multiple pregnancies and gestations under 35 weeks were excluded METHODS: we used a multivariate analysis with binary logistic regression, Ridge Regression and areas under the Receiver Operating Characteristic curves to determine the predictive ability of the proposed model. there was 197 (8.43%) women with excessive bleeding in the derivation cohort and 63 (6.61%) women in the validation cohort. Predictive factors in the final model were: maternal age, primiparity, duration of the first and second stages of labour, neonatal birth weight and antepartum haemoglobin levels. Accordingly, the predictive ability of this model in the derivation cohort was 0.90 (95% CI: 0.85-0.93), while it remained 0.83 (95% CI: 0.74-0.92) in the validation cohort. this predictive model is proved to have an excellent predictive ability in the derivation cohort, and its validation in a latter population equally shows a good ability for prediction. This model can be employed to identify women with a higher risk of postpartum haemorrhage. Copyright © 2017 Elsevier Ltd. All rights reserved.

Derivation and validation of a simple clinical risk-model in heart failure based on 6 minute walk test performance and NT-proBNP status--do we need specificity for sex and beta-blockers?

PubMed

Frankenstein, L; Goode, K; Ingle, L; Remppis, A; Schellberg, D; Nelles, M; Katus, H A; Clark, A L; Cleland, J G F; Zugck, C

2011-02-17

It is unclear whether risk prediction strategies in chronic heart failure (CHF) need to be specific for sex or beta-blockers. We examined this problem and developed and validated the consequent risk models based on 6-minute-walk-test and NT-proBNP. The derivation cohort comprised 636 German patients with systolic dysfunction. They were validated against 676 British patients with similar aetiology. ROC-curves for 1-year mortality identified cut-off values separately for specificity (none, sex, beta-blocker, both). Patients were grouped according to number of cut-offs met (group I/II/III - 0/1/2 cut-offs). Widest separation between groups was achieved with sex- and beta-blocker-specific cut offs. In the derivation population, 1-year mortality was 0%, 8%, 31% for group I, II and III, respectively. In the validation population, 1-year rates in the three risk groups were 2%, 7%, 14%, respectively, after application of the same cut-offs. Risk stratification for CHF should perhaps take sex and beta-blocker usage into account. We derived and independently validated relevant risk models based on 6-minute-walk-tests and NT-proBNP. Specifying sex and use of beta-blockers identified three distinct sub-groups with widely differing prognosis. In clinical practice, it may be appropriate to tailor the intensity of follow-up and/or the treatment strategy according to the risk-group. Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.

Validation of the DRAGON score in 12 stroke centers in anterior and posterior circulation.

PubMed

Strbian, Daniel; Seiffge, David J; Breuer, Lorenz; Numminen, Heikki; Michel, Patrik; Meretoja, Atte; Coote, Skye; Bordet, Régis; Obach, Victor; Weder, Bruno; Jung, Simon; Caso, Valeria; Curtze, Sami; Ollikainen, Jyrki; Lyrer, Philippe A; Eskandari, Ashraf; Mattle, Heinrich P; Chamorro, Angel; Leys, Didier; Bladin, Christopher; Davis, Stephen M; Köhrmann, Martin; Engelter, Stefan T; Tatlisumak, Turgut

2013-10-01

The DRAGON score predicts functional outcome in the hyperacute phase of intravenous thrombolysis treatment of ischemic stroke patients. We aimed to validate the score in a large multicenter cohort in anterior and posterior circulation. Prospectively collected data of consecutive ischemic stroke patients who received intravenous thrombolysis in 12 stroke centers were merged (n=5471). We excluded patients lacking data necessary to calculate the score and patients with missing 3-month modified Rankin scale scores. The final cohort comprised 4519 eligible patients. We assessed the performance of the DRAGON score with area under the receiver operating characteristic curve in the whole cohort for both good (modified Rankin scale score, 0-2) and miserable (modified Rankin scale score, 5-6) outcomes. Area under the receiver operating characteristic curve was 0.84 (0.82-0.85) for miserable outcome and 0.82 (0.80-0.83) for good outcome. Proportions of patients with good outcome were 96%, 93%, 78%, and 0% for 0 to 1, 2, 3, and 8 to 10 score points, respectively. Proportions of patients with miserable outcome were 0%, 2%, 4%, 89%, and 97% for 0 to 1, 2, 3, 8, and 9 to 10 points, respectively. When tested separately for anterior and posterior circulation, there was no difference in performance (P=0.55); areas under the receiver operating characteristic curve were 0.84 (0.83-0.86) and 0.82 (0.78-0.87), respectively. No sex-related difference in performance was observed (P=0.25). The DRAGON score showed very good performance in the large merged cohort in both anterior and posterior circulation strokes. The DRAGON score provides rapid estimation of patient prognosis and supports clinical decision-making in the hyperacute phase of stroke care (eg, when invasive add-on strategies are considered).

Identifying Meningitis During an Anthrax Mass Casualty Incident: Systematic Review of Systemic Anthrax Since 1880

PubMed Central

Katharios-Lanwermeyer, Stefan; Holty, Jon-Erik; Person, Marissa; Sejvar, James; Haberling, Dana; Tubbs, Heather; Meaney-Delman, Dana; Pillai, Satish K.; Hupert, Nathaniel; Bower, William A.; Hendricks, Katherine

2016-01-01

BACKGROUND Bacillus anthracis, the causative agent of anthrax, is a potential bioterrorism agent. Anthrax meningitis may be a manifestation of B. anthracis infection, has high mortality, and requires more aggressive treatment than anthrax without meningitis. Rapid identification and treatment of anthrax meningitis are essential for successful management of an anthrax mass casualty incident. METHODS Three hundred six published reports from 1880 through 2013 met pre-defined inclusion criteria. We calculated descriptive statistics for abstracted cases and conducted multivariable regression on separate derivation and validation cohorts to identify clinical diagnostic and prognostic factors for anthrax meningitis. RESULTS One hundred thirty-two of 363 (36%) cases with systemic anthrax met anthrax meningitis criteria. Severe headache, altered mental status, meningeal signs, and other neurological signs at presentation independently predicted meningitis in the derivation cohort and are proposed as a four-item screening tool for use during mass casualty incidents. Presence of any one factor on admission had a sensitivity for finding anthrax meningitis of 89% (83%) in the adult (pediatric) validation cohorts. Anthrax meningitis was unlikely in the absence of any of these signs or symptoms ([LR−]=0.12 [0.19] for adult [pediatric] cohorts), while presence of two or more factors made meningitis very likely ([LR+]=26.5 [29.2]). Survival of anthrax meningitis was predicted by treatment with a bactericidal agent (P=0.005) and use of multiple antimicrobials (P=0.012). CONCLUSIONS We developed an evidence-based triage tool for screening patients for meningitis during an anthrax mass casualty incident; its use could improve both patient outcomes and resource allocation in such an event. PMID:27025833

Identifying Meningitis During an Anthrax Mass Casualty Incident: Systematic Review of Systemic Anthrax Since 1880.

PubMed

Katharios-Lanwermeyer, Stefan; Holty, Jon-Erik; Person, Marissa; Sejvar, James; Haberling, Dana; Tubbs, Heather; Meaney-Delman, Dana; Pillai, Satish K; Hupert, Nathaniel; Bower, William A; Hendricks, Katherine

2016-06-15

Bacillus anthracis, the causative agent of anthrax, is a potential bioterrorism agent. Anthrax meningitis is a common manifestation of B. anthracis infection, has high mortality, and requires more aggressive treatment than anthrax without meningitis. Its rapid identification and treatment are essential for successful management of an anthrax mass casualty incident. Three hundred six published reports from 1880 through 2013 met predefined inclusion criteria. We calculated descriptive statistics for abstracted cases and conducted multivariable regression on separate derivation and validation cohorts to identify clinical diagnostic and prognostic factors for anthrax meningitis. One hundred thirty-two of 363 (36%) cases with systemic anthrax met anthrax meningitis criteria. Severe headache, altered mental status, meningeal signs, and other neurological signs at presentation independently predicted meningitis in the derivation cohort and were tested as a 4-item assessment tool for use during anthrax mass casualty incidents. Presence of any 1 factor on admission had a sensitivity for finding anthrax meningitis of 89% (83%) in the adult (pediatric) validation cohorts. Anthrax meningitis was unlikely in the absence of any of these signs or symptoms (likelihood ratio [LR]- = 0.12 [0.19] for adult [pediatric] cohorts), while presence of 2 or more made meningitis very likely (LR+ = 26.5 [30.0]). Survival of anthrax meningitis was predicted by treatment with a bactericidal agent (P = .005) and use of multiple antimicrobials (P = .01). We developed an evidence-based assessment tool for screening patients for meningitis during an anthrax mass casualty incident. Its use could improve both patient outcomes and resource allocation in such an event. Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Clinical Risk Score for Persistent Postconcussion Symptoms Among Children With Acute Concussion in the ED.

PubMed

Zemek, Roger; Barrowman, Nick; Freedman, Stephen B; Gravel, Jocelyn; Gagnon, Isabelle; McGahern, Candice; Aglipay, Mary; Sangha, Gurinder; Boutis, Kathy; Beer, Darcy; Craig, William; Burns, Emma; Farion, Ken J; Mikrogianakis, Angelo; Barlow, Karen; Dubrovsky, Alexander S; Meeuwisse, Willem; Gioia, Gerard; Meehan, William P; Beauchamp, Miriam H; Kamil, Yael; Grool, Anne M; Hoshizaki, Blaine; Anderson, Peter; Brooks, Brian L; Yeates, Keith Owen; Vassilyadi, Michael; Klassen, Terry; Keightley, Michelle; Richer, Lawrence; DeMatteo, Carol; Osmond, Martin H

2016-03-08

Approximately one-third of children experiencing acute concussion experience ongoing somatic, cognitive, and psychological or behavioral symptoms, referred to as persistent postconcussion symptoms (PPCS). However, validated and pragmatic tools enabling clinicians to identify patients at risk for PPCS do not exist. To derive and validate a clinical risk score for PPCS among children presenting to the emergency department. Prospective, multicenter cohort study (Predicting and Preventing Postconcussive Problems in Pediatrics [5P]) enrolled young patients (aged 5-<18 years) who presented within 48 hours of an acute head injury at 1 of 9 pediatric emergency departments within the Pediatric Emergency Research Canada (PERC) network from August 2013 through September 2014 (derivation cohort) and from October 2014 through June 2015 (validation cohort). Participants completed follow-up 28 days after the injury. All eligible patients had concussions consistent with the Zurich consensus diagnostic criteria. The primary outcome was PPCS risk score at 28 days, which was defined as 3 or more new or worsening symptoms using the patient-reported Postconcussion Symptom Inventory compared with recalled state of being prior to the injury. In total, 3063 patients (median age, 12.0 years [interquartile range, 9.2-14.6 years]; 1205 [39.3%] girls) were enrolled (n = 2006 in the derivation cohort; n = 1057 in the validation cohort) and 2584 of whom (n = 1701 [85%] in the derivation cohort; n = 883 [84%] in the validation cohort) completed follow-up at 28 days after the injury. Persistent postconcussion symptoms were present in 801 patients (31.0%) (n = 510 [30.0%] in the derivation cohort and n = 291 [33.0%] in the validation cohort). The 12-point PPCS risk score model for the derivation cohort included the variables of female sex, age of 13 years or older, physician-diagnosed migraine history, prior concussion with symptoms lasting longer than 1 week, headache, sensitivity to noise, fatigue, answering questions slowly, and 4 or more errors on the Balance Error Scoring System tandem stance. The area under the curve was 0.71 (95% CI, 0.69-0.74) for the derivation cohort and 0.68 (95% CI, 0.65-0.72) for the validation cohort. A clinical risk score developed among children presenting to the emergency department with concussion and head injury within the previous 48 hours had modest discrimination to stratify PPCS risk at 28 days. Before this score is adopted in clinical practice, further research is needed for external validation, assessment of accuracy in an office setting, and determination of clinical utility.

Expression profiles of loneliness-associated genes for survival prediction in cancer patients.

PubMed

You, Liang-Fu; Yeh, Jia-Rong; Su, Mu-Chun

2014-01-01

Influence of loneliness on human survival has been established epidemiologically, but genomic research remains undeveloped. We identified 34 loneliness-associated genes which were statistically significant for high- lonely and low-lonely individuals. With the univariate Cox proportional hazards regression model, we obtained corresponding regression coefficients for loneliness-associated genes fo individual cancer patients. Furthermore, risk scores could be generated with the combination of gene expression level multiplied by corresponding regression coefficients of loneliness-associated genes. We verified that high-risk score cancer patients had shorter mean survival time than their low-risk score counterparts. Then we validated the loneliness-associated gene signature in three independent brain cancer cohorts with Kaplan-Meier survival curves (n=77, 85 and 191), significantly separable by log-rank test with hazard ratios (HR) >1 and p-values <0.0001 (HR=2.94, 3.82, and 1.78). Moreover, we validated the loneliness-associated gene signature in bone cancer (HR=5.10, p-value=4.69e-3), lung cancer (HR=2.86, p-value=4.71e-5), ovarian cancer (HR=1.97, p-value=3.11e-5), and leukemia (HR=2.06, p-value=1.79e-4) cohorts. The last lymphoma cohort proved to have an HR=3.50, p-value=1.15e-7. Loneliness- associated genes had good survival prediction for cancer patients, especially bone cancer patients. Our study provided the first indication that expression of loneliness-associated genes are related to survival time of cancer patients.

PITX3 DNA methylation is an independent predictor of overall survival in patients with head and neck squamous cell carcinoma.

PubMed

Sailer, Verena; Holmes, Emily Eva; Gevensleben, Heidrun; Goltz, Diane; Dröge, Freya; Franzen, Alina; Dietrich, Jörn; Kristiansen, Glen; Bootz, Friedrich; Schröck, Andreas; Dietrich, Dimo

2017-01-01

Molecular biomarkers assisting risk-group assignment and subsequent treatment stratification are urgently needed for patients with squamous cell cancer of the head and neck region (HNSCC). Aberrant methylation is a frequent event in cancer and, therefore, a promising source for potential biomarkers. Here, the methylation status of the paired-like homeodomain transcription factor 3 ( PITX3 ) was evaluated in HNSCC. Using a quantitative real-time PCR, PITX3 methylation was assessed in a cohort of 326 HNSCC patients treated for localized or locally advanced disease (training cohort). The results were validated with Infinium HumanMethylation450 BeadChip data from a 528 HNSCC patient cohort (validation cohort) generated by The Cancer Genome Atlas (TCGA) Research Network. PITX3 methylation was significantly higher methylated in tumor compared to normal adjacent tissue (NAT; training cohort: median methylation NAT 32.3%, tumor 71.8%, p  < 0.001; validation cohort: median methylation NAT 16.9%, tumor 35.9%, p  < 0.001). PITX3 methylation was also significantly correlated with lymph node status both in the training ( p  = 0.006) and validation ( p  < 0.001) cohort. PITX3 methylation was significantly higher in HPV-associated (p16-positive) tumors compared to p16-negative tumors (training cohort: 73.7 vs. 66.2%, p  = 0.013; validation cohort: 40.0 vs. 33.1%, p  = 0.015). Hypermethylation was significantly associated with the risk of death (training cohort: hazard ratio (HR) = 1.80, [95% confidence interval (CI) 1.20-2.69], p  = 0.005; validation cohort: HR = 1.43, [95% CI 1.05-1.95], p  = 0.022). In multivariate Cox analyses, PITX3 added independent prognostic information. Messenger RNA (mRNA) expression analysis revealed an inverse correlation with PITX3 methylation in the TCGA cohort. PITX3 DNA methylation is an independent prognostic biomarker for overall survival in patients with HNSCC and might aid in the process of risk stratification for individualized treatment.

Early Detection of Increased Intracranial Pressure Episodes in Traumatic Brain Injury: External Validation in an Adult and in a Pediatric Cohort.

PubMed

Güiza, Fabian; Depreitere, Bart; Piper, Ian; Citerio, Giuseppe; Jorens, Philippe G; Maas, Andrew; Schuhmann, Martin U; Lo, Tsz-Yan Milly; Donald, Rob; Jones, Patricia; Maier, Gottlieb; Van den Berghe, Greet; Meyfroidt, Geert

2017-03-01

A model for early detection of episodes of increased intracranial pressure in traumatic brain injury patients has been previously developed and validated based on retrospective adult patient data from the multicenter Brain-IT database. The purpose of the present study is to validate this early detection model in different cohorts of recently treated adult and pediatric traumatic brain injury patients. Prognostic modeling. Noninterventional, observational, retrospective study. The adult validation cohort comprised recent traumatic brain injury patients from San Gerardo Hospital in Monza (n = 50), Leuven University Hospital (n = 26), Antwerp University Hospital (n = 19), Tübingen University Hospital (n = 18), and Southern General Hospital in Glasgow (n = 8). The pediatric validation cohort comprised patients from neurosurgical and intensive care centers in Edinburgh and Newcastle (n = 79). None. The model's performance was evaluated with respect to discrimination, calibration, overall performance, and clinical usefulness. In the recent adult validation cohort, the model retained excellent performance as in the original study. In the pediatric validation cohort, the model retained good discrimination and a positive net benefit, albeit with a performance drop in the remaining criteria. The obtained external validation results confirm the robustness of the model to predict future increased intracranial pressure events 30 minutes in advance, in adult and pediatric traumatic brain injury patients. These results are a large step toward an early warning system for increased intracranial pressure that can be generally applied. Furthermore, the sparseness of this model that uses only two routinely monitored signals as inputs (intracranial pressure and mean arterial blood pressure) is an additional asset.

Add-on LABA in a separate inhaler as asthma step-up therapy versus increased dose of ICS or ICS/LABA combination inhaler.

PubMed

Price, David B; Colice, Gene; Israel, Elliot; Roche, Nicolas; Postma, Dirkje S; Guilbert, Theresa W; van Aalderen, Willem M C; Grigg, Jonathan; Hillyer, Elizabeth V; Thomas, Victoria; Martin, Richard J

2016-04-01

Asthma management guidelines recommend adding a long-acting β 2 -agonist (LABA) or increasing the dose of inhaled corticosteroid (ICS) as step-up therapy for patients with uncontrolled asthma on ICS monotherapy. However, it is uncertain which option works best, which ICS particle size is most effective, and whether LABA should be administered by separate or combination inhalers. This historical, matched cohort study compared asthma-related outcomes for patients (aged 12-80 years) prescribed step-up therapy as a ≥50% extrafine ICS dose increase or add-on LABA, via either a separate inhaler or a fine-particle ICS/LABA fixed-dose combination (FDC) inhaler. Risk-domain asthma control was the primary end-point in comparisons of cohorts matched for asthma severity and control during the baseline year. After 1:2 cohort matching, the increased extrafine ICS versus separate ICS+LABA cohorts included 3232 and 6464 patients, respectively, and the fine-particle ICS/LABA FDC versus separate ICS+LABA cohorts included 7529 and 15 058 patients, respectively (overall mean age 42 years; 61-62% females). Over one outcome year, adjusted OR (95% CI) for achieving asthma control were 1.25 (1.13-1.38) for increased ICS versus separate ICS+LABA and 1.06 (1.05-1.09) for ICS/LABA FDC versus separate ICS+LABA. For patients with asthma, increased dose of extrafine-particle ICS, or add-on LABA via ICS/LABA combination inhaler, is associated with significantly better outcomes than ICS+LABA via separate inhalers.

Distinct brain imaging characteristics of autoantibody-mediated CNS conditions and multiple sclerosis.

PubMed

Jurynczyk, Maciej; Geraldes, Ruth; Probert, Fay; Woodhall, Mark R; Waters, Patrick; Tackley, George; DeLuca, Gabriele; Chandratre, Saleel; Leite, Maria I; Vincent, Angela; Palace, Jacqueline

2017-03-01

Brain imaging characteristics of MOG antibody disease are largely unknown and it is unclear whether they differ from those of multiple sclerosis and AQP4 antibody disease. The aim of this study was to identify brain imaging discriminators between those three inflammatory central nervous system diseases in adults and children to support diagnostic decisions, drive antibody testing and generate disease mechanism hypotheses. Clinical brain scans of 83 patients with brain lesions (67 in the training and 16 in the validation cohort, 65 adults and 18 children) with MOG antibody (n = 26), AQP4 antibody disease (n = 26) and multiple sclerosis (n = 31) recruited from Oxford neuromyelitis optica and multiple sclerosis clinical services were retrospectively and anonymously scored on a set of 29 predefined magnetic resonance imaging features by two independent raters. Principal component analysis was used to perform an overview of patients without a priori knowledge of the diagnosis. Orthogonal partial least squares discriminant analysis was used to build models separating diagnostic groups and identify best classifiers, which were then tested on an independent cohort set. Adults and children with MOG antibody disease frequently had fluffy brainstem lesions, often located in pons and/or adjacent to fourth ventricle. Children across all conditions showed more frequent bilateral, large, brainstem and deep grey matter lesions. MOG antibody disease spontaneously separated from multiple sclerosis but overlapped with AQP4 antibody disease. Multiple sclerosis was discriminated from MOG antibody disease and from AQP4 antibody disease with high predictive values, while MOG antibody disease could not be accurately discriminated from AQP4 antibody disease. Best classifiers between MOG antibody disease and multiple sclerosis were similar in adults and children, and included ovoid lesions adjacent to the body of lateral ventricles, Dawson's fingers, T1 hypointense lesions (multiple sclerosis), fluffy lesions and three lesions or less (MOG antibody). In the validation cohort patients with antibody-mediated conditions were differentiated from multiple sclerosis with high accuracy. Both antibody-mediated conditions can be clearly separated from multiple sclerosis on conventional brain imaging, both in adults and children. The overlap between MOG antibody oligodendrocytopathy and AQP4 antibody astrocytopathy suggests that the primary immune target is not the main substrate for brain lesion characteristics. This is also supported by the clear distinction between multiple sclerosis and MOG antibody disease both considered primary demyelinating conditions. We identify discriminatory features, which may be useful in classifying atypical multiple sclerosis, seronegative neuromyelitis optica spectrum disorders and relapsing acute disseminated encephalomyelitis, and characterizing cohorts for antibody discovery. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Whole transcriptome RNA-Seq analysis of breast cancer recurrence risk using formalin-fixed paraffin-embedded tumor tissue.

PubMed

Sinicropi, Dominick; Qu, Kunbin; Collin, Francois; Crager, Michael; Liu, Mei-Lan; Pelham, Robert J; Pho, Mylan; Dei Rossi, Andrew; Jeong, Jennie; Scott, Aaron; Ambannavar, Ranjana; Zheng, Christina; Mena, Raul; Esteban, Jose; Stephans, James; Morlan, John; Baker, Joffre

2012-01-01

RNA biomarkers discovered by RT-PCR-based gene expression profiling of archival formalin-fixed paraffin-embedded (FFPE) tissue form the basis for widely used clinical diagnostic tests; however, RT-PCR is practically constrained in the number of transcripts that can be interrogated. We have developed and optimized RNA-Seq library chemistry as well as bioinformatics and biostatistical methods for whole transcriptome profiling from FFPE tissue. The chemistry accommodates low RNA inputs and sample multiplexing. These methods both enable rediscovery of RNA biomarkers for disease recurrence risk that were previously identified by RT-PCR analysis of a cohort of 136 patients, and also identify a high percentage of recurrence risk markers that were previously discovered using DNA microarrays in a separate cohort of patients, evidence that this RNA-Seq technology has sufficient precision and sensitivity for biomarker discovery. More than two thousand RNAs are strongly associated with breast cancer recurrence risk in the 136 patient cohort (FDR <10%). Many of these are intronic RNAs for which corresponding exons are not also associated with disease recurrence. A number of the RNAs associated with recurrence risk belong to novel RNA networks. It will be important to test the validity of these novel associations in whole transcriptome RNA-Seq screens of other breast cancer cohorts.

Whole Transcriptome RNA-Seq Analysis of Breast Cancer Recurrence Risk Using Formalin-Fixed Paraffin-Embedded Tumor Tissue

PubMed Central

Sinicropi, Dominick; Qu, Kunbin; Collin, Francois; Crager, Michael; Liu, Mei-Lan; Pelham, Robert J.; Pho, Mylan; Rossi, Andrew Dei; Jeong, Jennie; Scott, Aaron; Ambannavar, Ranjana; Zheng, Christina; Mena, Raul; Esteban, Jose; Stephans, James; Morlan, John; Baker, Joffre

2012-01-01

RNA biomarkers discovered by RT-PCR-based gene expression profiling of archival formalin-fixed paraffin-embedded (FFPE) tissue form the basis for widely used clinical diagnostic tests; however, RT-PCR is practically constrained in the number of transcripts that can be interrogated. We have developed and optimized RNA-Seq library chemistry as well as bioinformatics and biostatistical methods for whole transcriptome profiling from FFPE tissue. The chemistry accommodates low RNA inputs and sample multiplexing. These methods both enable rediscovery of RNA biomarkers for disease recurrence risk that were previously identified by RT-PCR analysis of a cohort of 136 patients, and also identify a high percentage of recurrence risk markers that were previously discovered using DNA microarrays in a separate cohort of patients, evidence that this RNA-Seq technology has sufficient precision and sensitivity for biomarker discovery. More than two thousand RNAs are strongly associated with breast cancer recurrence risk in the 136 patient cohort (FDR <10%). Many of these are intronic RNAs for which corresponding exons are not also associated with disease recurrence. A number of the RNAs associated with recurrence risk belong to novel RNA networks. It will be important to test the validity of these novel associations in whole transcriptome RNA-Seq screens of other breast cancer cohorts. PMID:22808097

Prediction of Waitlist Mortality in Adult Heart Transplant Candidates: The Candidate Risk Score.

PubMed

Jasseron, Carine; Legeai, Camille; Jacquelinet, Christian; Leprince, Pascal; Cantrelle, Christelle; Audry, Benoît; Porcher, Raphael; Bastien, Olivier; Dorent, Richard

2017-09-01

The cardiac allocation system in France is currently based on urgency and geography. Medical urgency is defined by therapies without considering objective patient mortality risk factors. This study aimed to develop a waitlist mortality risk score from commonly available candidate variables. The study included all patients, aged 16 years or older, registered on the national registry CRISTAL for first single-organ heart transplantation between January 2010 and December 2014. This population was randomly divided in a 2:1 ratio into derivation and validation cohorts. The association of variables at listing with 1-year waitlist death or delisting for worsening medical condition was assessed within the derivation cohort. The predictors were used to generate a candidate risk score (CRS). Validation of the CRS was performed in the validation cohort. Concordance probability estimation (CPE) was used to evaluate the discriminative capacity of the models. During the study period, 2333 patients were newly listed. The derivation (n =1 555) and the validation cohorts (n = 778) were similar. Short-term mechanical circulatory support, natriuretic peptide decile, glomerular filtration rate, and total bilirubin level were included in a simplified model and incorporated into the score. The Concordance probability estimation of the CRS was 0.73 in the derivation cohort and 0.71 in the validation cohort. The correlation between observed and expected 1-year waitlist mortality in the validation cohort was 0.87. The candidate risk score provides an accurate objective prediction of waitlist mortality. It is currently being used to develop a modified cardiac allocation system in France.

Aged over 50 years and practising: separation and changes in nursing practice among New Zealand's older Registered Nurses.

PubMed

North, Nicola; Leung, William; Lee, Rochelle

2014-12-01

To describe temporary and permanent separation patterns and changes in nursing practice over 5 years, for the 2006 cohort of nurses aged ≥50 years in New Zealand. As ageing populations increase demand on nursing services, workforce projections need better information on work and retirement decision-making of large 'baby-boomer' cohorts. Retrospective cohort analysis using the Nursing Council of New Zealand administrative dataset. A cohort of all nurses aged ≥50 years on the register and practising in 2006 (n = 12,606) was tracked until 2011. After 5 years, a quarter (n = 3161) of the cohort (equivalent to 8·4% of all 2006 practising nurses) was no longer practising. There were no significant differences in permanent separation rates between the ages of 50-58; between 18-54% of annual separations re-entered the workforce. On re-entry, 56% returned to the same clinical area. Annual separations from the workforce declined sharply during the global financial crisis and more of those leaving re-entered the workforce. In 2006, half the cohort worked in hospitals. After 5 years, the number of cohort nurses working in hospitals fell by 45%, while those in community settings increased by 12%. Over 5 years, weekly nursing practice hours declined significantly for every age-band. To retain the experience of older nurses for longer, workforce strategies need to take account of patterns of leaving and re-entering the workforce, preferences for work hours and the differences between the sub-groups across employment settings and practice areas. © 2014 John Wiley & Sons Ltd.

Validation of nomograms for overall survival, cancer-specific survival, and recurrence in carcinoma of the major salivary glands.

PubMed

Hay, Ashley; Migliacci, Jocelyn; Zanoni, Daniella Karassawa; Patel, Snehal; Yu, Changhong; Kattan, Michael W; Ganly, Ian

2018-05-01

The purpose of this study was to investigate the performance of the Memorial Sloan Kettering Cancer Center salivary carcinoma nomograms predicting overall survival, cancer-specific survival, and recurrence with an external validation dataset. The validation dataset comprised 123 patients treated between 2010 and 2015 at our institution. They were evaluated by assessing discrimination (concordance index [C-index]) and calibration (plotting predicted vs actual probabilities for quintiles). The validation cohort (n = 123) showed some differences to the original cohort (n = 301). The validation cohort had less high-grade cancers (P = .006), less lymphovascular invasion (LVI; P < .001) and shorter follow-up of 19 months versus 45.6 months. Validation showed a C-index of 0.833 (95% confidence interval [CI] 0.758-0.908), 0.807 (95% CI 0.717-0.898), and 0.844 (95% CI 0.768-0.920) for overall survival, cancer-specific survival, and recurrence, respectively. The 3 salivary gland nomograms performed well using a contemporary validation dataset, despite limitations related to sample size, follow-up, and differences in clinical and pathology characteristics between the original and validation cohorts. © 2018 Wiley Periodicals, Inc.

Criteria To Screen for Chronic Sinonasal Disease

PubMed Central

Dixon, Anne E.; Sugar, Elizabeth A.; Zinreich, S. James; Slavin, Raymond G.; Corren, Jonathan; Naclerio, Robert M.; Ishii, Masaru; Cohen, Rubin I.; Brown, Ellen D.; Wise, Robert A.; Irvin, Charles G.

2009-01-01

Background: Sinusitis and rhinitis are associated with uncontrolled asthma. There are no simple, validated tools to screen for these diseases. The objective of this study was to assess instruments to assist in the diagnosis of chronic sinonasal disease. Methods: Participants without acute sinonasal symptoms underwent an extensive evaluation. The results were submitted to an expert panel that used the Delphi method to achieve consensus. Using the consensus diagnosis of the panel, we determined the sensitivity and specificity of test procedures to diagnose chronic sinonasal disease. We determined the reproducibility of the most sensitive and specific instrument in a separate cohort. Results: Fifty-nine participants were evaluated, and the expert panel reached consensus for all (42 participants with chronic sinonasal disease, 17 participants without chronic sinonasal disease). A six-item questionnaire based on the frequency of nasal symptoms was the most sensitive tool used to diagnose sinonasal disease (minimum specificity, 0.90). Reproducibility testing in a separate cohort of 63 participants (41 chronic sinonasal disease with asthma, 22 chronic sinonasal disease without asthma) showed a concordance correlation coefficient of 0.91 (95% CI, 0.85 to 0.94) when this questionnaire was limited to five items (ie, excluding a question on smell). This five-item questionnaire had a sensitivity of 0.90 (95% CI, 0.77 to 0.97), a specificity of 0.94 (95% CI, 0.71 to 1.00), and an area under the receiver operating characteristic curve of 0.97 (95% CI, 0.93 to 1.0). Sinus CT scans and nasal endoscopy lacked sensitivity for use in the diagnosis of chronic sinonasal disease. Conclusions: We have developed a sensitive, specific, and reproducible instrument to screen for chronic sinonasal disease. Validation studies of this five-item questionnaire are needed, including in patients with asthma. PMID:19581356

External validation of a risk assessment model for venous thromboembolism in the hospitalised acutely-ill medical patient (VTE-VALOURR).

PubMed

Mahan, Charles E; Liu, Yang; Turpie, A Graham; Vu, Jennifer T; Heddle, Nancy; Cook, Richard J; Dairkee, Undaleeb; Spyropoulos, Alex C

2014-10-01

Venous thromboembolic (VTE) risk assessment remains an important issue in hospitalised, acutely-ill medical patients, and several VTE risk assessment models (RAM) have been proposed. The purpose of this large retrospective cohort study was to externally validate the IMPROVE RAM using a large database of three acute care hospitals. We studied 41,486 hospitalisations (28,744 unique patients) with 1,240 VTE hospitalisations (1,135 unique patients) in the VTE cohort and 40,246 VTE-free hospitalisations (27,609 unique patients) in the control cohort. After chart review, 139 unique VTE patients were identified and 278 randomly-selected matched patients in the control cohort. Seven independent VTE risk factors as part of the RAM in the derivation cohort were identified. In the validation cohort, the incidence of VTE was 0.20%; 95% confidence interval (CI) 0.18-0.22, 1.04%; 95%CI 0.88-1.25, and 4.15%; 95%CI 2.79-8.12 in the low, moderate, and high VTE risk groups, respectively, which compared to rates of 0.45%, 1.3%, and 4.74% in the three risk categories of the derivation cohort. For the derivation and validation cohorts, the total percentage of patients in low, moderate and high VTE risk occurred in 68.6% vs 63.3%, 24.8% vs 31.1%, and 6.5% vs 5.5%, respectively. Overall, the area under the receiver-operator characteristics curve for the validation cohort was 0.7731. In conclusion, the IMPROVE RAM can accurately identify medical patients at low, moderate, and high VTE risk. This will tailor future thromboprophylactic strategies in this population as well as identify particularly high VTE risk patients in whom multimodal or more intensive prophylaxis may be beneficial.

Validation of the prognostic gene portfolio, ClinicoMolecular Triad Classification, using an independent prospective breast cancer cohort and external patient populations.

PubMed

Wang, Dong-Yu; Done, Susan J; Mc Cready, David R; Leong, Wey L

2014-07-04

Using genome-wide expression profiles of a prospective training cohort of breast cancer patients, ClinicoMolecular Triad Classification (CMTC) was recently developed to classify breast cancers into three clinically relevant groups to aid treatment decisions. CMTC was found to be both prognostic and predictive in a large external breast cancer cohort in that study. This study serves to validate the reproducibility of CMTC and its prognostic value using independent patient cohorts. An independent internal cohort (n = 284) and a new external cohort (n = 2,181) were used to validate the association of CMTC between clinicopathological factors, 12 known gene signatures, two molecular subtype classifiers, and 19 oncogenic signalling pathway activities, and to reproduce the abilities of CMTC to predict clinical outcomes of breast cancer. In addition, we also updated the outcome data of the original training cohort (n = 147). The original training cohort reached a statistically significant difference (p < 0.05) in disease-free survivals between the three CMTC groups after an additional two years of follow-up (median = 55 months). The prognostic value of the triad classification was reproduced in the second independent internal cohort and the new external validation cohort. CMTC achieved even higher prognostic significance when all available patients were analyzed (n = 4,851). Oncogenic pathways Myc, E2F1, Ras and β-catenin were again implicated in the high-risk groups. Both prospective internal cohorts and the independent external cohorts reproduced the triad classification of CMTC and its prognostic significance. CMTC is an independent prognostic predictor, and it outperformed 12 other known prognostic gene signatures, molecular subtype classifications, and all other standard prognostic clinicopathological factors. Our results support further development of CMTC portfolio into a guide for personalized breast cancer treatments.

Development of a quantitative multivariable radiographic method to evaluate anatomic changes associated with laminitis in the forefeet of donkeys.

PubMed

Collins, Simon N; Dyson, Sue J; Murray, Rachel C; Newton, J Richard; Burden, Faith; Trawford, Andrew F

2012-08-01

To establish and validate an objective method of radiographic diagnosis of anatomic changes in laminitic forefeet of donkeys on the basis of data from a comprehensive series of radiographic measurements. 85 donkeys with and 85 without forelimb laminitis for baseline data determination; a cohort of 44 donkeys with and 18 without forelimb laminitis was used for validation analyses. For each donkey, lateromedial radiographic views of 1 weight-bearing forelimb were obtained; images from 11 laminitic and 2 nonlaminitic donkeys were excluded (motion artifact) from baseline data determination. Data from an a priori selection of 19 measurements of anatomic features of laminitic and nonlaminitic donkey feet were analyzed by use of a novel application of multivariate statistical techniques. The resultant diagnostic models were validated in a blinded manner with data from the separate cohort of laminitic and nonlaminitic donkeys. Data were modeled, and robust statistical rules were established for the diagnosis of anatomic changes within laminitic donkey forefeet. Component 1 scores ≤ -3.5 were indicative of extreme anatomic change, and scores from -2.0 to 0.0 denoted modest change. Nonlaminitic donkeys with a score from 0.5 to 1.0 should be considered as at risk for laminitis. Results indicated that the radiographic procedures evaluated can be used for the identification, assessment, and monitoring of anatomic changes associated with laminitis. Screening assessments by use of this method may enable early detection of mild anatomic change and identification of at-risk donkeys.

Non-coding genomic regions possessing enhancer and silencer potential are associated with healthy aging and exceptional survival.

PubMed

Kim, Sangkyu; Welsh, David A; Myers, Leann; Cherry, Katie E; Wyckoff, Jennifer; Jazwinski, S Michal

2015-02-28

We have completed a genome-wide linkage scan for healthy aging using data collected from a family study, followed by fine-mapping by association in a separate population, the first such attempt reported. The family cohort consisted of parents of age 90 or above and their children ranging in age from 50 to 80. As a quantitative measure of healthy aging, we used a frailty index, called FI34, based on 34 health and function variables. The linkage scan found a single significant linkage peak on chromosome 12. Using an independent cohort of unrelated nonagenarians, we carried out a fine-scale association mapping of the region suggestive of linkage and identified three sites associated with healthy aging. These healthy-aging sites (HASs) are located in intergenic regions at 12q13-14. HAS-1 has been previously associated with multiple diseases, and an enhancer was recently mapped and experimentally validated within the site. HAS-2 is a previously uncharacterized site possessing genomic features suggestive of enhancer activity. HAS-3 contains features associated with Polycomb repression. The HASs also contain variants associated with exceptional longevity, based on a separate analysis. Our results provide insight into functional genomic networks involving non-coding regulatory elements that are involved in healthy aging and longevity.

Non-coding genomic regions possessing enhancer and silencer potential are associated with healthy aging and exceptional survival

PubMed Central

Kim, Sangkyu; Welsh, David A.; Myers, Leann; Cherry, Katie E.; Wyckoff, Jennifer; Jazwinski, S. Michal

2015-01-01

We have completed a genome-wide linkage scan for healthy aging using data collected from a family study, followed by fine-mapping by association in a separate population, the first such attempt reported. The family cohort consisted of parents of age 90 or above and their children ranging in age from 50 to 80. As a quantitative measure of healthy aging, we used a frailty index, called FI34, based on 34 health and function variables. The linkage scan found a single significant linkage peak on chromosome 12. Using an independent cohort of unrelated nonagenarians, we carried out a fine-scale association mapping of the region suggestive of linkage and identified three sites associated with healthy aging. These healthy-aging sites (HASs) are located in intergenic regions at 12q13–14. HAS-1 has been previously associated with multiple diseases, and an enhancer was recently mapped and experimentally validated within the site. HAS-2 is a previously uncharacterized site possessing genomic features suggestive of enhancer activity. HAS-3 contains features associated with Polycomb repression. The HASs also contain variants associated with exceptional longevity, based on a separate analysis. Our results provide insight into functional genomic networks involving non-coding regulatory elements that are involved in healthy aging and longevity. PMID:25682868

Impact of positive and negative lesion site remodeling on clinical outcomes: insights from PROSPECT.

PubMed

Inaba, Shinji; Mintz, Gary S; Farhat, Naim Z; Fajadet, Jean; Dudek, Dariusz; Marzocchi, Antonio; Templin, Barry; Weisz, Giora; Xu, Ke; de Bruyne, Bernard; Serruys, Patrick W; Stone, Gregg W; Maehara, Akiko

2014-01-01

This study investigated coronary artery remodeling patterns associated with clinical outcomes. In the prospective, multicenter PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree: An Imaging Study in Patients With Unstable Atherosclerotic Lesions) study, reported predictors of nonculprit lesion (NCL) major adverse cardiac events (MACE) were an intravascular ultrasound (IVUS) minimal lumen area (MLA) ≤4 mm(2), a plaque burden ≥70%, and a IVUS-virtual histology (VH) thin-cap fibroatheroma (TCFA), but not lesion site remodeling. Overall, 697 consecutive patients with an acute coronary syndrome were enrolled and underwent 3-vessel gray-scale and IVUS-VH; 3,223 NCLs were identified by IVUS. The remodeling index (RI) was calculated as the external elastic membrane area at the MLA site divided by the average of the proximal and distal reference external elastic membrane areas. First, one third of the patients were randomly selected to determine RI cutoffs related to NCL MACE (development cohort). Receiver-operating characteristic analysis showed that there were 2 separate cut points that predicted NCL MACE: RI = 0.8789 and RI = 1.0046 (area under the curve = 0.663). These cut points were used to define negative remodeling as an RI <0.88, intermediate remodeling as an RI of 0.88 to 1.00, and positive remodeling as an RI >1.00. Second, we used the remaining two-thirds of patients to validate these cut points with respect to lesion morphology and clinical outcomes (validation cohort). Kaplan-Meier curve analysis in the validation cohort showed that NCL MACE occurred more frequent (and equally) in negative and positive remodeling lesions compared with intermediate remodeling lesions. In this cohort, negative remodeling lesions had the smallest MLA, positive remodeling lesions had the largest plaque burden, and VH TCFA, especially VH TCFA with multiple necrotic cores, was most common in negatively remodeling lesions. The present study showed the novel concept that positive and negative lesion site remodeling was associated with unanticipated NCL MACE in the PROSPECT study. ( An Imaging Study in Patients With Unstable Atherosclerotic Lesions [PROSPECT]; NCT00180466). Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Clinical inquiries. What test is the best for diagnosing infectious mononucleosis?

PubMed

Bell, Amy Trelease; Fortune, Barbara; Sheeler, Robert

2006-09-01

Tests for antibodies to Epstein-Barr viral capsid antigen or Epstein-Barr nuclear antigen are the most sensitive, are highly specific, and are also the most expensive for diagnosing infectious mononucleosis (strength of recommendation [SOR]: C, based on validating cohort study). Heterophile antibody tests have similar specificity and are cheaper, but are less sensitive in children or in adults during the early days of the illness (SOR: C, based on validating cohort study). The polymerase chain reaction assay for Epstein-Barr virus DNA is more sensitive than the heterophile antibody test in children, is highly specific, but is also expensive (SOR: C, based on validating cohort study). The percentages of atypical lymphocytes and total lymphocytes on a complete blood count provide another specific and moderately sensitive, yet inexpensive, test (SOR: C, based on validating cohort study).

Validation of serum progesterone <35nmol/L as a predictor of miscarriage among women with threatened miscarriage.

PubMed

Lek, Sze Min; Ku, Chee Wai; Allen, John C; Malhotra, Rahul; Tan, Nguan Soon; Østbye, Truls; Tan, Thiam Chye

2017-03-06

Our recent paper, based on a pilot cohort of 119 women, showed that serum progesterone <35 nmol/L was prognostic of spontaneous miscarriage by 16 weeks in women with threatened miscarriage in early pregnancy. Using a larger cohort of women from the same setting (validation cohort), we aim to assess the validity of serum progesterone <35 nmol/L with the outcome of spontaneous miscarriage by 16 weeks. In a prospective cohort study, 360 pregnant women presenting with threatened miscarriage between gestation weeks 6-10 at a tertiary hospital emergency unit for women in Singapore were recruited for this study. The main outcome measure measured is spontaneous miscarriage prior to week 16 of gestation. Area under the ROC curve (AUC) and test characteristics (sensitivity, specificity, positive and negative predictive value) at a serum progesterone cutpoint of <35 nmol/L for predicting high and low risk of spontaneous miscarriage by 16 weeks were compared between the Pilot and Validation cohorts. Test characteristics and AUC values using serum progesterone <35 nmol/L in the validation cohort were not significantly different from those in the Pilot cohort, demonstrating excellent accuracy and reproducibility of the proposed serum progesterone cut-off level. The cut-off value for serum progesterone (35 nmol/L) demonstrated clinical relevance and allow clinicians to stratify patients into high and low risk groups for spontaneous miscarriage.

Validation and Potential Mechanisms of Red Cell Distribution Width as a Prognostic Marker in Heart Failure

PubMed Central

ALLEN, LARRY A.; FELKER, G. MICHAEL; MEHRA, MANDEEP R.; CHIONG, JUN R.; DUNLAP, STEPHANIE H.; GHALI, JALAL K.; LENIHAN, DANIEL J.; OREN, RON M.; WAGONER, LYNNE E.; SCHWARTZ, TODD A.; ADAMS, KIRKWOOD F.

2014-01-01

Background: Adverse outcomes have recently been linked to elevated red cell distribution width (RDW) in heart failure. Our study sought to validate the prognostic value of RDW in heart failure and to explore the potential mechanisms underlying this association. Methods and Results: Data from the Study of Anemia in a Heart Failure Population (STAMINA-HFP) registry, a prospective, multicenter cohort of ambulatory patients with heart failure supported multivariable modeling to assess relationships between RDW and outcomes. The association between RDW and iron metabolism, inflammation, and neurohormonal activation was studied in a separate cohort of heart failure patients from the United Investigators to Evaluate Heart Failure (UNITE-HF) Biomarker registry. RDW was independently predictive of outcome (for each 1% increase in RDW, hazard ratio for mortality 1.06, 95% CI 1.01-1.12; hazard ratio for hospitalization or mortality 1.06; 95% CI 1.02-1.10) after adjustment for other covariates. Increasing RDW correlated with decreasing hemoglobin, increasing interleukin-6, and impaired iron mobilization. Conclusions: Our results confirm previous observations that RDW is a strong, independent predictor of adverse outcome in chronic heart failure and suggest elevated RDW may indicate inflammatory stress and impaired iron mobilization. These findings encourage further research into the relationship between heart failure and the hematologic system. PMID:20206898

Validation and potential mechanisms of red cell distribution width as a prognostic marker in heart failure.

PubMed

Allen, Larry A; Felker, G Michael; Mehra, Mandeep R; Chiong, Jun R; Dunlap, Stephanie H; Ghali, Jalal K; Lenihan, Daniel J; Oren, Ron M; Wagoner, Lynne E; Schwartz, Todd A; Adams, Kirkwood F

2010-03-01

Adverse outcomes have recently been linked to elevated red cell distribution width (RDW) in heart failure. Our study sought to validate the prognostic value of RDW in heart failure and to explore the potential mechanisms underlying this association. Data from the Study of Anemia in a Heart Failure Population (STAMINA-HFP) registry, a prospective, multicenter cohort of ambulatory patients with heart failure supported multivariable modeling to assess relationships between RDW and outcomes. The association between RDW and iron metabolism, inflammation, and neurohormonal activation was studied in a separate cohort of heart failure patients from the United Investigators to Evaluate Heart Failure (UNITE-HF) Biomarker registry. RDW was independently predictive of outcome (for each 1% increase in RDW, hazard ratio for mortality 1.06, 95% CI 1.01-1.12; hazard ratio for hospitalization or mortality 1.06; 95% CI 1.02-1.10) after adjustment for other covariates. Increasing RDW correlated with decreasing hemoglobin, increasing interleukin-6, and impaired iron mobilization. Our results confirm previous observations that RDW is a strong, independent predictor of adverse outcome in chronic heart failure and suggest elevated RDW may indicate inflammatory stress and impaired iron mobilization. These findings encourage further research into the relationship between heart failure and the hematologic system. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Development of a clinical prediction rule for risk stratification of recurrent venous thromboembolism in patients with cancer-associated venous thromboembolism.

PubMed

Louzada, Martha L; Carrier, Marc; Lazo-Langner, Alejandro; Dao, Vi; Kovacs, Michael J; Ramsay, Timothy O; Rodger, Marc A; Zhang, Jerry; Lee, Agnes Y Y; Meyer, Guy; Wells, Philip S

2012-07-24

Long-term low-molecular-weight heparin (LMWH) is the current standard for treatment of venous thromboembolism (VTE) in cancer patients. Whether treatment strategies should vary according to individual risk of VTE recurrence remains unknown. We performed a retrospective cohort study and a validation study in patients with cancer-associated VTE to derive a clinical prediction rule that stratifies VTE recurrence risk. The cohort study of 543 patients determined the model with the best classification performance included 4 independent predictors (sex, primary tumor site, stage, and prior VTE) with 100% sensitivity, a wide separation of recurrence rates, 98.1% negative predictive value, and a negative likelihood ratio of 0.16. In this model, the score sum ranged between -3 and 3 score points. Patients with a score ≤ 0 had low risk (≤ 4.5%) for recurrence and patients with a score >1 had a high risk (≥ 19%) for VTE recurrence. Subsequently, we applied and validated the rule in an independent set of 819 patients from 2 randomized, controlled trials comparing low-molecular-weight heparin to coumarin treatment in cancer patients. By identifying VTE recurrence risk in cancer patients with VTE, we may be able to tailor treatment, improving clinical outcomes while minimizing costs.

Blinded Validation of Breath Biomarkers of Lung Cancer, a Potential Ancillary to Chest CT Screening

PubMed Central

Phillips, Michael; Bauer, Thomas L.; Cataneo, Renee N.; Lebauer, Cassie; Mundada, Mayur; Pass, Harvey I.; Ramakrishna, Naren; Rom, William N.; Vallières, Eric

2015-01-01

Background Breath volatile organic compounds (VOCs) have been reported as biomarkers of lung cancer, but it is not known if biomarkers identified in one group can identify disease in a separate independent cohort. Also, it is not known if combining breath biomarkers with chest CT has the potential to improve the sensitivity and specificity of lung cancer screening. Methods Model-building phase (unblinded): Breath VOCs were analyzed with gas chromatography mass spectrometry in 82 asymptomatic smokers having screening chest CT, 84 symptomatic high-risk subjects with a tissue diagnosis, 100 without a tissue diagnosis, and 35 healthy subjects. Multiple Monte Carlo simulations identified breath VOC mass ions with greater than random diagnostic accuracy for lung cancer, and these were combined in a multivariate predictive algorithm. Model-testing phase (blinded validation): We analyzed breath VOCs in an independent cohort of similar subjects (n = 70, 51, 75 and 19 respectively). The algorithm predicted discriminant function (DF) values in blinded replicate breath VOC samples analyzed independently at two laboratories (A and B). Outcome modeling: We modeled the expected effects of combining breath biomarkers with chest CT on the sensitivity and specificity of lung cancer screening. Results Unblinded model-building phase. The algorithm identified lung cancer with sensitivity 74.0%, specificity 70.7% and C-statistic 0.78. Blinded model-testing phase: The algorithm identified lung cancer at Laboratory A with sensitivity 68.0%, specificity 68.4%, C-statistic 0.71; and at Laboratory B with sensitivity 70.1%, specificity 68.0%, C-statistic 0.70, with linear correlation between replicates (r = 0.88). In a projected outcome model, breath biomarkers increased the sensitivity, specificity, and positive and negative predictive values of chest CT for lung cancer when the tests were combined in series or parallel. Conclusions Breath VOC mass ion biomarkers identified lung cancer in a separate independent cohort, in a blinded replicated study. Combining breath biomarkers with chest CT could potentially improve the sensitivity and specificity of lung cancer screening. Trial Registration ClinicalTrials.gov NCT00639067 PMID:26698306

Reliable Entity Subtyping in Non-small Cell Lung Cancer by Matrix-assisted Laser Desorption/Ionization Imaging Mass Spectrometry on Formalin-fixed Paraffin-embedded Tissue Specimens*

PubMed Central

Kriegsmann, Mark; Casadonte, Rita; Kriegsmann, Jörg; Dienemann, Hendrik; Schirmacher, Peter; Hendrik Kobarg, Jan; Schwamborn, Kristina; Stenzinger, Albrecht; Warth, Arne; Weichert, Wilko

2016-01-01

Histopathological subtyping of non-small cell lung cancer (NSCLC) into adenocarcinoma (ADC), and squamous cell carcinoma (SqCC) is of utmost relevance for treatment stratification. However, current immunohistochemistry (IHC) based typing approaches on biopsies are imperfect, therefore novel analytical methods for reliable subtyping are needed. We analyzed formalin-fixed paraffin-embedded tissue cores of NSCLC by Matrix-assisted laser desorption/ionization (MALDI) imaging on tissue microarrays to identify and validate discriminating MALDI imaging profiles for NSCLC subtyping. 110 ADC and 98 SqCC were used to train a Linear Discriminant Analysis (LDA) model. Results were validated on a separate set of 58 ADC and 60 SqCC. Selected differentially expressed proteins were identified by tandem mass spectrometry and validated by IHC. The LDA classification model incorporated 339 m/z values. In the validation cohort, in 117 cases (99.1%) MALDI classification on tissue cores was in accordance with the pathological diagnosis made on resection specimen. Overall, three cases in the combined cohorts were discordant, after reevaluation two were initially misclassified by pathology whereas one was classified incorrectly by MALDI. Identification of differentially expressed peptides detected well-known IHC discriminators (CK5, CK7), but also less well known differentially expressed proteins (CK15, HSP27). In conclusion, MALDI imaging on NSCLC tissue cores as small biopsy equivalents is capable to discriminate lung ADC and SqCC with a very high accuracy. In addition, replacing multislide IHC by an one-slide MALDI approach may also save tissue for subsequent predictive molecular testing. We therefore advocate to pursue routine diagnostic implementation strategies for MALDI imaging in solid tumor typing. PMID:27473201

Reliable Entity Subtyping in Non-small Cell Lung Cancer by Matrix-assisted Laser Desorption/Ionization Imaging Mass Spectrometry on Formalin-fixed Paraffin-embedded Tissue Specimens.

PubMed

Kriegsmann, Mark; Casadonte, Rita; Kriegsmann, Jörg; Dienemann, Hendrik; Schirmacher, Peter; Hendrik Kobarg, Jan; Schwamborn, Kristina; Stenzinger, Albrecht; Warth, Arne; Weichert, Wilko

2016-10-01

Histopathological subtyping of non-small cell lung cancer (NSCLC) into adenocarcinoma (ADC), and squamous cell carcinoma (SqCC) is of utmost relevance for treatment stratification. However, current immunohistochemistry (IHC) based typing approaches on biopsies are imperfect, therefore novel analytical methods for reliable subtyping are needed. We analyzed formalin-fixed paraffin-embedded tissue cores of NSCLC by Matrix-assisted laser desorption/ionization (MALDI) imaging on tissue microarrays to identify and validate discriminating MALDI imaging profiles for NSCLC subtyping. 110 ADC and 98 SqCC were used to train a Linear Discriminant Analysis (LDA) model. Results were validated on a separate set of 58 ADC and 60 SqCC. Selected differentially expressed proteins were identified by tandem mass spectrometry and validated by IHC. The LDA classification model incorporated 339 m/z values. In the validation cohort, in 117 cases (99.1%) MALDI classification on tissue cores was in accordance with the pathological diagnosis made on resection specimen. Overall, three cases in the combined cohorts were discordant, after reevaluation two were initially misclassified by pathology whereas one was classified incorrectly by MALDI. Identification of differentially expressed peptides detected well-known IHC discriminators (CK5, CK7), but also less well known differentially expressed proteins (CK15, HSP27). In conclusion, MALDI imaging on NSCLC tissue cores as small biopsy equivalents is capable to discriminate lung ADC and SqCC with a very high accuracy. In addition, replacing multislide IHC by an one-slide MALDI approach may also save tissue for subsequent predictive molecular testing. We therefore advocate to pursue routine diagnostic implementation strategies for MALDI imaging in solid tumor typing. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Validation of a Simple Score to Determine Risk of Early Rejection After Pediatric Heart Transplantation.

PubMed

Butts, Ryan J; Savage, Andrew J; Atz, Andrew M; Heal, Elisabeth M; Burnette, Ali L; Kavarana, Minoo M; Bradley, Scott M; Chowdhury, Shahryar M

2015-09-01

This study aimed to develop a reliable and feasible score to assess the risk of rejection in pediatric heart transplantation recipients during the first post-transplant year. The first post-transplant year is the most likely time for rejection to occur in pediatric heart transplantation. Rejection during this period is associated with worse outcomes. The United Network for Organ Sharing database was queried for pediatric patients (age <18 years) who underwent isolated orthotopic heart transplantation from January 1, 2000 to December 31, 2012. Transplantations were divided into a derivation cohort (n = 2,686) and a validation (n = 509) cohort. The validation cohort was randomly selected from 20% of transplantations from 2005 to 2012. Covariates found to be associated with rejection (p < 0.2) were included in the initial multivariable logistic regression model. The final model was derived by including only variables independently associated with rejection. A risk score was then developed using relative magnitudes of the covariates' odds ratio. The score was then tested in the validation cohort. A 9-point risk score using 3 variables (age, cardiac diagnosis, and panel reactive antibody) was developed. Mean score in the derivation and validation cohorts were 4.5 ± 2.6 and 4.8 ± 2.7, respectively. A higher score was associated with an increased rate of rejection (score = 0, 10.6% in the validation cohort vs. score = 9, 40%; p < 0.01). In weighted regression analysis, the model-predicted risk of rejection correlated closely with the actual rates of rejection in the validation cohort (R(2) = 0.86; p < 0.01). The rejection score is accurate in determining the risk of early rejection in pediatric heart transplantation recipients. The score has the potential to be used in clinical practice to aid in determining the immunosuppressant regimen and the frequency of rejection surveillance in the first post-transplant year. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Validation of the CORB75 (confusion, oxygen saturation, respiratory rate, blood pressure, and age ≥ 75 years) as a simpler pneumonia severity rule.

PubMed

Ochoa-Gondar, O; Vila-Corcoles, A; Rodriguez-Blanco, T; Hospital, I; Salsench, E; Ansa, X; Saun, N

2014-04-01

This study compares the ability of two simpler severity rules (classical CRB65 vs. proposed CORB75) in predicting short-term mortality in elderly patients with community-acquired pneumonia (CAP). A population-based study was undertaken involving 610 patients ≥ 65 years old with radiographically confirmed CAP diagnosed between 2008 and 2011 in Tarragona, Spain (350 cases in the derivation cohort, 260 cases in the validation cohort). Severity rules were calculated at the time of diagnosis, and 30-day mortality was considered as the dependent variable. The area under the receiver operating characteristic curves (AUC) was used to compare the discriminative power of the severity rules. Eighty deaths (46 in the derivation and 34 in the validation cohorts) were observed, which gives a mortality rate of 13.1 % (15.6 % for hospitalized and 3.3 % for outpatient cases). After multivariable analyses, besides CRB (confusion, respiration rate ≥ 30/min, systolic blood pressure <90 mmHg or diastolic ≤ 60 mmHg), peripheral oxygen saturation (≤ 90 %) and age ≥ 75 years appeared to be associated with increasing 30-day mortality in the derivation cohort. The model showed adequate calibration for the derivation and validation cohorts. A modified CORB75 scoring system (similar to the classical CRB65, but adding oxygen saturation and increasing the age to 75 years) was constructed. The AUC statistics for predicting mortality in the derivation and validation cohorts were 0.79 and 0.82, respectively. In the derivation cohort, a CORB75 score ≥ 2 showed 78.3 % sensitivity and 65.5 % specificity for mortality (in the validation cohort, these were 82.4 and 71.7 %, respectively). The proposed CORB75 scoring system has good discriminative power in predicting short-term mortality among elderly people with CAP, which supports its use for severity assessment of these patients in primary care.

Developing and validating a novel metabolic tumor volume risk stratification system for supplementing non-small cell lung cancer staging.

PubMed

Pu, Yonglin; Zhang, James X; Liu, Haiyan; Appelbaum, Daniel; Meng, Jianfeng; Penney, Bill C

2018-06-07

We hypothesized that whole-body metabolic tumor volume (MTVwb) could be used to supplement non-small cell lung cancer (NSCLC) staging due to its independent prognostic value. The goal of this study was to develop and validate a novel MTVwb risk stratification system to supplement NSCLC staging. We performed an IRB-approved retrospective review of 935 patients with NSCLC and FDG-avid tumor divided into modeling and validation cohorts based on the type of PET/CT scanner used for imaging. In addition, sensitivity analysis was conducted by dividing the patient population into two randomized cohorts. Cox regression and Kaplan-Meier survival analyses were performed to determine the prognostic value of the MTVwb risk stratification system. The cut-off values (10.0, 53.4 and 155.0 mL) between the MTVwb quartiles of the modeling cohort were applied to both the modeling and validation cohorts to determine each patient's MTVwb risk stratum. The survival analyses showed that a lower MTVwb risk stratum was associated with better overall survival (all p < 0.01), independent of TNM stage together with other clinical prognostic factors, and the discriminatory power of the MTVwb risk stratification system, as measured by Gönen and Heller's concordance index, was not significantly different from that of TNM stage in both cohorts. Also, the prognostic value of the MTVwb risk stratum was robust in the two randomized cohorts. The discordance rate between the MTVwb risk stratum and TNM stage or substage was 45.1% in the modeling cohort and 50.3% in the validation cohort. This study developed and validated a novel MTVwb risk stratification system, which has prognostic value independent of the TNM stage and other clinical prognostic factors in NSCLC, suggesting that it could be used for further NSCLC pretreatment assessment and for refining treatment decisions in individual patients.

Assessing and Refining Myocardial Infarction Risk Estimation among Patients with Human Immunodeficiency Virus

PubMed Central

Feinstein, Matthew J.; Nance, Robin M.; Drozd, Daniel R.; Ning, Hongyan; Delaney, Joseph A.; Heckbert, Susan R.; Budoff, Matthew J.; Mathews, William C.; Kitahata, Mari M.; Saag, Michael S.; Eron, Joseph J.; Moore, Richard D.; Achenbach, Chad J.; Lloyd-Jones, Donald M.; Crane, Heidi M.

2017-01-01

Importance Persons with human immunodeficiency virus (HIV) treated with antiretroviral therapy (ART) have improved longevity but are at elevated risk for myocardial infarction (MI) due to common MI risk factors and HIV-specific factors. Despite these elevated MI rates, optimal methods to predict MI risks for HIV-infected persons remain unclear. Objective To determine the extent to which existing and de novo estimation tools predict MI in a multi-center HIV cohort with rigorous MI adjudication. Design We evaluated the performance of standard-of-care and two new data-derived MI risk estimation models in the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) multi-center prospective clinical cohort. The new risk estimation models were validated in a cohort separate from the derivation cohort. Setting Clinical sites across the U.S. where HIV-infected adults receive medical care in inpatient and outpatient settings. Participants HIV-infected adults receiving care anytime since 1995 at 5 CNICS sites where MIs were adjudicated (N=19829). Exposures Common cardiovascular risk factors, HIV viral load, CD4 count, and medication use were used to calculate predicted event rates. Main Outcome and Measures Observed MI rates over the course of follow-up, scaled to 10 years using an observed prime approach to account for dropout and loss to follow-up prior to 10 years. Results MI rates were higher among blacks, older participants, and participants who were not virally suppressed. The 2013 Pooled Cohort Equations (PCEs), which predict composite rates of MI and stroke, adequately discriminated MI risk (Harrell’s C Statistic = 0.75). Two data-derived models incorporating HIV-specific covariates exhibited weak calibration in a validation sample and did not discriminate risk any better (Harrell’s C Statistic = 0.72 and 0.73) than the PCEs. The PCEs were moderately calibrated in CNICS but predicted consistently lower than observed prime rates of MI. The PCEs Conclusions and relevance The PCEs discriminated MI risk and were moderately calibrated in this multi-center HIV cohort. Adding HIV-specific factors did not improve model performance. As HIV-infected cohorts capture and assess outcomes of MI and stroke, the performance of risk estimation tools should be revisited. PMID:28002550

Prospective Dutch colorectal cancer cohort: an infrastructure for long-term observational, prognostic, predictive and (randomized) intervention research.

PubMed

Burbach, J P M; Kurk, S A; Coebergh van den Braak, R R J; Dik, V K; May, A M; Meijer, G A; Punt, C J A; Vink, G R; Los, M; Hoogerbrugge, N; Huijgens, P C; Ijzermans, J N M; Kuipers, E J; de Noo, M E; Pennings, J P; van der Velden, A M T; Verhoef, C; Siersema, P D; van Oijen, M G H; Verkooijen, H M; Koopman, M

2016-11-01

Systematic evaluation and validation of new prognostic and predictive markers, technologies and interventions for colorectal cancer (CRC) is crucial for optimizing patients' outcomes. With only 5-15% of patients participating in clinical trials, generalizability of results is poor. Moreover, current trials often lack the capacity for post-hoc subgroup analyses. For this purpose, a large observational cohort study, serving as a multiple trial and biobanking facility, was set up by the Dutch Colorectal Cancer Group (DCCG). The Prospective Dutch ColoRectal Cancer cohort is a prospective multidisciplinary nationwide observational cohort study in the Netherlands (yearly CRC incidence of 15 500). All CRC patients (stage I-IV) are eligible for inclusion, and longitudinal clinical data are registered. Patients give separate consent for the collection of blood and tumor tissue, filling out questionnaires, and broad randomization for studies according to the innovative cohort multiple randomized controlled trial design (cmRCT), serving as an alternative study design for the classic RCT. Objectives of the study include: 1) systematically collected long-term clinical data, patient-reported outcomes and biomaterials from daily CRC practice; and 2) to facilitate future basic, translational and clinical research including interventional and cost-effectiveness studies for both national and international research groups with short inclusion periods, even for studies with stringent inclusion criteria. Seven months after initiation 650 patients have been enrolled, eight centers participate, 15 centers await IRB approval and nine embedded cohort- or cmRCT-designed studies are currently recruiting patients. This cohort provides a unique multidisciplinary data, biobank, and patient-reported outcomes collection initiative, serving as an infrastructure for various kinds of research aiming to improve treatment outcomes in CRC patients. This comprehensive design may serve as an example for other tumor types.

Conditional Disease Development extracted from Longitudinal Health Care Cohort Data using Layered Network Construction

PubMed Central

Kannan, Venkateshan; Swartz, Fredrik; Kiani, Narsis A.; Silberberg, Gilad; Tsipras, Giorgos; Gomez-Cabrero, David; Alexanderson, Kristina; Tegnèr, Jesper

2016-01-01

Health care data holds great promise to be used in clinical decision support systems. However, frequent near-synonymous diagnoses recorded separately, as well as the sheer magnitude and complexity of the disease data makes it challenging to extract non-trivial conclusions beyond confirmatory associations from such a web of interactions. Here we present a systematic methodology to derive statistically valid conditional development of diseases. To this end we utilize a cohort of 5,512,469 individuals followed over 13 years at inpatient care, including data on disability pension and cause of death. By introducing a causal information fraction measure and taking advantage of the composite structure in the ICD codes, we extract an effective directed lower dimensional network representation (100 nodes and 130 edges) of our cohort. Unpacking composite nodes into bipartite graphs retrieves, for example, that individuals with behavioral disorders are more likely to be followed by prescription drug poisoning episodes, whereas women with leiomyoma were more likely to subsequently experience endometriosis. The conditional disease development represent putative causal relations, indicating possible novel clinical relationships and pathophysiological associations that have not been explored yet. PMID:27211115

Conditional Disease Development extracted from Longitudinal Health Care Cohort Data using Layered Network Construction.

PubMed

Kannan, Venkateshan; Swartz, Fredrik; Kiani, Narsis A; Silberberg, Gilad; Tsipras, Giorgos; Gomez-Cabrero, David; Alexanderson, Kristina; Tegnèr, Jesper

2016-05-23

Health care data holds great promise to be used in clinical decision support systems. However, frequent near-synonymous diagnoses recorded separately, as well as the sheer magnitude and complexity of the disease data makes it challenging to extract non-trivial conclusions beyond confirmatory associations from such a web of interactions. Here we present a systematic methodology to derive statistically valid conditional development of diseases. To this end we utilize a cohort of 5,512,469 individuals followed over 13 years at inpatient care, including data on disability pension and cause of death. By introducing a causal information fraction measure and taking advantage of the composite structure in the ICD codes, we extract an effective directed lower dimensional network representation (100 nodes and 130 edges) of our cohort. Unpacking composite nodes into bipartite graphs retrieves, for example, that individuals with behavioral disorders are more likely to be followed by prescription drug poisoning episodes, whereas women with leiomyoma were more likely to subsequently experience endometriosis. The conditional disease development represent putative causal relations, indicating possible novel clinical relationships and pathophysiological associations that have not been explored yet.

Predictive validity of the personal qualities assessment for selection of medical students in Scotland.

PubMed

Dowell, Jon; Lumsden, Mary Ann; Powis, David; Munro, Don; Bore, Miles; Makubate, Boikanyo; Kumwenda, Ben

2011-01-01

The Personal Qualities Assessment (PQA) was developed to enhance medical student selection by measuring a range of non-cognitive attributes in the applicants to medical school. Applicants to the five Scottish medical schools were invited to pilot the test in 2001 and 2002. To evaluate the predictive validity of PQA for selecting medical students. A longitudinal cohort study was conducted in which PQA scores were compared with senior year medical school performance. Consent to access performance markers was obtained from 626 students (61.6% of 1017 entrants in 2002-2003). Linkable Foundation Year (4th) rankings were available for 411 (66%) students and objective structured clinical examination (OSCE) rankings for 335 (54%) of those consenting. Both samples were representative of the original cohort. No significant correlations were detected between separate elements of the PQA assessment and student performance. However, using the algorithm advocated by Powis et al. those defined as 'non-extreme' (<±1.5 SD from the cohort mean scores; SD, standard deviation) character types on the involved-detached and on the libertarian-communitarian moral orientation scales were ranked higher in OSCEs (average of 7.5% or 25 out of 335, p = 0.049). This study was limited by high attrition and basic outcome markers which are insensitive to relevant non-cognitive characteristics. However, it is the largest currently available study of predictive validity for the PQA assessment. There was one finding of significance: that those students who were identified by PQA as 'not extreme' on the two personal characteristics scales performed better in an OSCE measure of professionalism. Futures studies are required since psychometric testing for both cognitive and non-cognitive attributes are increasingly used in admission process and these should include more and better measures of professionalism against which to correlate non-cognitive traits.

Amyotrophic lateral sclerosis outcome measures and the role of albumin and creatinine: a population-based study.

PubMed

Chiò, Adriano; Calvo, Andrea; Bovio, Giacomo; Canosa, Antonio; Bertuzzo, Davide; Galmozzi, Francesco; Cugnasco, Paolo; Clerico, Marinella; De Mercanti, Stefania; Bersano, Enrica; Cammarosano, Stefania; Ilardi, Antonio; Manera, Umberto; Moglia, Cristina; Sideri, Riccardo; Marinou, Kalliopi; Bottacchi, Edo; Pisano, Fabrizio; Cantello, Roberto; Mazzini, Letizia; Mora, Gabriele

2014-09-01

There is an urgent need to identify reliable biomarkers of amyotrophic lateral sclerosis (ALS) progression for clinical practice and pharmacological trials. To correlate several hematological markers evaluated at diagnosis with ALS outcome in a population-based series of patients (discovery cohort) and replicate the findings in an independent validation cohort from an ALS tertiary center. The discovery cohort included 712 patients with ALS from the Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis from January 1, 2007, to December 31, 2011. The validation cohort comprised 122 patients with ALS at different stages of disease consecutively seen at an ALS tertiary center between January 1, 2007, and January 1, 2009. The following hematological factors were investigated and correlated with survival: total leukocytes, neutrophils, lymphocytes, monocytes, glucose, creatinine, uric acid, albumin, bilirubin, total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, creatine kinase, thyroid-stimulating hormones, and erythrocyte sedimentation rate; all analyses were performed separately by sex. The patient of the validation cohort also underwent bioelectrical impedance analysis for the calculation of fat-free mass. Of the 712 patients in the examined period in Piemonte and Valle d'Aosta, 638 (89.6%) were included in the study. Only serum albumin (men: ≤ 4.3 vs >4.3 mg/dL, P < .001; women: ≤ 4.3 vs >4.3 mg/dL, P < .001) and creatinine levels (men: ≤ 0.82 vs >0.82 mg/dL, P = .004; women: ≤ 0.65 vs >0.05 mg/dL, P = .004) and lymphocyte count (men: ≤ 1700 vs >1700/μL, P = .04; women: ≤ 1700 vs >1700/μL, P = .02) were significantly associated with ALS outcome in both sexes with a dose-response effect (better survival with increasing levels). These findings were confirmed in the validation cohort. Multivariable analysis showed that serum albumin (men: hazard ratio [HR], 1.39; 95% CI, 1.05-1.90; P = .02; women: HR, 1.73; 95 % CI, 1.35-2.39; P = .001) and creatinine (men: HR, 1.47; 95% CI, 1.11-1.95; P = .007; women: HR, 1.49; 95% CI, 1.07-2.05; P = .02) were independent predictors of survival in both sexes; no other hematological factor was retained in the model. In patients with ALS, serum albumin was correlated with markers of inflammatory state while serum creatinine was correlated with fat-free mass, which is a marker of muscle mass. In ALS, serum albumin and creatinine are independent markers of outcome in both sexes. Creatinine reflects the muscle waste whereas albumin is connected with inflammatory state. Both creatinine and albumin are reliable markers of the severity of clinical status in patients with ALS and can be used in defining prognosis at the time of diagnosis.

A Severe Sepsis Mortality Prediction Model and Score for Use with Administrative Data

PubMed Central

Ford, Dee W.; Goodwin, Andrew J.; Simpson, Annie N.; Johnson, Emily; Nadig, Nandita; Simpson, Kit N.

2016-01-01

Objective Administrative data is used for research, quality improvement, and health policy in severe sepsis. However, there is not a sepsis-specific tool applicable to administrative data with which to adjust for illness severity. Our objective was to develop, internally validate, and externally validate a severe sepsis mortality prediction model and associated mortality prediction score. Design Retrospective cohort study using 2012 administrative data from five US states. Three cohorts of patients with severe sepsis were created: 1) ICD-9-CM codes for severe sepsis/septic shock, 2) ‘Martin’ approach, and 3) ‘Angus’ approach. The model was developed and internally validated in ICD-9-CM cohort and externally validated in other cohorts. Integer point values for each predictor variable were generated to create a sepsis severity score. Setting Acute care, non-federal hospitals in NY, MD, FL, MI, and WA Subjects Patients in one of three severe sepsis cohorts: 1) explicitly coded (n=108,448), 2) Martin cohort (n=139,094), and 3) Angus cohort (n=523,637) Interventions None Measurements and Main Results Maximum likelihood estimation logistic regression to develop a predictive model for in-hospital mortality. Model calibration and discrimination assessed via Hosmer-Lemeshow goodness-of-fit (GOF) and C-statistics respectively. Primary cohort subset into risk deciles and observed versus predicted mortality plotted. GOF demonstrated p>0.05 for each cohort demonstrating sound calibration. C-statistic ranged from low of 0.709 (sepsis severity score) to high of 0.838 (Angus cohort) suggesting good to excellent model discrimination. Comparison of observed versus expected mortality was robust although accuracy decreased in highest risk decile. Conclusions Our sepsis severity model and score is a tool that provides reliable risk adjustment for administrative data. PMID:26496452

Sex-Specific Associations between Particulate Matter Exposure and Gene Expression in Independent Discovery and Validation Cohorts of Middle-Aged Men and Women.

PubMed

Vrijens, Karen; Winckelmans, Ellen; Tsamou, Maria; Baeyens, Willy; De Boever, Patrick; Jennen, Danyel; de Kok, Theo M; Den Hond, Elly; Lefebvre, Wouter; Plusquin, Michelle; Reynders, Hans; Schoeters, Greet; Van Larebeke, Nicolas; Vanpoucke, Charlotte; Kleinjans, Jos; Nawrot, Tim S

2017-04-01

Particulate matter (PM) exposure leads to premature death, mainly due to respiratory and cardiovascular diseases. Identification of transcriptomic biomarkers of air pollution exposure and effect in a healthy adult population. Microarray analyses were performed in 98 healthy volunteers (48 men, 50 women). The expression of eight sex-specific candidate biomarker genes (significantly associated with PM 10 in the discovery cohort and with a reported link to air pollution-related disease) was measured with qPCR in an independent validation cohort (75 men, 94 women). Pathway analysis was performed using Gene Set Enrichment Analysis. Average daily PM 2.5 and PM 10 exposures over 2-years were estimated for each participant's residential address using spatiotemporal interpolation in combination with a dispersion model. Average long-term PM 10 was 25.9 (± 5.4) and 23.7 (± 2.3) μg/m 3 in the discovery and validation cohorts, respectively. In discovery analysis, associations between PM 10 and the expression of individual genes differed by sex. In the validation cohort, long-term PM 10 was associated with the expression of DNAJB5 and EAPP in men and ARHGAP4 ( p = 0.053) in women. AKAP6 and LIMK1 were significantly associated with PM 10 in women, although associations differed in direction between the discovery and validation cohorts. Expression of the eight candidate genes in the discovery cohort differentiated between validation cohort participants with high versus low PM 10 exposure (area under the receiver operating curve = 0.92; 95% CI: 0.85, 1.00; p = 0.0002 in men, 0.86; 95% CI: 0.76, 0.96; p = 0.004 in women). Expression of the sex-specific candidate genes identified in the discovery population predicted PM 10 exposure in an independent cohort of adults from the same area. Confirmation in other populations may further support this as a new approach for exposure assessment, and may contribute to the discovery of molecular mechanisms for PM-induced health effects.

Development and initial cohort validation of the Arthritis Research UK Musculoskeletal Health Questionnaire (MSK-HQ) for use across musculoskeletal care pathways

PubMed Central

Hill, Jonathan C; Kang, Sujin; Benedetto, Elena; Myers, Helen; Blackburn, Steven; Smith, Stephanie; Hay, Elaine; Rees, Jonathan; Beard, David; Glyn-Jones, Sion; Barker, Karen; Ellis, Benjamin; Fitzpatrick, Ray; Price, Andrew

2016-01-01

Objectives Current musculoskeletal outcome tools are fragmented across different healthcare settings and conditions. Our objectives were to develop and validate a single musculoskeletal outcome measure for use throughout the pathway and patients with different musculoskeletal conditions: the Arthritis Research UK Musculoskeletal Health Questionnaire (MSK-HQ). Setting A consensus workshop with stakeholders from across the musculoskeletal community, workshops and individual interviews with a broad mix of musculoskeletal patients identified and prioritised outcomes for MSK-HQ inclusion. Initial psychometric validation was conducted in four cohorts from community physiotherapy, and secondary care orthopaedic hip, knee and shoulder clinics. Participants Stakeholders (n=29) included primary care, physiotherapy, orthopaedic and rheumatology patients (n=8); general practitioners, physiotherapists, orthopaedists, rheumatologists and pain specialists (n=7), patient and professional national body representatives (n=10), and researchers (n=4). The four validation cohorts included 570 participants (n=210 physiotherapy, n=150 hip, n=150 knee, n=60 shoulder patients). Outcome measures Outcomes included the MSK-HQ's acceptability, feasibility, comprehension, readability and responder burden. The validation cohort outcomes were the MSK-HQ's completion rate, test–retest reliability and convergent validity with reference standards (EQ-5D-5L, Oxford Hip, Knee, Shoulder Scores, and the Keele MSK-PROM). Results Musculoskeletal domains prioritised were pain severity, physical function, work interference, social interference, sleep, fatigue, emotional health, physical activity, independence, understanding, confidence to self-manage and overall impact. Patients reported MSK-HQ items to be ‘highly relevant’ and ‘easy to understand’. Completion rates were high (94.2%), with scores normally distributed, and no floor/ceiling effects. Test–retest reliability was excellent, and convergent validity was strong (correlations 0.81–0.88). Conclusions A new musculoskeletal outcome measure has been developed through a coproduction process with patients to capture prioritised outcomes for use throughout the pathway and with different musculoskeletal conditions. Four validation cohorts found that the MSK-HQ had high completion rates, excellent test–retest reliability and strong convergent validity with reference standards. Further validation studies are ongoing, including a cohort with rheumatoid/inflammatory arthritis. PMID:27496243

Quantitative analysis of normal tissue effects in the clinic (QUANTEC) guideline validation using quality of life questionnaire datasets for parotid gland constraints to avoid causing xerostomia during head-and-neck radiotherapy.

PubMed

Lee, Tsair-Fwu; Fang, Fu-Min

2013-03-01

To perform a validation test of the quantitative analysis of normal tissue effects in the clinic (QUANTEC) guidelines against quality of life (QoL) questionnaire datasets collected prospectively from patients with head and neck (HN) cancers, including HN squamous cell carcinoma (HNSCC) and nasopharyngeal carcinoma (NPC). QoL questionnaire datasets from 95 patients with NPC and 142 with HNSCC were analyzed separately. The European Organization for Research and Treatment of Cancer H&N35 QoL questionnaire was used as the endpoint evaluation. The primary endpoint (grade 3(+) xerostomia) was defined as moderate to severe xerostomia 3 and 12 months after the completion of RT, and excluded patients with grade 3(+) xerostomia at the baseline. The Lyman-Kutcher-Burman normal tissue complication probability (NTCP) model was used to describe the incidence of xerostomia. Negative predictive values (NPVs) were used to determine the rate of correctly predicting the lack of complications. NTCP fitted parameters were TD₅₀=37.8 Gy (CI: 29.1-46.9 Gy), m=0.59 (CI: 0.48-0.80) and TD50=43.9 Gy (CI: 33.2-52.8 Gy), m=0.48 (CI: 0.37-0.76) at the 3-month and 12-month time points, respectively. For QUANTEC validation, HN and HNSCC data validation gave similar results at 3 months; at mean doses to the spared parotid of ≤20 and ≤25 Gy, the QoL dataset showed approximately 22% and 28% rates of xerostomia, respectively. At 12 months, the rates of xerostomia were approximately 13% and 19%, respectively. For NPC cases, the dataset showed approximately 0% and 33% (∼67% NPV) rates of xerostomia at 3 months. At 12 months, both rates of xerostomia were approximately 0% (∼100% NPV), which differed significantly from the results for the HNSCC cohort. The QoL datasets validated the QUANTEC guidelines and suggested that the modified QUANTEC 20/20-Gy spared-gland guideline is suitable for clinical use in HNSCC cohorts to effectively avoid xerostomia, and the QUANTEC 25-Gy guideline is justified for NPC cohorts. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Risk Prediction of New Adjacent Vertebral Fractures After PVP for Patients with Vertebral Compression Fractures: Development of a Prediction Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhong, Bin-Yan; He, Shi-Cheng; Zhu, Hai-Dong

PurposeWe aim to determine the predictors of new adjacent vertebral fractures (AVCFs) after percutaneous vertebroplasty (PVP) in patients with osteoporotic vertebral compression fractures (OVCFs) and to construct a risk prediction score to estimate a 2-year new AVCF risk-by-risk factor condition.Materials and MethodsPatients with OVCFs who underwent their first PVP between December 2006 and December 2013 at Hospital A (training cohort) and Hospital B (validation cohort) were included in this study. In training cohort, we assessed the independent risk predictors and developed the probability of new adjacent OVCFs (PNAV) score system using the Cox proportional hazard regression analysis. The accuracy ofmore » this system was then validated in both training and validation cohorts by concordance (c) statistic.Results421 patients (training cohort: n = 256; validation cohort: n = 165) were included in this study. In training cohort, new AVCFs after the first PVP treatment occurred in 33 (12.9%) patients. The independent risk factors were intradiscal cement leakage and preexisting old vertebral compression fracture(s). The estimated 2-year absolute risk of new AVCFs ranged from less than 4% in patients with neither independent risk factors to more than 45% in individuals with both factors.ConclusionsThe PNAV score is an objective and easy approach to predict the risk of new AVCFs.« less

Validating Dimensions of Psychosis Symptomatology: Neural Correlates and 20-year Outcomes

PubMed Central

Kotov, Roman; Foti, Dan; Li, Kaiqiao; Bromet, Evelyn J.; Hajcak, Greg; Ruggero, Camilo J.

2016-01-01

Heterogeneity of psychosis presents significant challenges for classification. Between two and 12 symptom dimensions have been proposed, and consensus is lacking. The present study sought to identify uniquely informative models by comparing the validity of these alternatives. An epidemiologic cohort of 628 first-admission inpatients with psychosis was interviewed 6 times over two decades and completed an electrophysiological assessment of error processing at year 20. We first analyzed a comprehensive set of 49 symptoms rated by interviewers at baseline, progressively extracting from one to 12 factors. Next, we compared the ability of resulting factor solutions to (a) account for concurrent neural dysfunction and (b) predict 20-year role, social, residential, and global functioning, and life satisfaction. A four-factor model showed incremental validity with all outcomes, and more complex models did not improve explanatory power. The four dimensions—reality distortion, disorganization, inexpressivity, and apathy/asociality—were replicable in 5 follow-ups, internally consistent, stable across assessments, and showed strong discriminant validity. These results reaffirm the value of separating disorganization and reality distortion, are consistent with recent findings distinguishing inexpressivity and apathy/asociality, and suggest that these four dimensions are fundamental to understanding neural abnormalities and long-term outcomes in psychosis. PMID:27819471

Validation of the prognostic gene portfolio, ClinicoMolecular Triad Classification, using an independent prospective breast cancer cohort and external patient populations

PubMed Central

2014-01-01

Introduction Using genome-wide expression profiles of a prospective training cohort of breast cancer patients, ClinicoMolecular Triad Classification (CMTC) was recently developed to classify breast cancers into three clinically relevant groups to aid treatment decisions. CMTC was found to be both prognostic and predictive in a large external breast cancer cohort in that study. This study serves to validate the reproducibility of CMTC and its prognostic value using independent patient cohorts. Methods An independent internal cohort (n = 284) and a new external cohort (n = 2,181) were used to validate the association of CMTC between clinicopathological factors, 12 known gene signatures, two molecular subtype classifiers, and 19 oncogenic signalling pathway activities, and to reproduce the abilities of CMTC to predict clinical outcomes of breast cancer. In addition, we also updated the outcome data of the original training cohort (n = 147). Results The original training cohort reached a statistically significant difference (p < 0.05) in disease-free survivals between the three CMTC groups after an additional two years of follow-up (median = 55 months). The prognostic value of the triad classification was reproduced in the second independent internal cohort and the new external validation cohort. CMTC achieved even higher prognostic significance when all available patients were analyzed (n = 4,851). Oncogenic pathways Myc, E2F1, Ras and β-catenin were again implicated in the high-risk groups. Conclusions Both prospective internal cohorts and the independent external cohorts reproduced the triad classification of CMTC and its prognostic significance. CMTC is an independent prognostic predictor, and it outperformed 12 other known prognostic gene signatures, molecular subtype classifications, and all other standard prognostic clinicopathological factors. Our results support further development of CMTC portfolio into a guide for personalized breast cancer treatments. PMID:24996446

Gender Differences of Children's Developmental Trajectory from 6 to 60 Months in the Taiwan Birth Cohort Pilot Study

ERIC Educational Resources Information Center

Lung, For-Wey; Chiang, Tung-Liang; Lin, Shio-Jean; Feng, Jui-Ying; Chen, Po-Fei; Shu, Bih-Ching

2011-01-01

The parental report instrument is the most efficient developmental detection method and has shown high validity with professional assessment instruments. The reliability and validity of the Taiwan Birth Cohort Study (TBCS) 6-, 18- and 36-month scales have already been established. In this study, the reliability and validity of the 60-month scale…

Sex-Specific Associations between Particulate Matter Exposure and Gene Expression in Independent Discovery and Validation Cohorts of Middle-Aged Men and Women

PubMed Central

Vrijens, Karen; Winckelmans, Ellen; Tsamou, Maria; Baeyens, Willy; De Boever, Patrick; Jennen, Danyel; de Kok, Theo M.; Den Hond, Elly; Lefebvre, Wouter; Plusquin, Michelle; Reynders, Hans; Schoeters, Greet; Van Larebeke, Nicolas; Vanpoucke, Charlotte; Kleinjans, Jos; Nawrot, Tim S.

2016-01-01

Background: Particulate matter (PM) exposure leads to premature death, mainly due to respiratory and cardiovascular diseases. Objectives: Identification of transcriptomic biomarkers of air pollution exposure and effect in a healthy adult population. Methods: Microarray analyses were performed in 98 healthy volunteers (48 men, 50 women). The expression of eight sex-specific candidate biomarker genes (significantly associated with PM10 in the discovery cohort and with a reported link to air pollution-related disease) was measured with qPCR in an independent validation cohort (75 men, 94 women). Pathway analysis was performed using Gene Set Enrichment Analysis. Average daily PM2.5 and PM10 exposures over 2-years were estimated for each participant’s residential address using spatiotemporal interpolation in combination with a dispersion model. Results: Average long-term PM10 was 25.9 (± 5.4) and 23.7 (± 2.3) μg/m3 in the discovery and validation cohorts, respectively. In discovery analysis, associations between PM10 and the expression of individual genes differed by sex. In the validation cohort, long-term PM10 was associated with the expression of DNAJB5 and EAPP in men and ARHGAP4 (p = 0.053) in women. AKAP6 and LIMK1 were significantly associated with PM10 in women, although associations differed in direction between the discovery and validation cohorts. Expression of the eight candidate genes in the discovery cohort differentiated between validation cohort participants with high versus low PM10 exposure (area under the receiver operating curve = 0.92; 95% CI: 0.85, 1.00; p = 0.0002 in men, 0.86; 95% CI: 0.76, 0.96; p = 0.004 in women). Conclusions: Expression of the sex-specific candidate genes identified in the discovery population predicted PM10 exposure in an independent cohort of adults from the same area. Confirmation in other populations may further support this as a new approach for exposure assessment, and may contribute to the discovery of molecular mechanisms for PM-induced health effects. Citation: Vrijens K, Winckelmans E, Tsamou M, Baeyens W, De Boever P, Jennen D, de Kok TM, Den Hond E, Lefebvre W, Plusquin M, Reynders H, Schoeters G, Van Larebeke N, Vanpoucke C, Kleinjans J, Nawrot TS. 2017. Sex-specific associations between particulate matter exposure and gene expression in independent discovery and validation cohorts of middle-aged men and women. Environ Health Perspect 125:660–669; http://dx.doi.org/10.1289/EHP370 PMID:27740511

Consequences of an Extended Recruitment on Participation in the Follow-Up of a Child Study: Results from the German IDEFICS Cohort.

PubMed

Langeheine, Malte; Pohlabeln, Hermann; Ahrens, Wolfgang; Rach, Stefan

2017-01-01

Declining response proportions in population-based studies are often countered by extended recruitment efforts at baseline that may, however, result in higher attrition in a subsequent follow-up. This study analysed the effect of extended recruitment efforts on attrition at the first follow-up of a child cohort. We used paradata (i.e. information about the process of data collection) from the German IDEFICS cohort investigating dietary- and life style-induced health effects on children to quantify recruitment effort and classify respondents as completing the recruitment early vs. late for baseline and follow-up separately. Multilevel logistic regression models were used to investigate the association between recruitment effort and attrition at follow-up (loss to follow-up) adjusted for sociodemographic and health related variables. Individuals who were late respondents at baseline and early respondents at the follow-up had a higher chance of attrition (odds ratio 1.65, 95% confidence interval (CI) 1.19, 2.28) as compared to other groups. An investigation of reasons for non-participation revealed that members of this group were more likely to be not reachable by phone. An extended recruitment effort at baseline of a child cohort study is not per se associated with a higher chance of attrition at follow-up. Much care should be taken to collect valid telephone numbers. © 2016 John Wiley & Sons Ltd.

Criteria for the validity of clinical trials of treatments of cohorts of cancer patients based on the Hardin Jones principle.

PubMed Central

Pauling, L; Herman, Z S

1989-01-01

With the assumption of the validity of the Hardin Jones principle that the death rate of members of a homogeneous cohort of cancer patients is constant, three criteria for the validity of clinical trials of cancer treatments are formulated. These criteria are satisfied by most published clinical trials, but one trial was found to violate all three, rendering the validity of its reported results uncertain. PMID:2780542

Blood-based protein biomarkers for diagnosis of Alzheimer disease.

PubMed

Doecke, James D; Laws, Simon M; Faux, Noel G; Wilson, William; Burnham, Samantha C; Lam, Chiou-Peng; Mondal, Alinda; Bedo, Justin; Bush, Ashley I; Brown, Belinda; De Ruyck, Karl; Ellis, Kathryn A; Fowler, Christopher; Gupta, Veer B; Head, Richard; Macaulay, S Lance; Pertile, Kelly; Rowe, Christopher C; Rembach, Alan; Rodrigues, Mark; Rumble, Rebecca; Szoeke, Cassandra; Taddei, Kevin; Taddei, Tania; Trounson, Brett; Ames, David; Masters, Colin L; Martins, Ralph N

2012-10-01

To identify plasma biomarkers for the diagnosis of Alzheimer disease (AD). Baseline plasma screening of 151 multiplexed analytes combined with targeted biomarker and clinical pathology data. General community-based, prospective, longitudinal study of aging. A total of 754 healthy individuals serving as controls and 207 participants with AD from the Australian Imaging Biomarker and Lifestyle study (AIBL) cohort with identified biomarkers that were validated in 58 healthy controls and 112 individuals with AD from the Alzheimer Disease Neuroimaging Initiative (ADNI) cohort. A biomarker panel was identified that included markers significantly increased (cortisol, pancreatic polypeptide, insulinlike growth factor binding protein 2, β(2) microglobulin, vascular cell adhesion molecule 1, carcinoembryonic antigen, matrix metalloprotein 2, CD40, macrophage inflammatory protein 1α, superoxide dismutase, and homocysteine) and decreased (apolipoprotein E, epidermal growth factor receptor, hemoglobin, calcium, zinc, interleukin 17, and albumin) in AD. Cross-validated accuracy measures from the AIBL cohort reached a mean (SD) of 85% (3.0%) for sensitivity and specificity and 93% (3.0) for the area under the receiver operating characteristic curve. A second validation using the ADNI cohort attained accuracy measures of 80% (3.0%) for sensitivity and specificity and 85% (3.0) for area under the receiver operating characteristic curve. This study identified a panel of plasma biomarkers that distinguish individuals with AD from cognitively healthy control subjects with high sensitivity and specificity. Cross-validation within the AIBL cohort and further validation within the ADNI cohort provides strong evidence that the identified biomarkers are important for AD diagnosis.

Preliminary appraisal of the reliability and validity of the Colorado State University Feline Acute Pain Scale.

PubMed

Shipley, Hilary; Guedes, Alonso; Graham, Lynelle; Goudie-DeAngelis, Elizabeth; Wendt-Hornickle, Erin

2018-05-01

Objectives The objective of this study was to determine the inter-rater reliability and convergent validity of the Colorado State University Feline Acute Pain Scale (CSU-FAPS) in a preliminary appraisal of its performance in a clinical teaching setting. Methods Sixty-eight female cats were assessed for pain after ovariohysterectomy. A cohort of 21 cats was examined independently by four raters (two board-certified anesthesiologists and two anesthesia residents) with the CSU-FAPS, and intra-class correlation coefficient (ICC) was used to determine inter-rater reliability. Weighted Cohen's kappa was used to determine inter-rater reliability centered on the 'need to reassess analgesic plan' (dichotomous scale). A separate cohort of 47 cats was evaluated independently by two raters (one board-certified anesthesiologist and one veterinary small animal rotating intern) using the CSU-FAPS and the Glasgow Composite Measure Pain Scale (CMPS-Feline), and Spearman rank-order correlation was determined to assess convergent validity. Reliability was interpreted using Altman's classification as very good, good, moderate, fair and poor. Validity was considered adequate if correlation coefficients were between 0.4 and 0.8. Results The ICC was 0.61 for anesthesiologists and 0.67 for residents, indicating good reliability. Weighted Cohen's kappa was 0.79 for anesthesiologists and 0.44 for residents, indicating moderate to good reliability. The Spearman rank correlation indicated a statistically significant ( P = 0.0003) positive correlation (0.31; 95% confidence interval 0.14-0.46) between the CSU-FAPS and the CMPS-Feline. Conclusions and relevance The CSU-FAPS showed moderate-to-good inter-rater reliability when used by veterinarians to assess pain level or need to reassess analgesic plan after ovariohysterectomy in cats. The validity fell short of current guidelines for correlation coefficients and further refinement and testing are warranted to improve its performance.

Electroencephalography as a clinical tool for diagnosing and monitoring attention deficit hyperactivity disorder: a cross-sectional study

PubMed Central

Helgadóttir, Halla; Gudmundsson, Ólafur Ó; Baldursson, Gísli; Magnússon, Páll; Blin, Nicolas; Brynjólfsdóttir, Berglind; Emilsdóttir, Ásdís; Gudmundsdóttir, Gudrún B; Lorange, Málfrídur; Newman, Paula K; Jóhannesson, Gísli H; Johnsen, Kristinn

2015-01-01

Objectives The aim of this study was to develop and test, for the first time, a multivariate diagnostic classifier of attention deficit hyperactivity disorder (ADHD) based on EEG coherence measures and chronological age. Setting The participants were recruited in two specialised centres and three schools in Reykjavik. Participants The data are from a large cross-sectional cohort of 310 patients with ADHD and 351 controls, covering an age range from 5.8 to 14 years. ADHD was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM-IV) criteria using the K-SADS-PL semistructured interview. Participants in the control group were reported to be free of any mental or developmental disorders by their parents and had a score of less than 1.5 SDs above the age-appropriate norm on the ADHD Rating Scale-IV. Other than moderate or severe intellectual disability, no additional exclusion criteria were applied in order that the cohort reflected the typical cross section of patients with ADHD. Results Diagnostic classifiers were developed using statistical pattern recognition for the entire age range and for specific age ranges and were tested using cross-validation and by application to a separate cohort of recordings not used in the development process. The age-specific classification approach was more accurate (76% accuracy in the independent test cohort; 81% cross-validation accuracy) than the age-independent version (76%; 73%). Chronological age was found to be an important classification feature. Conclusions The novel application of EEG-based classification methods presented here can offer significant benefit to the clinician by improving both the accuracy of initial diagnosis and ongoing monitoring of children and adolescents with ADHD. The most accurate possible diagnosis at a single point in time can be obtained by the age-specific classifiers, but the age-independent classifiers are also useful as they enable longitudinal monitoring of brain function. PMID:25596195

Pretreatment levels of the fatty acid handling proteins H-FABP and CD36 predict response to olanzapine in recent-onset schizophrenia patients.

PubMed

Tomasik, Jakub; Schwarz, Emanuel; Lago, Santiago G; Rothermundt, Matthias; Leweke, F Markus; van Beveren, Nico J M; Guest, Paul C; Rahmoune, Hassan; Steiner, Johann; Bahn, Sabine

2016-02-01

Traditional schizophrenia pharmacotherapy remains a subjective trial and error process involving administration, titration and switching of drugs multiple times until an adequate response is achieved. Despite this time-consuming and costly process, not all patients show an adequate response to treatment. As a consequence, relapse is a common occurrence and early intervention is hampered. Here, we have attempted to identify candidate blood biomarkers associated with drug response in 121 initially antipsychotic-free recent-onset schizophrenia patients treated with widely-used antipsychotics, namely olanzapine (n=40), quetiapine (n=23), risperidone (n=30) and a mixture of these drugs (n=28). Patients were recruited and investigated as two separate cohorts to allow biomarker validation. Data analysis showed the most significant relationship between pre-treatment levels of heart-type fatty acid binding protein (H-FABP) and response to olanzapine (p=0.008, F=8.6, β=70.4 in the discovery cohort and p=0.003, F=15.2, β=24.4 in the validation cohort, adjusted for relevant confounding variables). In a functional follow-up analysis of this finding, we tested an independent cohort of 10 patients treated with olanzapine and found that baseline levels of plasma H-FABP and expression of the binding partner for H-FABP, fatty acid translocase (CD36), on monocytes predicted the reduction of psychotic symptoms (p=0.040, F=6.0, β=116.3 and p=0.012, F=11.9, β=-0.0054, respectively). We also identified a set of serum molecules changed after treatment with antipsychotic medication, in particular olanzapine. These molecules are predominantly involved in cellular development and metabolism. Taken together, our findings suggest an association between biomarkers involved in fatty acid metabolism and response to olanzapine, while other proteins may serve as surrogate markers associated with drug efficacy and side effects. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Development of Decision Support Formulas for the Prediction of Bladder Outlet Obstruction and Prostatic Surgery in Patients With Lower Urinary Tract Symptom/Benign Prostatic Hyperplasia: Part II, External Validation and Usability Testing of a Smartphone App.

PubMed

Choo, Min Soo; Jeong, Seong Jin; Cho, Sung Yong; Yoo, Changwon; Jeong, Chang Wook; Ku, Ja Hyeon; Oh, Seung-June

2017-04-01

We aimed to externally validate the prediction model we developed for having bladder outlet obstruction (BOO) and requiring prostatic surgery using 2 independent data sets from tertiary referral centers, and also aimed to validate a mobile app for using this model through usability testing. Formulas and nomograms predicting whether a subject has BOO and needs prostatic surgery were validated with an external validation cohort from Seoul National University Bundang Hospital and Seoul Metropolitan Government-Seoul National University Boramae Medical Center between January 2004 and April 2015. A smartphone-based app was developed, and 8 young urologists were enrolled for usability testing to identify any human factor issues of the app. A total of 642 patients were included in the external validation cohort. No significant differences were found in the baseline characteristics of major parameters between the original (n=1,179) and the external validation cohort, except for the maximal flow rate. Predictions of requiring prostatic surgery in the validation cohort showed a sensitivity of 80.6%, a specificity of 73.2%, a positive predictive value of 49.7%, and a negative predictive value of 92.0%, and area under receiver operating curve of 0.84. The calibration plot indicated that the predictions have good correspondence. The decision curve showed also a high net benefit. Similar evaluation results using the external validation cohort were seen in the predictions of having BOO. Overall results of the usability test demonstrated that the app was user-friendly with no major human factor issues. External validation of these newly developed a prediction model demonstrated a moderate level of discrimination, adequate calibration, and high net benefit gains for predicting both having BOO and requiring prostatic surgery. Also a smartphone app implementing the prediction model was user-friendly with no major human factor issue.

Development and validation of the Surgical Outcome Risk Tool (SORT)

PubMed Central

Protopapa, K L; Simpson, J C; Smith, N C E; Moonesinghe, S R

2014-01-01

Background Existing risk stratification tools have limitations and clinical experience suggests they are not used routinely. The aim of this study was to develop and validate a preoperative risk stratification tool to predict 30-day mortality after non-cardiac surgery in adults by analysis of data from the observational National Confidential Enquiry into Patient Outcome and Death (NCEPOD) Knowing the Risk study. Methods The data set was split into derivation and validation cohorts. Logistic regression was used to construct a model in the derivation cohort to create the Surgical Outcome Risk Tool (SORT), which was tested in the validation cohort. Results Prospective data for 19 097 cases in 326 hospitals were obtained from the NCEPOD study. Following exclusion of 2309, details of 16 788 patients were analysed (derivation cohort 11 219, validation cohort 5569). A model of 45 risk factors was refined on repeated regression analyses to develop a model comprising six variables: American Society of Anesthesiologists Physical Status (ASA-PS) grade, urgency of surgery (expedited, urgent, immediate), high-risk surgical specialty (gastrointestinal, thoracic, vascular), surgical severity (from minor to complex major), cancer and age 65 years or over. In the validation cohort, the SORT was well calibrated and demonstrated better discrimination than the ASA-PS and Surgical Risk Scale; areas under the receiver operating characteristic (ROC) curve were 0·91 (95 per cent c.i. 0·88 to 0·94), 0·87 (0·84 to 0·91) and 0·88 (0·84 to 0·92) respectively (P < 0·001). Conclusion The SORT allows rapid and simple data entry of six preoperative variables, and provides a percentage mortality risk for individuals undergoing surgery. PMID:25388883

Comparison of in vivo binding properties of the 18-kDa translocator protein (TSPO) ligands [(18)F]PBR102 and [ (18)F]PBR111 in a model of excitotoxin-induced neuroinflammation.

PubMed

Callaghan, P D; Wimberley, C A; Rahardjo, G L; Berghofer, P J; Pham, T Q; Jackson, T; Zahra, D; Bourdier, T; Wyatt, N; Greguric, I; Howell, N R; Siegele, R; Pastuovic, Z; Mattner, F; Loc'h, C; Gregoire, M C; Katsifis, A

2015-01-01

The in vivo binding parameters of the novel imidazopyridine TSPO ligand [(18)F]PBR102 were assessed and compared with those of [(18)F]PBR111 in a rodent model of neuroinflammation. The validity of the key assumptions of the simplified reference tissue model (SRTM) for estimation of binding potential (BP) was determined, with validation against a two-tissue compartment model (2TC). Acute neuroinflammation was assessed 7 days after unilateral stereotaxic administration of (R,S)-α-amino-3-hydroxy-5-methyl-4-isoxazolopropionique (AMPA) in anaesthetized adult Wistar rats. Anaesthetized rats were implanted with a femoral arterial cannula then injected with a low mass of [(18)F]PBR102 or [(18)F]PBR111 and dynamic images were acquired over 60 min using an INVEON PET/CT camera. Another population of rats underwent the same PET protocol after pretreatment with a presaturating mass of the same unlabelled tracer (1 mg/kg) to assess the validity of the reference region for SRTM analysis. Arterial blood was sampled during imaging, allowing pharmacokinetic determination of radiotracer concentrations. Plasma activity concentration-time curves were corrected for unchanged tracer based on metabolic characterization experiments in a separate cohort of Wistar rats. The stability of neuroinflammation in both imaging cohorts was assessed by [(125)I] CLINDE TSPO quantitative autoradiography, OX42/GFAP immunohistochemistry, Fluoro-Jade C histology, and elemental mapping using microparticle-induced x-ray emission spectroscopy. The BP of each ligand were assessed in the two cohorts of lesioned animals using both SRTM and a 2TC with arterial parent compound concentration, coupled with the results from the presaturation cohort for comparison and validation of the SRTM. The BPs of [(18)F]PBR102 [(18)F]PBR111 were equivalent, with improved signal-to-noise ratio and sensitivity compared with [(11)C]PK11195. The presaturation study showed differences in the volume of distribution between the ipsilateral striatum and the striatum contralateral to the injury (0.7) indicating that an assumption of the SRTM was not met. The modelling indicated that the BPs were consistent for both ligands. Between the SRTM and 2TC model, the BPs were highly correlated, but there was a bias in BP. [(18)F]PBR102 and [(18)F]PBR111 have equivalent binding properties in vivo, displaying significantly greater BPs with lower signal-to-noise ratio than [(11)C]PK11195. While an assumption of the SRTM was not met, this modelling approach was validated against 2TC modelling for both ligands, facilitating future use in longitudinal PET imaging of neuroinflammation.

A universal definition of ARDS: the PaO2/FiO2 ratio under a standard ventilatory setting--a prospective, multicenter validation study.

PubMed

Villar, Jesús; Pérez-Méndez, Lina; Blanco, Jesús; Añón, José Manuel; Blanch, Lluís; Belda, Javier; Santos-Bouza, Antonio; Fernández, Rosa Lidia; Kacmarek, Robert M

2013-04-01

The PaO2/FiO2 is an integral part of the assessment of patients with acute respiratory distress syndrome (ARDS). The American-European Consensus Conference definition does not mandate any standardization procedure. We hypothesized that the use of PaO2/FiO2 calculated under a standard ventilatory setting within 24 h of ARDS diagnosis allows a more clinically relevant ARDS classification. We studied 452 ARDS patients enrolled prospectively in two independent, multicenter cohorts treated with protective mechanical ventilation. At the time of ARDS diagnosis, patients had a PaO2/FiO2 ≤ 200. In the derivation cohort (n = 170), we measured PaO2/FiO2 with two levels of positive end-expiratory pressure (PEEP) (≥ 5 and ≥ 10 cmH2O) and two levels of FiO2 (≥ 0.5 and 1.0) at ARDS onset and 24 h later. Dependent upon PaO2 response, patients were reclassified into three groups: mild (PaO2/FiO2 > 200), moderate (PaO2/FiO2 101-200), and severe (PaO2/FiO2 ≤ 100) ARDS. The primary outcome measure was ICU mortality. The standard ventilatory setting that reached the highest significance difference in mortality among these categories was tested in a separate cohort (n = 282). The only standard ventilatory setting that identified the three PaO2/FiO2 risk categories in the derivation cohort was PEEP ≥ 10 cmH2O and FiO2 ≥ 0.5 at 24 h after ARDS onset (p = 0.0001). Using this ventilatory setting, patients in the validation cohort were reclassified as having mild ARDS (n = 47, mortality 17 %), moderate ARDS (n = 149, mortality 40.9 %), and severe ARDS (n = 86, mortality 58.1 %) (p = 0.00001). Our method for assessing PaO2/FiO2 greatly improved risk stratification of ARDS and could be used for enrolling appropriate ARDS patients into therapeutic clinical trials.

A novel thyroid function index associated with opposite therapeutic outcomes in advanced hepatocellular carcinoma patients receiving chemotherapy or sorafenib.

PubMed

Chu, Yu-De; Lin, Kwang-Huei; Huang, Ya-Hui; Lin, Chen-Chun; Hung, Chien-Fu; Yeh, Ta-Sen; Lee, Wei-Chen; Yeh, Chau-Ting

2018-05-21

A sustained proportion of advanced hepatocellular carcinoma (HCC) patients worldwide received either chemotherapy or sorafenib. However, to date, effective and convenient biomarkers to predict their therapeutic outcomes remained elusive. Hypothyroidism was associated with favorable anticancer treatment outcomes in several advanced cancers. Here, we aimed to investigate the potential of using thyroid-stimulating hormone (TSH) and free T4 (FT4) levels as biomarkers to predict clinical outcomes in HCC patients receiving chemotherapy or sorafenib. Total 123 advanced HCC patients at Barcelona Clinical Liver Cancer Stage C were included. They were separated into two cohorts, one treated by sorafenib (n = 62) and the other by chemotherapy (n = 61). Clinical data including TSH and FT4 were retrieved and correlated with treatment outcomes. Because of restriction in local insurance policy, the baseline liver function reserve was better in patients receiving sorafenib. Therefore, the two cohorts were analyzed separately. The results showed that a higher (> median) TSH × FT4 value was independently associated with favorable time-to-tumor progression (P = 0.006) and overall survival (P = 0.002) if chemotherapy was provided; whereas it was associated with unfavorable time-to-tumor progression (P = 0.017) and overall survival (P = 0.001) if sorafenib was administrated. These opposite associations remained valid when patients with Child-Pugh class A liver function from either cohort were included for analysis. A novel thyroid function index, TSH × FT4, significantly predicted opposite clinical outcomes in advanced HCC patients receiving sorafenib or chemotherapy treatment. © 2018 John Wiley & Sons Australia, Ltd.

Immunogenicity and reactogenicity of the human rotavirus vaccine, RIX4414 oral suspension, when co-administered with routine childhood vaccines in Chinese infants.

PubMed

Li, Rong-Cheng; Huang, Teng; Li, Yanping; Wang, Lao-Hong; Tao, Junhui; Fu, Botao; Si, Guoai; Nong, Yi; Mo, Zhaojun; Liao, XueYan; Luan, Ivy; Tang, Haiwen; Rathi, Niraj; Karkada, Naveen; Han, Htay Htay

2016-03-03

This study evaluated the immunogenicity of the human rotavirus (RV) vaccine (RIX4414) when co-administered with routine childhood vaccines in Chinese infants (NCT01171963). Healthy infants aged 6-16 weeks received 2 doses of either RIX4414 or placebo according to a 0, 1-month schedule. Infants received routine diphtheria-tetanus-acellular pertussis (DTPa) and oral poliovirus (OPV) vaccines either separately from or concomitantly with RIX4414/placebo (separate and co-administration cohorts, respectively). Anti-RV IgA seroconversion rates (one month post-dose-2) and seropositivity rates (at one year of age) were measured using ELISA. Immune responses against the DTPa and OPV antigens were measured one month post-DTPa dose-3 in the co-administration cohort. Solicited local and general symptoms were recorded for 8-days post-vaccination (total cohort). The according-to-protocol immunogenicity population included 511 infants in the separate cohort and 275 in the co-administration cohort. One month post-RIX4414 dose-2, anti-RV IgA seroconversion rates were 74.7% (95% confidence interval [CI]: 68.9-79.9) and 64.2% (95% CI: 55.4-72.3) in the separate and co-administration cohorts; seropositivity rates at one year of age were 71.5% (95% CI: 65.5-77.1) and 50.0% (95% CI: 40.9-59.1), respectively. One month post-DTPa dose-3, all infants in the co-administration cohort were seroprotected against diphtheria and tetanus, and seropositive for pertussis toxoid, pertactin and filamentous haemaglutinin. Two months post-OPV dose-3, seroprotection rates against anti-poliovirus types 1, 2 and 3 were >99% in the co-administration cohort. Reactogenicity profiles were similar in both cohorts. RIX4414 was immunogenic and well-tolerated in Chinese infants and did not appear to interfere with the immunogenicity and reactogenicity of co-administered routine childhood vaccines.

Immunogenicity and reactogenicity of the human rotavirus vaccine, RIX4414 oral suspension, when co-administered with routine childhood vaccines in Chinese infants

PubMed Central

Li, Rong-cheng; Huang, Teng; Li, Yanping; Wang, Lao-Hong; Tao, Junhui; Fu, Botao; Si, Guoai; Nong, Yi; Mo, Zhaojun; Liao, XueYan; Luan, Ivy; Tang, Haiwen; Rathi, Niraj; Karkada, Naveen; Han, Htay Htay

2016-01-01

Abstract This study evaluated the immunogenicity of the human rotavirus (RV) vaccine (RIX4414) when co-administered with routine childhood vaccines in Chinese infants (NCT01171963). Healthy infants aged 6–16 weeks received 2 doses of either RIX4414 or placebo according to a 0, 1-month schedule. Infants received routine diphtheria-tetanus-acellular pertussis (DTPa) and oral poliovirus (OPV) vaccines either separately from or concomitantly with RIX4414/placebo (separate and co-administration cohorts, respectively). Anti-RV IgA seroconversion rates (one month post-dose-2) and seropositivity rates (at one year of age) were measured using ELISA. Immune responses against the DTPa and OPV antigens were measured one month post-DTPa dose-3 in the co-administration cohort. Solicited local and general symptoms were recorded for 8-days post-vaccination (total cohort). The according-to-protocol immunogenicity population included 511 infants in the separate cohort and 275 in the co-administration cohort. One month post-RIX4414 dose-2, anti-RV IgA seroconversion rates were 74.7% (95% confidence interval [CI]: 68.9–79.9) and 64.2% (95% CI: 55.4–72.3) in the separate and co-administration cohorts; seropositivity rates at one year of age were 71.5% (95% CI: 65.5–77.1) and 50.0% (95% CI: 40.9–59.1), respectively. One month post-DTPa dose-3, all infants in the co-administration cohort were seroprotected against diphtheria and tetanus, and seropositive for pertussis toxoid, pertactin and filamentous haemaglutinin. Two months post-OPV dose-3, seroprotection rates against anti-poliovirus types 1, 2 and 3 were >99% in the co-administration cohort. Reactogenicity profiles were similar in both cohorts. RIX4414 was immunogenic and well-tolerated in Chinese infants and did not appear to interfere with the immunogenicity and reactogenicity of co-administered routine childhood vaccines. PMID:27149266

Internal validation of the prognostic index for spine metastasis (PRISM) for stratifying survival in patients treated with spinal stereotactic radiosurgery.

PubMed

Jensen, Garrett; Tang, Chad; Hess, Kenneth R; Bishop, Andrew J; Pan, Hubert Y; Li, Jing; Yang, James N; Tannir, Nizar M; Amini, Behrang; Tatsui, Claudio; Rhines, Laurence; Brown, Paul D; Ghia, Amol J

2017-01-01

We sought to validate the Prognostic Index for Spinal Metastases (PRISM), a scoring system that stratifies patients into subgroups by overall survival.Methods and materials: The PRISM was previously created from multivariate Cox regression with patients enrolled in prospective single institution trials of stereotactic spine radiosurgery (SSRS) for spinal metastasis. We assess model calibration and discrimination within a validation cohort of patients treated off-trial with SSRS for metastatic disease at the same institution. The training and validation cohorts consisted of 205 and 249 patients respectively. Similar survival trends were shown in the 4 PRISM. Survival was significantly different between PRISM subgroups (P<0.0001). C-index for the validation cohort was 0.68 after stratification into subgroups. We internally validated the PRISM with patients treated off-protocol, demonstrating that it can distinguish subgroups by survival, which will be useful for individualizing treatment of spinal metastases and stratifying patients for clinical trials.

Using Laboratory Test Results at Hospital Admission to Predict Short-term Survival in Critically Ill Patients With Metastatic or Advanced Cancer.

PubMed

Cheng, Lee; DeJesus, Alma Y; Rodriguez, Maria A

2017-04-01

Accurately estimating the life expectancy of critically ill patients with metastatic or advanced cancer is a crucial step in planning appropriate palliative or supportive care. We evaluated the results of laboratory tests performed within two days of hospital admission to predict the likelihood of death within 14 days. We retrospectively selected patients 18 years or older with metastatic or advanced cancer who were admitted to intensive care units or palliative and supportive care services in our hospital. We evaluated whether the following are independent predictors in a logistic regression model: age, sex, comorbidities, and the results of seven commonly available laboratory tests. The end point was death within 14 days in or out of the hospital. Of 901 patients in the development cohort and 45% died within 14 days. The risk of death within 14 days after admission increased with increasing age, lactate dehydrogenase levels, and white blood cell counts and decreasing albumin levels and platelet counts (P < 0.01). The model predictions were confirmed using a separate validation cohort. The areas under the receiver operating characteristic curves were 0.74 and 0.70 for the development and validation cohorts, respectively, indicating good discriminatory ability for the model. Our results suggest that laboratory test results performed within two days of admission are valuable in predicting death within 14 days for patients with metastatic or advanced cancer. Such results may provide an objective assessment tool for physicians and help them initiate conversations with patients and families about end-of-life care. Copyright © 2017 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Mutational landscape of gastric adenocarcinoma in Chinese: implications for prognosis and therapy.

PubMed

Chen, Kexin; Yang, Da; Li, Xiangchun; Sun, Baocun; Song, Fengju; Cao, Wenfeng; Brat, Daniel J; Gao, Zhibo; Li, Haixin; Liang, Han; Zhao, Yanrui; Zheng, Hong; Li, Miao; Buckner, Jan; Patterson, Scott D; Ye, Xiang; Reinhard, Christoph; Bhathena, Anahita; Joshi, Deepa; Mischel, Paul S; Croce, Carlo M; Wang, Yi Michael; Raghavakaimal, Sreekumar; Li, Hui; Lu, Xin; Pan, Yang; Chang, Han; Ba, Sujuan; Luo, Longhai; Cavenee, Webster K; Zhang, Wei; Hao, Xishan

2015-01-27

Gastric cancer (GC) is a highly heterogeneous disease. To identify potential clinically actionable therapeutic targets that may inform individualized treatment strategies, we performed whole-exome sequencing on 78 GCs of differing histologies and anatomic locations, as well as whole-genome sequencing on two GC cases, each with three primary tumors and two matching lymph node metastases. The data showed two distinct GC subtypes with either high-clonality (HiC) or low-clonality (LoC). The HiC subtype of intratumoral heterogeneity was associated with older age, TP53 (tumor protein P53) mutation, enriched C > G transition, and significantly shorter survival, whereas the LoC subtype was associated with younger age, ARID1A (AT rich interactive domain 1A) mutation, and significantly longer survival. Phylogenetic tree analysis of whole-genome sequencing data from multiple samples of two patients supported the clonal evolution of GC metastasis and revealed the accumulation of genetic defects that necessitate combination therapeutics. The most recurrently mutated genes, which were validated in a separate cohort of 216 cases by targeted sequencing, were members of the homologous recombination DNA repair, Wnt, and PI3K-ERBB pathways. Notably, the drugable NRG1 (neuregulin-1) and ERBB4 (V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 4) ligand-receptor pair were mutated in 10% of GC cases. Mutations of the BRCA2 (breast cancer 2, early onset) gene, found in 8% of our cohort and validated in The Cancer Genome Atlas GC cohort, were associated with significantly longer survivals. These data define distinct clinicogenetic forms of GC in the Chinese population that are characterized by specific mutation sets that can be investigated for efficacy of single and combination therapies.

Validation of a patient-level medication regimen complexity index as a possible tool to identify patients for medication therapy management intervention.

PubMed

Hirsch, Jan D; Metz, Kelli R; Hosokawa, Patrick W; Libby, Anne M

2014-08-01

The Medication Regimen Complexity Index (MRCI) is a 65-item instrument that can be used to quantify medication regimen complexity at the patient level, capturing all prescribed and over-the-counter medications. Although the MRCI has been used in several studies, the narrow scope of the initial validation limits application at a population or clinical practice level. To conduct a MRCI validation pertinent to the desired clinical use to identify patients for medication therapy management interventions. An expert panel of clinical pharmacists ranked medication regimen complexity for two samples of cases: a single-disease cohort (diabetes mellitus) and a multiple-disease cohort (diabetes mellitus, hypertension, human immunodeficiency virus infection, geriatric depression). Cases for expert panel review were selected from 400 ambulatory clinic patients, and each case description included data that were available via claims or electronic medical records (EMRs). Construct validity was assessed using patient-level MRCI scores, medication count, and additional patient data. Concordance was evaluated using weighted κ agreement statistic, and correlations were determined using Spearman rank-order correlation coefficient (ρ) or Kendall τ. Moderate to good concordance between patient-level MRCI scores and expert medication regimen complexity ranking was observed (claims data, consensus ranking: single-disease cohort 0.55, multiple disease cohort 0.63). In contrast, only fair to moderate concordance was observed for medication count (single-disease cohort 0.33, multiple-disease cohort 0.48). Adding more-detailed administration directions from EMR data did not improve concordance. MRCI convergent validity was supported by strong correlations with medication count (all cohorts 0.90) and moderate correlations with morbidity measures (e.g., all cohorts; number of comorbidities 0.46, Chronic Disease Score 0.46). Nonsignificant correlation of MRCI scores with age and gender (all cohorts 0.08 and 0.06, respectively) supported MRCI divergent validity. This study used cross-sectional, retrospective patient data for a small number of patients and clinical pharmacists from only two universities; therefore, results may have limited generalizability. The patient-level MRCI is a valid tool for assessing medication regimen complexity that can be applied by using data commonly found in claims and EMR databases and could be useful to identify patients who may benefit from medication therapy management. © 2014 The Authors Pharmacotherapy published by Wiley Periodicals, Inc. on behalf of Pharmacotherapy Publications, Inc.

Independent validation of a new reirradiation risk score (RRRS) for glioma patients predicting post-recurrence survival: A multicenter DKTK/ROG analysis.

PubMed

Niyazi, Maximilian; Adeberg, Sebastian; Kaul, David; Boulesteix, Anne-Laure; Bougatf, Nina; Fleischmann, Daniel F; Grün, Arne; Krämer, Anna; Rödel, Claus; Eckert, Franziska; Paulsen, Frank; Kessel, Kerstin A; Combs, Stephanie E; Oehlke, Oliver; Grosu, Anca-Ligia; Seidlitz, Annekatrin; Lattermann, Annika; Krause, Mechthild; Baumann, Michael; Guberina, Maja; Stuschke, Martin; Budach, Volker; Belka, Claus; Debus, Jürgen

2018-04-01

Reirradiation (reRT) is a valid option with considerable efficacy in patients with recurrent high-grade glioma, but it is still not known which patients might be optimal candidates for a second course of irradiation. This study validated a newly developed prognostic score independently in an external patient cohort. The reRT risk score (RRRS) is based on a linear combination of initial histology, clinical performance status, and age derived from a multivariable model of 353 patients. This score can predict post-recurrence survival (PRS) after reRT. The validation dataset consisted of 212 patients. The RRRS differentiates three prognostic groups. Discrimination and calibration were maintained in the validation group. Median PRS times in the development cohort for the good/intermediate/poor risk categories were 14.2, 9.1, and 5.3 months, respectively. The respective groups within the validation cohort displayed median PRS times of 13.8, 8.8, and 3.8 months, respectively. Uno's C for development data was 0.64 (CI: 0.60-0.69) and for validation data 0.63 (CI: 0.58-0.68). The RRRS has been successfully validated in an independent patient cohort. This linear combination of three easily determined clinicopathological factors allows for a reliable classification of patients and may be used as stratification factor for future trials. Copyright © 2018 Elsevier B.V. All rights reserved.

Potential serum biomarkers from a metabolomics study of autism

PubMed Central

Wang, Han; Liang, Shuang; Wang, Maoqing; Gao, Jingquan; Sun, Caihong; Wang, Jia; Xia, Wei; Wu, Shiying; Sumner, Susan J.; Zhang, Fengyu; Sun, Changhao; Wu, Lijie

2016-01-01

Background Early detection and diagnosis are very important for autism. Current diagnosis of autism relies mainly on some observational questionnaires and interview tools that may involve a great variability. We performed a metabolomics analysis of serum to identify potential biomarkers for the early diagnosis and clinical evaluation of autism. Methods We analyzed a discovery cohort of patients with autism and participants without autism in the Chinese Han population using ultra-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UPLC/Q-TOF MS/MS) to detect metabolic changes in serum associated with autism. The potential metabolite candidates for biomarkers were individually validated in an additional independent cohort of cases and controls. We built a multiple logistic regression model to evaluate the validated biomarkers. Results We included 73 patients and 63 controls in the discovery cohort and 100 cases and 100 controls in the validation cohort. Metabolomic analysis of serum in the discovery stage identified 17 metabolites, 11 of which were validated in an independent cohort. A multiple logistic regression model built on the 11 validated metabolites fit well in both cohorts. The model consistently showed that autism was associated with 2 particular metabolites: sphingosine 1-phosphate and docosahexaenoic acid. Limitations While autism is diagnosed predominantly in boys, we were unable to perform the analysis by sex owing to difficulty recruiting enough female patients. Other limitations include the need to perform test–retest assessment within the same individual and the relatively small sample size. Conclusion Two metabolites have potential as biomarkers for the clinical diagnosis and evaluation of autism. PMID:26395811

Leveraging biospecimen resources for discovery or validation of markers for early cancer detection.

PubMed

Schully, Sheri D; Carrick, Danielle M; Mechanic, Leah E; Srivastava, Sudhir; Anderson, Garnet L; Baron, John A; Berg, Christine D; Cullen, Jennifer; Diamandis, Eleftherios P; Doria-Rose, V Paul; Goddard, Katrina A B; Hankinson, Susan E; Kushi, Lawrence H; Larson, Eric B; McShane, Lisa M; Schilsky, Richard L; Shak, Steven; Skates, Steven J; Urban, Nicole; Kramer, Barnett S; Khoury, Muin J; Ransohoff, David F

2015-04-01

Validation of early detection cancer biomarkers has proven to be disappointing when initial promising claims have often not been reproducible in diagnostic samples or did not extend to prediagnostic samples. The previously reported lack of rigorous internal validity (systematic differences between compared groups) and external validity (lack of generalizability beyond compared groups) may be effectively addressed by utilizing blood specimens and data collected within well-conducted cohort studies. Cohort studies with prediagnostic specimens (eg, blood specimens collected prior to development of clinical symptoms) and clinical data have recently been used to assess the validity of some early detection biomarkers. With this background, the Division of Cancer Control and Population Sciences (DCCPS) and the Division of Cancer Prevention (DCP) of the National Cancer Institute (NCI) held a joint workshop in August 2013. The goal was to advance early detection cancer research by considering how the infrastructure of cohort studies that already exist or are being developed might be leveraged to include appropriate blood specimens, including prediagnostic specimens, ideally collected at periodic intervals, along with clinical data about symptom status and cancer diagnosis. Three overarching recommendations emerged from the discussions: 1) facilitate sharing of existing specimens and data, 2) encourage collaboration among scientists developing biomarkers and those conducting observational cohort studies or managing healthcare systems with cohorts followed over time, and 3) conduct pilot projects that identify and address key logistic and feasibility issues regarding how appropriate specimens and clinical data might be collected at reasonable effort and cost within existing or future cohorts. © Published by Oxford University Press 2015.

Leveraging Biospecimen Resources for Discovery or Validation of Markers for Early Cancer Detection

PubMed Central

Carrick, Danielle M.; Mechanic, Leah E.; Srivastava, Sudhir; Anderson, Garnet L.; Baron, John A.; Berg, Christine D.; Cullen, Jennifer; Diamandis, Eleftherios P.; Doria-Rose, V. Paul; Goddard, Katrina A. B.; Hankinson, Susan E.; Kushi, Lawrence H.; Larson, Eric B.; McShane, Lisa M.; Schilsky, Richard L.; Shak, Steven; Skates, Steven J.; Urban, Nicole; Kramer, Barnett S.; Khoury, Muin J.; Ransohoff, David F.

2015-01-01

Validation of early detection cancer biomarkers has proven to be disappointing when initial promising claims have often not been reproducible in diagnostic samples or did not extend to prediagnostic samples. The previously reported lack of rigorous internal validity (systematic differences between compared groups) and external validity (lack of generalizability beyond compared groups) may be effectively addressed by utilizing blood specimens and data collected within well-conducted cohort studies. Cohort studies with prediagnostic specimens (eg, blood specimens collected prior to development of clinical symptoms) and clinical data have recently been used to assess the validity of some early detection biomarkers. With this background, the Division of Cancer Control and Population Sciences (DCCPS) and the Division of Cancer Prevention (DCP) of the National Cancer Institute (NCI) held a joint workshop in August 2013. The goal was to advance early detection cancer research by considering how the infrastructure of cohort studies that already exist or are being developed might be leveraged to include appropriate blood specimens, including prediagnostic specimens, ideally collected at periodic intervals, along with clinical data about symptom status and cancer diagnosis. Three overarching recommendations emerged from the discussions: 1) facilitate sharing of existing specimens and data, 2) encourage collaboration among scientists developing biomarkers and those conducting observational cohort studies or managing healthcare systems with cohorts followed over time, and 3) conduct pilot projects that identify and address key logistic and feasibility issues regarding how appropriate specimens and clinical data might be collected at reasonable effort and cost within existing or future cohorts. PMID:25688116

Thrombomodulin gene variants are associated with increased mortality after coronary artery bypass surgery in replicated analyses.

PubMed

Lobato, Robert L; White, William D; Mathew, Joseph P; Newman, Mark F; Smith, Peter K; McCants, Charles B; Alexander, John H; Podgoreanu, Mihai V

2011-09-13

We tested the hypothesis that genetic variation in thrombotic and inflammatory pathways is independently associated with long-term mortality after coronary artery bypass graft (CABG) surgery. Two separate cohorts of patients undergoing CABG surgery at a single institution were examined, and all-cause mortality between 30 days and 5 years after the index CABG was ascertained from the National Death Index. In a discovery cohort of 1018 patients, a panel of 90 single-nucleotide polymorphisms (SNPs) in 49 candidate genes was tested with Cox proportional hazard models to identify clinical and genomic multivariate predictors of incident death. After adjustment for multiple comparisons and clinical predictors of mortality, the homozygote minor allele of a common variant in the thrombomodulin (THBD) gene (rs1042579) was independently associated with significantly increased risk of all-cause mortality (hazard ratio, 2.26; 95% CI, 1.31 to 3.92; P=0.003). Six tag SNPs in the THBD gene, 1 of which (rs3176123) in complete linkage disequilibrium with rs1042579, were then assessed in an independent validation cohort of 930 patients. After multivariate adjustment for the clinical predictors identified in the discovery cohort and multiple testing, the homozygote minor allele of rs3176123 independently predicted all-cause mortality (hazard ratio, 3.6; 95% CI, 1.67 to 7.78; P=0.001). In 2 independent cardiac surgery cohorts, linked common allelic variants in the THBD gene are independently associated with increased long-term mortality risk after CABG and significantly improve the classification ability of traditional postoperative mortality prediction models.

Risk score to predict gastrointestinal bleeding after acute ischemic stroke.

PubMed

Ji, Ruijun; Shen, Haipeng; Pan, Yuesong; Wang, Penglian; Liu, Gaifen; Wang, Yilong; Li, Hao; Singhal, Aneesh B; Wang, Yongjun

2014-07-25

Gastrointestinal bleeding (GIB) is a common and often serious complication after stroke. Although several risk factors for post-stroke GIB have been identified, no reliable or validated scoring system is currently available to predict GIB after acute stroke in routine clinical practice or clinical trials. In the present study, we aimed to develop and validate a risk model (acute ischemic stroke associated gastrointestinal bleeding score, the AIS-GIB score) to predict in-hospital GIB after acute ischemic stroke. The AIS-GIB score was developed from data in the China National Stroke Registry (CNSR). Eligible patients in the CNSR were randomly divided into derivation (60%) and internal validation (40%) cohorts. External validation was performed using data from the prospective Chinese Intracranial Atherosclerosis Study (CICAS). Independent predictors of in-hospital GIB were obtained using multivariable logistic regression in the derivation cohort, and β-coefficients were used to generate point scoring system for the AIS-GIB. The area under the receiver operating characteristic curve (AUROC) and the Hosmer-Lemeshow goodness-of-fit test were used to assess model discrimination and calibration, respectively. A total of 8,820, 5,882, and 2,938 patients were enrolled in the derivation, internal validation and external validation cohorts. The overall in-hospital GIB after AIS was 2.6%, 2.3%, and 1.5% in the derivation, internal, and external validation cohort, respectively. An 18-point AIS-GIB score was developed from the set of independent predictors of GIB including age, gender, history of hypertension, hepatic cirrhosis, peptic ulcer or previous GIB, pre-stroke dependence, admission National Institutes of Health stroke scale score, Glasgow Coma Scale score and stroke subtype (Oxfordshire). The AIS-GIB score showed good discrimination in the derivation (0.79; 95% CI, 0.764-0.825), internal (0.78; 95% CI, 0.74-0.82) and external (0.76; 95% CI, 0.71-0.82) validation cohorts. The AIS-GIB score was well calibrated in the derivation (P = 0.42), internal (P = 0.45) and external (P = 0.86) validation cohorts. The AIS-GIB score is a valid clinical grading scale to predict in-hospital GIB after AIS. Further studies on the effect of the AIS-GIB score on reducing GIB and improving outcome after AIS are warranted.

Development and initial cohort validation of the Arthritis Research UK Musculoskeletal Health Questionnaire (MSK-HQ) for use across musculoskeletal care pathways.

PubMed

Hill, Jonathan C; Kang, Sujin; Benedetto, Elena; Myers, Helen; Blackburn, Steven; Smith, Stephanie; Dunn, Kate M; Hay, Elaine; Rees, Jonathan; Beard, David; Glyn-Jones, Sion; Barker, Karen; Ellis, Benjamin; Fitzpatrick, Ray; Price, Andrew

2016-08-05

Current musculoskeletal outcome tools are fragmented across different healthcare settings and conditions. Our objectives were to develop and validate a single musculoskeletal outcome measure for use throughout the pathway and patients with different musculoskeletal conditions: the Arthritis Research UK Musculoskeletal Health Questionnaire (MSK-HQ). A consensus workshop with stakeholders from across the musculoskeletal community, workshops and individual interviews with a broad mix of musculoskeletal patients identified and prioritised outcomes for MSK-HQ inclusion. Initial psychometric validation was conducted in four cohorts from community physiotherapy, and secondary care orthopaedic hip, knee and shoulder clinics. Stakeholders (n=29) included primary care, physiotherapy, orthopaedic and rheumatology patients (n=8); general practitioners, physiotherapists, orthopaedists, rheumatologists and pain specialists (n=7), patient and professional national body representatives (n=10), and researchers (n=4). The four validation cohorts included 570 participants (n=210 physiotherapy, n=150 hip, n=150 knee, n=60 shoulder patients). Outcomes included the MSK-HQ's acceptability, feasibility, comprehension, readability and responder burden. The validation cohort outcomes were the MSK-HQ's completion rate, test-retest reliability and convergent validity with reference standards (EQ-5D-5L, Oxford Hip, Knee, Shoulder Scores, and the Keele MSK-PROM). Musculoskeletal domains prioritised were pain severity, physical function, work interference, social interference, sleep, fatigue, emotional health, physical activity, independence, understanding, confidence to self-manage and overall impact. Patients reported MSK-HQ items to be 'highly relevant' and 'easy to understand'. Completion rates were high (94.2%), with scores normally distributed, and no floor/ceiling effects. Test-retest reliability was excellent, and convergent validity was strong (correlations 0.81-0.88). A new musculoskeletal outcome measure has been developed through a coproduction process with patients to capture prioritised outcomes for use throughout the pathway and with different musculoskeletal conditions. Four validation cohorts found that the MSK-HQ had high completion rates, excellent test-retest reliability and strong convergent validity with reference standards. Further validation studies are ongoing, including a cohort with rheumatoid/inflammatory arthritis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Perioperative Respiratory Adverse Events in Pediatric Ambulatory Anesthesia: Development and Validation of a Risk Prediction Tool.

PubMed

Subramanyam, Rajeev; Yeramaneni, Samrat; Hossain, Mohamed Monir; Anneken, Amy M; Varughese, Anna M

2016-05-01

Perioperative respiratory adverse events (PRAEs) are the most common cause of serious adverse events in children receiving anesthesia. Our primary aim of this study was to develop and validate a risk prediction tool for the occurrence of PRAE from the onset of anesthesia induction until discharge from the postanesthesia care unit in children younger than 18 years undergoing elective ambulatory anesthesia for surgery and radiology. The incidence of PRAE was studied. We analyzed data from 19,059 patients from our department's quality improvement database. The predictor variables were age, sex, ASA physical status, morbid obesity, preexisting pulmonary disorder, preexisting neurologic disorder, and location of ambulatory anesthesia (surgery or radiology). Composite PRAE was defined as the presence of any 1 of the following events: intraoperative bronchospasm, intraoperative laryngospasm, postoperative apnea, postoperative laryngospasm, postoperative bronchospasm, or postoperative prolonged oxygen requirement. Development and validation of the risk prediction tool for PRAE were performed using a split sampling technique to split the database into 2 independent cohorts based on the year when the patient received ambulatory anesthesia for surgery and radiology using logistic regression. A risk score was developed based on the regression coefficients from the validation tool. The performance of the risk prediction tool was assessed by using tests of discrimination and calibration. The overall incidence of composite PRAE was 2.8%. The derivation cohort included 8904 patients, and the validation cohort included 10,155 patients. The risk of PRAE was 3.9% in the development cohort and 1.8% in the validation cohort. Age ≤ 3 years (versus >3 years), ASA physical status II or III (versus ASA physical status I), morbid obesity, preexisting pulmonary disorder, and surgery (versus radiology) significantly predicted the occurrence of PRAE in a multivariable logistic regression model. A risk score in the range of 0 to 3 was assigned to each significant variable in the logistic regression model, and final score for all risk factors ranged from 0 to 11. A cutoff score of 4 was derived from a receiver operating characteristic curve to determine the high-risk category. The model C-statistic and the corresponding SE for the derivation and validation cohort was 0.64 ± 0.01 and 0.63 ± 0.02, respectively. Sensitivity and SE of the risk prediction tool to identify children at risk for PRAE was 77.6 ± 0.02 in the derivation cohort and 76.2 ± 0.03 in the validation cohort. The risk tool developed and validated from our study cohort identified 5 risk factors: age ≤ 3 years (versus >3 years), ASA physical status II and III (versus ASA physical status I), morbid obesity, preexisting pulmonary disorder, and surgery (versus radiology) for PRAE. This tool can be used to provide an individual risk score for each patient to predict the risk of PRAE in the preoperative period.

Development and validation of a prediction model for functional decline in older medical inpatients.

PubMed

Takada, Toshihiko; Fukuma, Shingo; Yamamoto, Yosuke; Tsugihashi, Yukio; Nagano, Hiroyuki; Hayashi, Michio; Miyashita, Jun; Azuma, Teruhisa; Fukuhara, Shunichi

2018-05-17

To prevent functional decline in older inpatients, identification of high-risk patients is crucial. The aim of this study was to develop and validate a prediction model to assess the risk of functional decline in older medical inpatients. In this retrospective cohort study, patients ≥65 years admitted acutely to medical wards were included. The healthcare database of 246 acute care hospitals (n = 229,913) was used for derivation, and two acute care hospitals (n = 1767 and 5443, respectively) were used for validation. Data were collected using a national administrative claims and discharge database. Functional decline was defined as a decline of the Katz score at discharge compared with on admission. About 6% of patients in the derivation cohort and 9% and 2% in each validation cohort developed functional decline. A model with 7 items, age, body mass index, living in a nursing home, ambulance use, need for assistance in walking, dementia, and bedsore, was developed. On internal validation, it demonstrated a c-statistic of 0.77 (95% confidence interval (CI) = 0.767-0.771) and good fit on the calibration plot. On external validation, the c-statistics were 0.79 (95% CI = 0.77-0.81) and 0.75 (95% CI = 0.73-0.77) for each cohort, respectively. Calibration plots showed good fit in one cohort and overestimation in the other one. A prediction model for functional decline in older medical inpatients was derived and validated. It is expected that use of the model would lead to early identification of high-risk patients and introducing early intervention. Copyright © 2018 Elsevier B.V. All rights reserved.

DNA methylation array analysis identifies breast cancer associated RPTOR, MGRN1 and RAPSN hypomethylation in peripheral blood DNA.

PubMed

Tang, Qiuqiong; Holland-Letz, Tim; Slynko, Alla; Cuk, Katarina; Marme, Frederik; Schott, Sarah; Heil, Jörg; Qu, Bin; Golatta, Michael; Bewerunge-Hudler, Melanie; Sutter, Christian; Surowy, Harald; Wappenschmidt, Barbara; Schmutzler, Rita; Hoth, Markus; Bugert, Peter; Bartram, Claus R; Sohn, Christof; Schneeweiss, Andreas; Yang, Rongxi; Burwinkel, Barbara

2016-09-27

DNA methylation changes in peripheral blood DNA have been shown to be associated with solid tumors. We sought to identify methylation alterations in whole blood DNA that are associated with breast cancer (BC). Epigenome-wide DNA methylation profiling on blood DNA from BC cases and healthy controls was performed by applying Infinium HumanMethylation450K BeadChips. Promising CpG sites were selected and validated in three independent larger sample cohorts via MassARRAY EpiTyper assays. CpG sites located in three genes (cg06418238 in RPTOR, cg00736299 in MGRN1 and cg27466532 in RAPSN), which showed significant hypomethylation in BC patients compared to healthy controls in the discovery cohort (p < 1.00 x 10-6) were selected and successfully validated in three independent cohorts (validation I, n =211; validation II, n=378; validation III, n=520). The observed methylation differences are likely not cell-type specific, as the differences were only seen in whole blood, but not in specific sub cell-types of leucocytes. Moreover, we observed in quartile analysis that women in the lower methylation quartiles of these three loci had higher ORs than women in the higher quartiles. The combined AUC of three loci was 0.79 (95%CI 0.73-0.85) in validation cohort I, and was 0.60 (95%CI 0.54-0.66) and 0.62 (95%CI 0.57-0.67) in validation cohort II and III, respectively. Our study suggests that hypomethylation of CpG sites in RPTOR, MGRN1 and RAPSN in blood is associated with BC and might serve as blood-based marker supplements for BC if these could be verified in prospective studies.

Confounder summary scores when comparing the effects of multiple drug exposures.

PubMed

Cadarette, Suzanne M; Gagne, Joshua J; Solomon, Daniel H; Katz, Jeffrey N; Stürmer, Til

2010-01-01

Little information is available comparing methods to adjust for confounding when considering multiple drug exposures. We compared three analytic strategies to control for confounding based on measured variables: conventional multivariable, exposure propensity score (EPS), and disease risk score (DRS). Each method was applied to a dataset (2000-2006) recently used to examine the comparative effectiveness of four drugs. The relative effectiveness of risedronate, nasal calcitonin, and raloxifene in preventing non-vertebral fracture, were each compared to alendronate. EPSs were derived both by using multinomial logistic regression (single model EPS) and by three separate logistic regression models (separate model EPS). DRSs were derived and event rates compared using Cox proportional hazard models. DRSs derived among the entire cohort (full cohort DRS) was compared to DRSs derived only among the referent alendronate (unexposed cohort DRS). Less than 8% deviation from the base estimate (conventional multivariable) was observed applying single model EPS, separate model EPS or full cohort DRS. Applying the unexposed cohort DRS when background risk for fracture differed between comparison drug exposure cohorts resulted in -7 to + 13% deviation from our base estimate. With sufficient numbers of exposed and outcomes, either conventional multivariable, EPS or full cohort DRS may be used to adjust for confounding to compare the effects of multiple drug exposures. However, our data also suggest that unexposed cohort DRS may be problematic when background risks differ between referent and exposed groups. Further empirical and simulation studies will help to clarify the generalizability of our findings.

Analysis of model development strategies: predicting ventral hernia recurrence.

PubMed

Holihan, Julie L; Li, Linda T; Askenasy, Erik P; Greenberg, Jacob A; Keith, Jerrod N; Martindale, Robert G; Roth, J Scott; Liang, Mike K

2016-11-01

There have been many attempts to identify variables associated with ventral hernia recurrence; however, it is unclear which statistical modeling approach results in models with greatest internal and external validity. We aim to assess the predictive accuracy of models developed using five common variable selection strategies to determine variables associated with hernia recurrence. Two multicenter ventral hernia databases were used. Database 1 was randomly split into "development" and "internal validation" cohorts. Database 2 was designated "external validation". The dependent variable for model development was hernia recurrence. Five variable selection strategies were used: (1) "clinical"-variables considered clinically relevant, (2) "selective stepwise"-all variables with a P value <0.20 were assessed in a step-backward model, (3) "liberal stepwise"-all variables were included and step-backward regression was performed, (4) "restrictive internal resampling," and (5) "liberal internal resampling." Variables were included with P < 0.05 for the Restrictive model and P < 0.10 for the Liberal model. A time-to-event analysis using Cox regression was performed using these strategies. The predictive accuracy of the developed models was tested on the internal and external validation cohorts using Harrell's C-statistic where C > 0.70 was considered "reasonable". The recurrence rate was 32.9% (n = 173/526; median/range follow-up, 20/1-58 mo) for the development cohort, 36.0% (n = 95/264, median/range follow-up 20/1-61 mo) for the internal validation cohort, and 12.7% (n = 155/1224, median/range follow-up 9/1-50 mo) for the external validation cohort. Internal validation demonstrated reasonable predictive accuracy (C-statistics = 0.772, 0.760, 0.767, 0.757, 0.763), while on external validation, predictive accuracy dipped precipitously (C-statistic = 0.561, 0.557, 0.562, 0.553, 0.560). Predictive accuracy was equally adequate on internal validation among models; however, on external validation, all five models failed to demonstrate utility. Future studies should report multiple variable selection techniques and demonstrate predictive accuracy on external data sets for model validation. Copyright © 2016 Elsevier Inc. All rights reserved.

A Risk Prediction Score for Kidney Failure or Mortality in Rhabdomyolysis

PubMed Central

McMahon, Gearoid M.; Zeng, Xiaoxi; Waikar, Sushrut S.

2016-01-01

IMPORTANCE Rhabdomyolysis ranges in severity from asymptomatic elevations in creatine phosphokinase levels to a life-threatening disorder characterized by severe acute kidney injury requiring hemodialysis or continuous renal replacement therapy (RRT). OBJECTIVE To develop a risk prediction tool to identify patients at greatest risk of RRT or in-hospital mortality. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study of 2371 patients admitted between January 1, 2000, and March 31, 2011, to 2 large teaching hospitals in Boston, Massachusetts, with creatine phosphokinase levels in excess of 5000 U/L within 3 days of admission. The derivation cohort consisted of 1397 patients from Massachusetts General Hospital, and the validation cohort comprised 974 patients from Brigham and Women’s Hospital. MAIN OUTCOMES AND MEASURES The composite of RRT or in-hospital mortality. RESULTS The causes and outcomes of rhabdomyolysis were similar between the derivation and validation cohorts. In total, the composite outcome occurred in 19.0% of patients (8.0% required RRT and 14.1% died during hospitalization). The highest rates of the composite outcome were from compartment syndrome (41.2%), sepsis (39.3%), and following cardiac arrest (58.5%). The lowest rates were from myositis (1.7%), exercise (3.2%), and seizures (6.0%). The independent predictors of the composite outcome were age, female sex, cause of rhabdomyolysis, and values of initial creatinine, creatine phosphokinase, phosphate, calcium, and bicarbonate. We developed a risk-prediction score from these variables in the derivation cohort and subsequently applied it in the validation cohort. The C statistic for the prediction model was 0.82 (95% CI, 0.80–0.85) in the derivation cohort and 0.83 (0.80–0.86) in the validation cohort. The Hosmer-Lemeshow P values were .14 and .28, respectively. In the validation cohort, among the patients with the lowest risk score (<5), 2.3% died or needed RRT. Among the patients with the highest risk score (>10), 61.2% died or needed RRT. CONCLUSIONS AND RELEVANCE Outcomes from rhabdomyolysis vary widely depending on the clinical context. The risk of RRT or in-hospital mortality in patients with rhabdomyolysis can be estimated using commonly available demographic, clinical, and laboratory variables on admission. PMID:24000014

Mammary stem cell and macrophage markers are enriched in normal tissue adjacent to inflammatory breast cancer.

PubMed

Reddy, Jay P; Atkinson, Rachel L; Larson, Richard; Burks, Jared K; Smith, Daniel; Debeb, Bisrat G; Ruffell, Brian; Creighton, Chad J; Bambhroliya, Arvind; Reuben, James M; Van Laere, Steven J; Krishnamurthy, Savitri; Symmans, William F; Brewster, Abenaa M; Woodward, Wendy A

2018-06-01

We hypothesized that breast tissue not involved by tumor in inflammatory breast cancer (IBC) patients contains intrinsic differences, including increased mammary stem cells and macrophage infiltration, which may promote the IBC phenotype. Normal breast parenchyma ≥ 5 cm away from primary tumors was obtained from mastectomy specimens. This included an initial cohort of 8 IBC patients and 60 non-IBC patients followed by a validation cohort of 19 IBC patients and 25 non-IBC patients. Samples were immunostained for either CD44 + CD49f + CD133/2 + mammary stem cell markers or the CD68 macrophage marker and correlated with IBC status. Quantitation of positive cells was determined using inForm software from PerkinElmer. We also examined the association between IBC status and previously published tumorigenic stem cell and IBC tumor signatures in the validation cohort samples. 8 of 8 IBC samples expressed isolated CD44 + CD49f + CD133/2 + stem cell marked cells in the initial cohort as opposed to 0/60 non-IBC samples (p = 0.001). Similarly, the median number of CD44 + CD49f + CD133/2 + cells was significantly higher in the IBC validation cohort as opposed to the non-IBC validation cohort (25.7 vs. 14.2, p = 0.007). 7 of 8 IBC samples expressed CD68 + histologically confirmed macrophages in initial cohort as opposed to 12/48 non-IBC samples (p = 0.001). In the validation cohort, the median number of CD68 + cells in IBC was 3.7 versus 1.0 in the non-IBC cohort (p = 0.06). IBC normal tissue was positively associated with a tumorigenic stem cell signature (p = 0.02) and with a 79-gene IBC signature (p < 0.001). Normal tissue from IBC patients is enriched for both mammary stem cells and macrophages and has higher association with both a tumorigenic stem cell signature and IBC-specific tumor signature. Collectively, these data suggest that IBC normal tissue differs from non-IBC tissue. Whether these changes occur before the tumor develops or is induced by tumor warrants further investigation.

Improving Visualization and Interpretation of Metabolome-Wide Association Studies: An Application in a Population-Based Cohort Using Untargeted 1H NMR Metabolic Profiling.

PubMed

Castagné, Raphaële; Boulangé, Claire Laurence; Karaman, Ibrahim; Campanella, Gianluca; Santos Ferreira, Diana L; Kaluarachchi, Manuja R; Lehne, Benjamin; Moayyeri, Alireza; Lewis, Matthew R; Spagou, Konstantina; Dona, Anthony C; Evangelos, Vangelis; Tracy, Russell; Greenland, Philip; Lindon, John C; Herrington, David; Ebbels, Timothy M D; Elliott, Paul; Tzoulaki, Ioanna; Chadeau-Hyam, Marc

2017-10-06

1 H NMR spectroscopy of biofluids generates reproducible data allowing detection and quantification of small molecules in large population cohorts. Statistical models to analyze such data are now well-established, and the use of univariate metabolome wide association studies (MWAS) investigating the spectral features separately has emerged as a computationally efficient and interpretable alternative to multivariate models. The MWAS rely on the accurate estimation of a metabolome wide significance level (MWSL) to be applied to control the family wise error rate. Subsequent interpretation requires efficient visualization and formal feature annotation, which, in-turn, call for efficient prioritization of spectral variables of interest. Using human serum 1 H NMR spectroscopic profiles from 3948 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), we have performed a series of MWAS for serum levels of glucose. We first propose an extension of the conventional MWSL that yields stable estimates of the MWSL across the different model parameterizations and distributional features of the outcome. We propose both efficient visualization methods and a strategy based on subsampling and internal validation to prioritize the associations. Our work proposes and illustrates practical and scalable solutions to facilitate the implementation of the MWAS approach and improve interpretation in large cohort studies.

Improving Visualization and Interpretation of Metabolome-Wide Association Studies: An Application in a Population-Based Cohort Using Untargeted 1H NMR Metabolic Profiling

PubMed Central

2017-01-01

1H NMR spectroscopy of biofluids generates reproducible data allowing detection and quantification of small molecules in large population cohorts. Statistical models to analyze such data are now well-established, and the use of univariate metabolome wide association studies (MWAS) investigating the spectral features separately has emerged as a computationally efficient and interpretable alternative to multivariate models. The MWAS rely on the accurate estimation of a metabolome wide significance level (MWSL) to be applied to control the family wise error rate. Subsequent interpretation requires efficient visualization and formal feature annotation, which, in-turn, call for efficient prioritization of spectral variables of interest. Using human serum 1H NMR spectroscopic profiles from 3948 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), we have performed a series of MWAS for serum levels of glucose. We first propose an extension of the conventional MWSL that yields stable estimates of the MWSL across the different model parameterizations and distributional features of the outcome. We propose both efficient visualization methods and a strategy based on subsampling and internal validation to prioritize the associations. Our work proposes and illustrates practical and scalable solutions to facilitate the implementation of the MWAS approach and improve interpretation in large cohort studies. PMID:28823158

Systemic Inflammatory Response Syndrome After Major Abdominal Surgery Predicted by Early Upregulation of TLR4 and TLR5.

PubMed

Lahiri, Rajiv; Derwa, Yannick; Bashir, Zora; Giles, Edward; Torrance, Hew D T; Owen, Helen C; O'Dwyer, Michael J; O'Brien, Alastair; Stagg, Andrew J; Bhattacharya, Satyajit; Foster, Graham R; Alazawi, William

2016-05-01

To study innate immune pathways in patients undergoing hepatopancreaticobiliary surgery to understand mechanisms leading to enhanced inflammatory responses and identifying biomarkers of adverse clinical consequences. Patients undergoing major abdominal surgery are at risk of life-threatening systemic inflammatory response syndrome (SIRS) and sepsis. Early identification of at-risk patients would allow tailored postoperative care and improve survival. Two separate cohorts of patients undergoing major hepatopancreaticobiliary surgery were studied (combined n = 69). Bloods were taken preoperatively, on day 1 and day 2 postoperatively. Peripheral blood mononuclear cells and serum were separated and immune phenotype and function assessed ex vivo. Early innate immune dysfunction was evident in 12 patients who subsequently developed SIRS (postoperative day 6) compared with 27 who did not, when no clinical evidence of SIRS was apparent (preoperatively or days 1 and 2). Serum interleukin (IL)-6 concentration and monocyte Toll-like receptor (TLR)/NF-κB/IL-6 functional pathways were significantly upregulated and overactive in patients who developed SIRS (P < 0.0001). Interferon α-mediated STAT1 phosphorylation was higher preoperatively in patients who developed SIRS. Increased TLR4 and TLR5 gene expression in whole blood was demonstrated in a separate validation cohort of 30 patients undergoing similar surgery. Expression of TLR4/5 on monocytes, particularly intermediate CD14CD16 monocytes, on day 1 or 2 predicted SIRS with accuracy 0.89 to 1.0 (areas under receiver operator curves). These data demonstrate the mechanism for IL-6 overproduction in patients who develop postoperative SIRS and identify markers that predict patients at risk of SIRS 5 days before the onset of clinical signs.

Biological Marker Analysis as Part of the CIBERES-RTIC Cancer-SEPAR Strategic Project on Lung Cancer.

PubMed

Monsó, Eduard; Montuenga, Luis M; Sánchez de Cos, Julio; Villena, Cristina

2015-09-01

The aim of the Clinical and Molecular Staging of Stage I-IIp Lung Cancer Project is to identify molecular variables that improve the prognostic and predictive accuracy of TMN classification in stage I/IIp non-small cell lung cancer (NSCLC). Clinical data and lung tissue, tumor and blood samples will be collected from 3 patient cohorts created for this purpose. The prognostic protein signature will be validated from these samples, and micro-RNA, ALK, Ros1, Pdl-1, and TKT, TKTL1 y G6PD expression will be analyzed. Tissue inflammatory markers and stromal cell markers will also be analyzed. Methylation of p16, DAPK, RASSF1a, APC and CDH13 genes in the tissue samples will be determined, and inflammatory markers in peripheral blood will also be analyzed. Variables that improve the prognostic and predictive accuracy of TNM in NSCLC by molecular staging may be identified from this extensive analytical panel. Copyright © 2014 SEPAR. Published by Elsevier Espana. All rights reserved.

Analysis of blood-based gene expression in idiopathic Parkinson disease.

PubMed

Shamir, Ron; Klein, Christine; Amar, David; Vollstedt, Eva-Juliane; Bonin, Michael; Usenovic, Marija; Wong, Yvette C; Maver, Ales; Poths, Sven; Safer, Hershel; Corvol, Jean-Christophe; Lesage, Suzanne; Lavi, Ofer; Deuschl, Günther; Kuhlenbaeumer, Gregor; Pawlack, Heike; Ulitsky, Igor; Kasten, Meike; Riess, Olaf; Brice, Alexis; Peterlin, Borut; Krainc, Dimitri

2017-10-17

To examine whether gene expression analysis of a large-scale Parkinson disease (PD) patient cohort produces a robust blood-based PD gene signature compared to previous studies that have used relatively small cohorts (≤220 samples). Whole-blood gene expression profiles were collected from a total of 523 individuals. After preprocessing, the data contained 486 gene profiles (n = 205 PD, n = 233 controls, n = 48 other neurodegenerative diseases) that were partitioned into training, validation, and independent test cohorts to identify and validate a gene signature. Batch-effect reduction and cross-validation were performed to ensure signature reliability. Finally, functional and pathway enrichment analyses were applied to the signature to identify PD-associated gene networks. A gene signature of 100 probes that mapped to 87 genes, corresponding to 64 upregulated and 23 downregulated genes differentiating between patients with idiopathic PD and controls, was identified with the training cohort and successfully replicated in both an independent validation cohort (area under the curve [AUC] = 0.79, p = 7.13E-6) and a subsequent independent test cohort (AUC = 0.74, p = 4.2E-4). Network analysis of the signature revealed gene enrichment in pathways, including metabolism, oxidation, and ubiquitination/proteasomal activity, and misregulation of mitochondria-localized genes, including downregulation of COX4I1 , ATP5A1 , and VDAC3 . We present a large-scale study of PD gene expression profiling. This work identifies a reliable blood-based PD signature and highlights the importance of large-scale patient cohorts in developing potential PD biomarkers. © 2017 American Academy of Neurology.

Characterizing Heterogeneity within Head and Neck Lesions Using Cluster Analysis of Multi-Parametric MRI Data.

PubMed

Borri, Marco; Schmidt, Maria A; Powell, Ceri; Koh, Dow-Mu; Riddell, Angela M; Partridge, Mike; Bhide, Shreerang A; Nutting, Christopher M; Harrington, Kevin J; Newbold, Katie L; Leach, Martin O

2015-01-01

To describe a methodology, based on cluster analysis, to partition multi-parametric functional imaging data into groups (or clusters) of similar functional characteristics, with the aim of characterizing functional heterogeneity within head and neck tumour volumes. To evaluate the performance of the proposed approach on a set of longitudinal MRI data, analysing the evolution of the obtained sub-sets with treatment. The cluster analysis workflow was applied to a combination of dynamic contrast-enhanced and diffusion-weighted imaging MRI data from a cohort of squamous cell carcinoma of the head and neck patients. Cumulative distributions of voxels, containing pre and post-treatment data and including both primary tumours and lymph nodes, were partitioned into k clusters (k = 2, 3 or 4). Principal component analysis and cluster validation were employed to investigate data composition and to independently determine the optimal number of clusters. The evolution of the resulting sub-regions with induction chemotherapy treatment was assessed relative to the number of clusters. The clustering algorithm was able to separate clusters which significantly reduced in voxel number following induction chemotherapy from clusters with a non-significant reduction. Partitioning with the optimal number of clusters (k = 4), determined with cluster validation, produced the best separation between reducing and non-reducing clusters. The proposed methodology was able to identify tumour sub-regions with distinct functional properties, independently separating clusters which were affected differently by treatment. This work demonstrates that unsupervised cluster analysis, with no prior knowledge of the data, can be employed to provide a multi-parametric characterization of functional heterogeneity within tumour volumes.

Derivation and validation of the prediabetes self-assessment screening score after acute pancreatitis (PERSEUS).

PubMed

Soo, Danielle H E; Pendharkar, Sayali A; Jivanji, Chirag J; Gillies, Nicola A; Windsor, John A; Petrov, Maxim S

2017-10-01

Approximately 40% of patients develop abnormal glucose metabolism after a single episode of acute pancreatitis. This study aimed to develop and validate a prediabetes self-assessment screening score for patients after acute pancreatitis. Data from non-overlapping training (n=82) and validation (n=80) cohorts were analysed. Univariate logistic and linear regression identified variables associated with prediabetes after acute pancreatitis. Multivariate logistic regression developed the score, ranging from 0 to 215. The area under the receiver-operating characteristic curve (AUROC), Hosmer-Lemeshow χ 2 statistic, and calibration plots were used to assess model discrimination and calibration. The developed score was validated using data from the validation cohort. The score had an AUROC of 0.88 (95% CI, 0.80-0.97) and Hosmer-Lemeshow χ 2 statistic of 5.75 (p=0.676). Patients with a score of ≥75 had a 94.1% probability of having prediabetes, and were 29 times more likely to have prediabetes than those with a score of <75. The AUROC in the validation cohort was 0.81 (95% CI, 0.70-0.92) and the Hosmer-Lemeshow χ 2 statistic was 5.50 (p=0.599). Model calibration of the score showed good calibration in both cohorts. The developed and validated score, called PERSEUS, is the first instrument to identify individuals who are at high risk of developing abnormal glucose metabolism following an episode of acute pancreatitis. Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Development and validation of a novel predictive scoring model for microvascular invasion in patients with hepatocellular carcinoma.

PubMed

Zhao, Hui; Hua, Ye; Dai, Tu; He, Jian; Tang, Min; Fu, Xu; Mao, Liang; Jin, Huihan; Qiu, Yudong

2017-03-01

Microvascular invasion (MVI) in patients with hepatocellular carcinoma (HCC) cannot be accurately predicted preoperatively. This study aimed to establish a predictive scoring model of MVI in solitary HCC patients without macroscopic vascular invasion. A total of 309 consecutive HCC patients who underwent curative hepatectomy were divided into the derivation (n=206) and validation cohort (n=103). A predictive scoring model of MVI was established according to the valuable predictors in the derivation cohort based on multivariate logistic regression analysis. The performance of the predictive model was evaluated in the derivation and validation cohorts. Preoperative imaging features on CECT, such as intratumoral arteries, non-nodular type of HCC and absence of radiological tumor capsule were independent predictors for MVI. The predictive scoring model was established according to the β coefficients of the 3 predictors. Area under receiver operating characteristic (AUROC) of the predictive scoring model was 0.872 (95% CI, 0.817-0.928) and 0.856 (95% CI, 0.771-0.940) in the derivation and validation cohorts. The positive and negative predictive values were 76.5% and 88.0% in the derivation cohort and 74.4% and 88.3% in the validation cohort. The performance of the model was similar between the patients with tumor size ≤5cm and >5cm in AUROC (P=0.910). The predictive scoring model based on intratumoral arteries, non-nodular type of HCC, and absence of the radiological tumor capsule on preoperative CECT is of great value in the prediction of MVI regardless of tumor size. Copyright © 2017 Elsevier B.V. All rights reserved.

Lean body mass: the development and validation of prediction equations in healthy adults

PubMed Central

2013-01-01

Background There is a loss of lean body mass (LBM) with increasing age. A low LBM has been associated with increased adverse effects from prescribed medications such as chemotherapy. Accurate assessment of LBM may allow for more accurate drug prescribing. The aims of this study were to develop new prediction equations (PEs) for LBM with anthropometric and biochemical variables from a development cohort and then validate the best performing PEs in validation cohorts. Methods PEs were developed in a cohort of 188 healthy subjects and then validated in a convenience cohort of 52 healthy subjects. The best performing anthropometric PE was then compared to published anthropometric PEs in an older (age ≥ 50 years) cohort of 2287 people. Best subset regression analysis was used to derive PEs. Correlation, Bland-Altman and Sheiner & Beal methods were used to validate and compare the PEs against dual X-ray absorptiometry (DXA)-derived LBM. Results The PE which included biochemistry variables performed only marginally better than the anthropometric PE. The anthropometric PE on average over-estimated LBM by 0.74 kg in the combined cohort. Across gender (male vs. female), body mass index (< 22, 22- < 27, 27- < 30 and ≥30 kg/m2) and age groups (50–64, 65–79 and ≥80 years), the maximum mean over-estimation of the anthropometric PE was 1.36 kg. Conclusions A new anthropometric PE has been developed that offers an alternative for clinicians when access to DXA is limited. Further research is required to determine the clinical utility and if it will improve the safety of medication use. PMID:24499708

A classification prognostic score to predict OS in stage IV well-differentiated neuroendocrine tumors

PubMed Central

Pusceddu, Sara; Barretta, Francesco; Trama, Annalisa; Botta, Laura; Milione, Massimo; Buzzoni, Roberto; De Braud, Filippo; Mazzaferro, Vincenzo; Pastorino, Ugo; Seregni, Ettore; Mariani, Luigi; Gatta, Gemma; Di Bartolomeo, Maria; Femia, Daniela; Prinzi, Natalie; Coppa, Jorgelina; Panzuto, Francesco; Antonuzzo, Lorenzo; Bajetta, Emilio; Brizzi, Maria Pia; Campana, Davide; Catena, Laura; Comber, Harry; Dwane, Fiona; Fazio, Nicola; Faggiano, Antongiulio; Giuffrida, Dario; Henau, Kris; Ibrahim, Toni; Marconcini, Riccardo; Massironi, Sara; Žakelj, Maja Primic; Spada, Francesca; Tafuto, Salvatore; Van Eycken, Elizabeth; Van der Zwan, Jan Maaten; Žagar, Tina; Giacomelli, Luca; Miceli, Rosalba; Aroldi, Francesca; Bongiovanni, Alberto; Berardi, Rossana; Brighi, Nicole; Cingarlini, Sara; Cauchi, Carolina; Cavalcoli, Federica; Carnaghi, Carlo; Corti, Francesca; Duro, Marilina; Davì, Maria Vittoria; De Divitiis, Chiara; Ermacora, Paola; La Salvia, Anna; Luppi, Gabriele; Lo Russo, Giuseppe; Nichetti, Federico; Raimondi, Alessandra; Perfetti, Vittorio; Razzore, Paola; Rinzivillo, Maria; Siesling, Sabine; Torchio, Martina; Van Dijk, Boukje; Visser, Otto; Vernieri, Claudio

2018-01-01

No validated prognostic tool is available for predicting overall survival (OS) of patients with well-differentiated neuroendocrine tumors (WDNETs). This study, conducted in three independent cohorts of patients from five different European countries, aimed to develop and validate a classification prognostic score for OS in patients with stage IV WDNETs. We retrospectively collected data on 1387 patients: (i) patients treated at the Istituto Nazionale Tumori (Milan, Italy; n = 515); (ii) European cohort of rare NET patients included in the European RARECAREnet database (n = 457); (iii) Italian multicentric cohort of pancreatic NET (pNETs) patients treated at 24 Italian institutions (n = 415). The score was developed using data from patients included in cohort (i) (training set); external validation was performed by applying the score to the data of the two independent cohorts (ii) and (iii) evaluating both calibration and discriminative ability (Harrell C statistic). We used data on age, primary tumor site, metastasis (synchronous vs metachronous), Ki-67, functional status and primary surgery to build the score, which was developed for classifying patients into three groups with differential 10-year OS: (I) favorable risk group: 10-year OS ≥70%; (II) intermediate risk group: 30% ≤ 10-year OS < 70%; (III) poor risk group: 10-year OS <30%. The Harrell C statistic was 0.661 in the training set, and 0.626 and 0.601 in the RARECAREnet and Italian multicentric validation sets, respectively. In conclusion, based on the analysis of three ‘field-practice’ cohorts collected in different settings, we defined and validated a prognostic score to classify patients into three groups with different long-term prognoses. PMID:29559553

Clinical Nomograms to Predict Stone-Free Rates after Shock-Wave Lithotripsy: Development and Internal-Validation

PubMed Central

Kim, Jung Kwon; Ha, Seung Beom; Jeon, Chan Hoo; Oh, Jong Jin; Cho, Sung Yong; Oh, Seung-June; Kim, Hyeon Hoe; Jeong, Chang Wook

2016-01-01

Purpose Shock-wave lithotripsy (SWL) is accepted as the first line treatment modality for uncomplicated upper urinary tract stones; however, validated prediction models with regards to stone-free rates (SFRs) are still needed. We aimed to develop nomograms predicting SFRs after the first and within the third session of SWL. Computed tomography (CT) information was also modeled for constructing nomograms. Materials and Methods From March 2006 to December 2013, 3028 patients were treated with SWL for ureter and renal stones at our three tertiary institutions. Four cohorts were constructed: Total-development, Total-validation, CT-development, and CT-validation cohorts. The nomograms were developed using multivariate logistic regression models with selected significant variables in a univariate logistic regression model. A C-index was used to assess the discrimination accuracy of nomograms and calibration plots were used to analyze the consistency of prediction. Results The SFR, after the first and within the third session, was 48.3% and 68.8%, respectively. Significant variables were sex, stone location, stone number, and maximal stone diameter in the Total-development cohort, and mean Hounsfield unit (HU) and grade of hydronephrosis (HN) were additional parameters in the CT-development cohort. The C-indices were 0.712 and 0.723 for after the first and within the third session of SWL in the Total-development cohort, and 0.755 and 0.756, in the CT-development cohort, respectively. The calibration plots showed good correspondences. Conclusions We constructed and validated nomograms to predict SFR after SWL. To the best of our knowledge, these are the first graphical nomograms to be modeled with CT information. These may be useful for patient counseling and treatment decision-making. PMID:26890006

Metagenomic analysis of faecal microbiome as a tool towards targeted non-invasive biomarkers for colorectal cancer.

PubMed

Yu, Jun; Feng, Qiang; Wong, Sunny Hei; Zhang, Dongya; Liang, Qiao Yi; Qin, Youwen; Tang, Longqing; Zhao, Hui; Stenvang, Jan; Li, Yanli; Wang, Xiaokai; Xu, Xiaoqiang; Chen, Ning; Wu, William Ka Kei; Al-Aama, Jumana; Nielsen, Hans Jørgen; Kiilerich, Pia; Jensen, Benjamin Anderschou Holbech; Yau, Tung On; Lan, Zhou; Jia, Huijue; Li, Junhua; Xiao, Liang; Lam, Thomas Yuen Tung; Ng, Siew Chien; Cheng, Alfred Sze-Lok; Wong, Vincent Wai-Sun; Chan, Francis Ka Leung; Xu, Xun; Yang, Huanming; Madsen, Lise; Datz, Christian; Tilg, Herbert; Wang, Jian; Brünner, Nils; Kristiansen, Karsten; Arumugam, Manimozhiyan; Sung, Joseph Jao-Yiu; Wang, Jun

2017-01-01

To evaluate the potential for diagnosing colorectal cancer (CRC) from faecal metagenomes. We performed metagenome-wide association studies on faecal samples from 74 patients with CRC and 54 controls from China, and validated the results in 16 patients and 24 controls from Denmark. We further validated the biomarkers in two published cohorts from France and Austria. Finally, we employed targeted quantitative PCR (qPCR) assays to evaluate diagnostic potential of selected biomarkers in an independent Chinese cohort of 47 patients and 109 controls. Besides confirming known associations of Fusobacterium nucleatum and Peptostreptococcus stomatis with CRC, we found significant associations with several species, including Parvimonas micra and Solobacterium moorei. We identified 20 microbial gene markers that differentiated CRC and control microbiomes, and validated 4 markers in the Danish cohort. In the French and Austrian cohorts, these four genes distinguished CRC metagenomes from controls with areas under the receiver-operating curve (AUC) of 0.72 and 0.77, respectively. qPCR measurements of two of these genes accurately classified patients with CRC in the independent Chinese cohort with AUC=0.84 and OR of 23. These genes were enriched in early-stage (I-II) patient microbiomes, highlighting the potential for using faecal metagenomic biomarkers for early diagnosis of CRC. We present the first metagenomic profiling study of CRC faecal microbiomes to discover and validate microbial biomarkers in ethnically different cohorts, and to independently validate selected biomarkers using an affordable clinically relevant technology. Our study thus takes a step further towards affordable non-invasive early diagnostic biomarkers for CRC from faecal samples. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Risk score for identifying adults with CSF pleocytosis and negative CSF Gram stain at low risk for an urgent treatable cause.

PubMed

Hasbun, Rodrigo; Bijlsma, Merijn; Brouwer, Matthijs C; Khoury, Nabil; Hadi, Christiane M; van der Ende, Arie; Wootton, Susan H; Salazar, Lucrecia; Hossain, Md Monir; Beilke, Mark; van de Beek, Diederik

2013-08-01

We aimed to derive and validate a risk score that identifies adults with cerebrospinal fluid (CSF) pleocytosis and a negative CSF Gram stain at low risk for an urgent treatable cause. Patients with CSF pleocytosis and a negative CSF Gram stain were stratified into a prospective derivation (n = 193) and a retrospective validation (n = 567) cohort. Clinically related baseline characteristics were grouped into three composite variables, each independently associated with a set of predefined urgent treatable causes. We subsequently derived a risk score classifying patients into low (0 composite variables present) or high (≥ 1 composite variables present) risk for an urgent treatable cause. The sensitivity of the risk score was determined in the validation cohort and in a prospective case series of 214 adults with CSF-culture proven bacterial meningitis, CSF pleocytosis and a negative Gram stain. A total of 41 of 193 patients (21%) in the derivation cohort and 71 of 567 (13%) in the validation cohort had an urgent treatable cause. Sensitivity of the dichotomized risk score to detect an urgent treatable cause was 100.0% (95% CI 93.9-100.0%) in the validation cohort and 100.0% (95% CI 97.8-100.0%) in bacterial meningitis patients. The risk score can be used to identify adults with CSF pleocytosis and a negative CSF Gram stain at low risk for an urgent treatable cause. Copyright © 2013 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

RISK SCORE FOR IDENTIFYING ADULTS WITH CSF PLEOCYTOSIS AND NEGATIVE CSF GRAM STAIN AT LOW RISK FOR AN URGENT TREATABLE CAUSE

PubMed Central

Hasbun, Rodrigo; Bijlsma, Merijn; Brouwer, Matthijs C; Khoury, Nabil; Hadi, Christiane M; van der Ende, Arie; Wootton, Susan H.; Salazar, Lucrecia; Hossain, Md Monir; Beilke, Mark; van de Beek, Diederik

2013-01-01

Background We aimed to derive and validate a risk score that identifies adults with cerebrospinal fluid (CSF) pleocytosis and a negative CSF Gram stain at low risk for an urgent treatable cause. Methods Patients with CSF pleocytosis and a negative CSF Gram stain were stratified into a prospective derivation (n=193) and a retrospective validation (n=567) cohort. Clinically related baseline characteristics were grouped into three composite variables, each independently associated with a set of predefined urgent treatable causes. We subsequently derived a risk score classifying patients into low (0 composite variables present) or high ( ≥ 1 composite variables present) risk for an urgent treatable cause. The sensitivity of the risk score was determined in the validation cohort and in a prospective case series of 214 adults with CSF-culture proven bacterial meningitis, CSF pleocytosis and a negative Gram stain. Findings A total of 41 of 193 patients (21%) in the derivation cohort and 71 of 567 (13%) in the validation cohort had an urgent treatable cause. Sensitivity of the dichotomized risk score to detect an urgent treatable cause was 100.0% (95%CI 93.9-100.0%) in the validation cohort and 100.0% (95%CI 97.8-100.0%) in bacterial meningitis patients. Interpretation The risk score can be used to identify adults with CSF pleocytosis and a negative CSF Gram stain at low risk for an urgent treatable cause. PMID:23619080

Validating dimensions of psychosis symptomatology: Neural correlates and 20-year outcomes.

PubMed

Kotov, Roman; Foti, Dan; Li, Kaiqiao; Bromet, Evelyn J; Hajcak, Greg; Ruggero, Camilo J

2016-11-01

Heterogeneity of psychosis presents significant challenges for classification. Between 2 and 12 symptom dimensions have been proposed, and consensus is lacking. The present study sought to identify uniquely informative models by comparing the validity of these alternatives. An epidemiologic cohort of 628 first-admission inpatients with psychosis was interviewed 6 times over 2 decades and completed an electrophysiological assessment of error processing at year 20. We first analyzed a comprehensive set of 49 symptoms rated by interviewers at baseline, progressively extracting from 1 to 12 factors. Next, we compared the ability of resulting factor solutions to (a) account for concurrent neural dysfunction and (b) predict 20-year role, social, residential, and global functioning, and life satisfaction. A four-factor model showed incremental validity with all outcomes, and more complex models did not improve explanatory power. The 4 dimensions-reality distortion, disorganization, inexpressivity, and apathy/asociality-were replicable in 5 follow-ups, internally consistent, stable across assessments, and showed strong discriminant validity. These results reaffirm the value of separating disorganization and reality distortion, are consistent with recent findings distinguishing inexpressivity and apathy/asociality, and suggest that these 4 dimensions are fundamental to understanding neural abnormalities and long-term outcomes in psychosis. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

The fecal hemoglobin concentration, age and sex test score: Development and external validation of a simple prediction tool for colorectal cancer detection in symptomatic patients.

PubMed

Cubiella, Joaquín; Digby, Jayne; Rodríguez-Alonso, Lorena; Vega, Pablo; Salve, María; Díaz-Ondina, Marta; Strachan, Judith A; Mowat, Craig; McDonald, Paula J; Carey, Francis A; Godber, Ian M; Younes, Hakim Ben; Rodriguez-Moranta, Francisco; Quintero, Enrique; Álvarez-Sánchez, Victoria; Fernández-Bañares, Fernando; Boadas, Jaume; Campo, Rafel; Bujanda, Luis; Garayoa, Ana; Ferrandez, Ángel; Piñol, Virginia; Rodríguez-Alcalde, Daniel; Guardiola, Jordi; Steele, Robert J C; Fraser, Callum G

2017-05-15

Prediction models for colorectal cancer (CRC) detection in symptomatic patients, based on easily obtainable variables such as fecal haemoglobin concentration (f-Hb), age and sex, may simplify CRC diagnosis. We developed, and then externally validated, a multivariable prediction model, the FAST Score, with data from five diagnostic test accuracy studies that evaluated quantitative fecal immunochemical tests in symptomatic patients referred for colonoscopy. The diagnostic accuracy of the Score in derivation and validation cohorts was compared statistically with the area under the curve (AUC) and the Chi-square test. 1,572 and 3,976 patients were examined in these cohorts, respectively. For CRC, the odds ratio (OR) of the variables included in the Score were: age (years): 1.03 (95% confidence intervals (CI): 1.02-1.05), male sex: 1.6 (95% CI: 1.1-2.3) and f-Hb (0-<20 µg Hb/g feces): 2.0 (95% CI: 0.7-5.5), (20-<200 µg Hb/g): 16.8 (95% CI: 6.6-42.0), ≥200 µg Hb/g: 65.7 (95% CI: 26.3-164.1). The AUC for CRC detection was 0.88 (95% CI: 0.85-0.90) in the derivation and 0.91 (95% CI: 0.90-093; p = 0.005) in the validation cohort. At the two Score thresholds with 90% (4.50) and 99% (2.12) sensitivity for CRC, the Score had equivalent sensitivity, although the specificity was higher in the validation cohort (p < 0.001). Accordingly, the validation cohort was divided into three groups: high (21.4% of the cohort, positive predictive value-PPV: 21.7%), intermediate (59.8%, PPV: 0.9%) and low (18.8%, PPV: 0.0%) risk for CRC. The FAST Score is an easy to calculate prediction tool, highly accurate for CRC detection in symptomatic patients. © 2017 UICC.

Relative validity and reproducibility of a French dietary history questionnaire

PubMed Central

Van Liere, Marti J.; Lucas, François; Clavel, Françoise; Slimani, Nadia; Villeminot, Sylvie

1997-01-01

Background A self-administered dietary history questionnaire, especially developed for use in a large French prospective cohort study, was tested for accuracy of food intake measurement by comparing it to the average of 9–12 24-hour recalls. This questionnaire was structured according to the French meal pattern. An important feature of the questionnaire was the separation into a quantification part and qualification part. The first part quantifies consumption by frequency and portion sizes per food group or food item. The second part provides more detailed qualitative information on separate items within one food group. The total number of food items in the questionnaire was 238. Methods The questionnaire was administered twice to 119 study subjects, with an interval of approximately one year (1990–1991). During that year, 24-hour recalls were carried out monthly. Reproducibility and relative validity of the questionnaire were assessed. Results The correlation coefficients for reproducibility ranged from 0.40 to 0.74 for foods and from 0.54 to 0.75 for nutrients. The correlation coefficients for relative validity ranged from 0.10 to 0.71 for foods and from 0.29 to 0.81 for nutrients (adjustment for total energy and attenuation for nutrients). Percentage of subjects classified in the same or adjacent quintile by questionnaire as well as by 24-hour recall was on average 76% for foods and 72% for nutrients. Conclusions These data indicate that this questionnaire can be used to classify study subjects according to their food or nutrient intake over a one-year period, within a known degree of precision. PMID:9126541

SU-F-R-24: Identifying Prognostic Imaging Biomarkers in Early Stage Lung Cancer Using Radiomics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zeng, X; Wu, J; Cui, Y

2016-06-15

Purpose: Patients diagnosed with early stage lung cancer have favorable outcomes when treated with surgery or stereotactic radiotherapy. However, a significant proportion (∼20%) of patients will develop metastatic disease and eventually die of the disease. The purpose of this work is to identify quantitative imaging biomarkers from CT for predicting overall survival in early stage lung cancer. Methods: In this institutional review board-approved HIPPA-compliant retrospective study, we retrospectively analyzed the diagnostic CT scans of 110 patients with early stage lung cancer. Data from 70 patients were used for training/discovery purposes, while those of remaining 40 patients were used for independentmore » validation. We extracted 191 radiomic features, including statistical, histogram, morphological, and texture features. Cox proportional hazard regression model, coupled with the least absolute shrinkage and selection operator (LASSO), was used to predict overall survival based on the radiomic features. Results: The optimal prognostic model included three image features from the Law’s feature and wavelet texture. In the discovery cohort, this model achieved a concordance index or CI=0.67, and it separated the low-risk from high-risk groups in predicting overall survival (hazard ratio=2.72, log-rank p=0.007). In the independent validation cohort, this radiomic signature achieved a CI=0.62, and significantly stratified the low-risk and high-risk groups in terms of overall survival (hazard ratio=2.20, log-rank p=0.042). Conclusion: We identified CT imaging characteristics associated with overall survival in early stage lung cancer. If prospectively validated, this could potentially help identify high-risk patients who might benefit from adjuvant systemic therapy.« less

Detection of Gastric Cancer with Novel Methylated DNA Markers: Discovery, Tissue Validation, and Pilot Testing in Plasma.

PubMed

Anderson, Bradley W; Suh, Yun-Suhk; Choi, Boram; Lee, Hyuk-Joon; Yab, Tracy C; Taylor, William; Dukek, Brian A; Berger, Calise K; Cao, Xiaoming; Foote, Patrick H; Devens, Mary E; Boardman, Lisa A; Kisiel, John B; Mahoney, Douglas W; Slettedahl, Seth W; Allawi, Hatim T; Lidgard, Graham P; Smyrk, Thomas C; Yang, Han-Kwang; Ahlquist, David A

2018-05-29

Gastric adenocarcinoma (GAC) is the third most common cause of cancer mortality worldwide. Accurate and affordable non-invasive detection methods have potential value for screening and surveillance. Herein, we identify novel methylated DNA markers (MDMs) for GAC, validate their discrimination for GAC in tissues from geographically separate cohorts, explore marker acquisition through the oncogenic cascade, and describe distributions of candidate MDMs in plasma from GAC cases and normal controls. Following discovery by unbiased whole methylome sequencing, candidate MDMs were validated by blinded methylation-specific PCR in archival case-control tissues from U.S. and South Korean patients. Top MDMs were then assayed by an analytically sensitive method (quantitative real-time allele-specific target and signal amplification) in a blinded pilot study on archival plasma from GAC cases and normal controls. Whole methylome discovery yielded novel and highly discriminant candidate MDMs. In tissue, a panel of candidate MDMs detected GAC in 92-100% of U.S. and S. Korean cohorts at 100% specificity. Levels of most MDMs increased progressively from normal mucosa through metaplasia, adenoma, and GAC with variation in points of greatest marker acquisition. In plasma, a 3 marker panel ( ELMO1 , ZNF569 , C13orf18) detected 86% (95% CI 71-95%) of GACs at 95% specificity. Novel MDMs appear to accurately discriminate GAC from normal controls in both tissue and plasma. The point of aberrant methylation during oncogenesis varies by MDM, which may have relevance to marker selection in clinical applications. Further exploration of these MDMs for GAC screening and surveillance is warranted. Copyright ©2018, American Association for Cancer Research.

Differentiation between Wegener's granulomatosis and microscopic polyangiitis by an artificial neural network and by traditional methods.

PubMed

Linder, Roland; Orth, Isabelle; Hagen, E Christian; van der Woude, Fokko J; Schmitt, Wilhelm H

2011-06-01

To investigate the operating characteristics of the American College of Rheumatology (ACR) traditional format criteria for Wegener's granulomatosis (WG), the Sørensen criteria for WG and microscopic polyangiitis (MPA), and the Chapel Hill nomenclature for WG and MPA. Further, to develop and validate improved criteria for distinguishing WG from MPA by an artificial neural network (ANN) and by traditional approaches [classification tree (CT), logistic regression (LR)]. All criteria were applied to 240 patients with WG and 78 patients with MPA recruited by a multicenter study. To generate new classification criteria (ANN, CT, LR), 23 clinical measurements were assessed. Validation was performed by applying the same approaches to an independent monocenter cohort of 46 patients with WG and 21 patients with MPA. A total of 70.8% of the patients with WG and 7.7% of the patients with MPA from the multicenter cohort fulfilled the ACR criteria for WG (accuracy 76.1%). The accuracy of the Chapel Hill criteria for WG and MPA was only 35.0% and 55.3% (Sørensen criteria: 67.2% and 92.4%). In contrast, the ANN and CT achieved an accuracy of 94.3%, based on 4 measurements (involvement of nose, sinus, ear, and pulmonary nodules), all associated with WG. LR led to an accuracy of 92.8%. Inclusion of antineutrophil cytoplasmic antibodies did not improve the allocation. Validation of methods resulted in accuracy of 91.0% (ANN and CT) and 88.1% (LR). The ACR, Sørensen, and Chapel Hill criteria did not reliably separate WG from MPA. In contrast, an appropriately trained ANN and a CT differentiated between these disorders and performed better than LR.

New criteria for inflammatory back pain in patients with chronic back pain: a real patient exercise by experts from the Assessment of SpondyloArthritis international Society (ASAS).

PubMed

Sieper, J; van der Heijde, D; Landewé, R; Brandt, J; Burgos-Vagas, R; Collantes-Estevez, E; Dijkmans, B; Dougados, M; Khan, M A; Leirisalo-Repo, M; van der Linden, S; Maksymowych, W P; Mielants, H; Olivieri, I; Rudwaleit, M

2009-06-01

Inflammatory back pain (IBP) is an important clinical symptom in patients with axial spondyloarthritis (SpA), and relevant for classification and diagnosis. In the present report, a new approach for the development of IBP classification criteria is discussed. Rheumatologists (n = 13) who are experts in SpA took part in a 2-day international workshop to investigate 20 patients with back pain and possible SpA. Each expert documented the presence/absence of clinical parameters typical for IBP, and judged whether IBP was considered present or absent based on the received information. This expert judgement was used as the dependent variable in a logistic regression analysis in order to identify those individual IBP parameters that contributed best to a diagnosis of IBP. The new set of IBP criteria was validated in a separate cohort of patients (n = 648). Five parameters best explained IBP according to the experts. These were: (1) improvement with exercise (odds ratio (OR) 23.1); (2) pain at night (OR 20.4); (3) insidious onset (OR 12.7); (4) age at onset <40 years (OR 9.9); and (5) no improvement with rest (OR 7.7). If at least four out of these five parameters were fulfilled, the criteria had a sensitivity of 77.0% and specificity of 91.7% in the patients participating in the workshop, and 79.6% and 72.4%, respectively, in the validation cohort. This new approach with real patients defines a set of IBP definition criteria using overall expert judgement on IBP as the gold standard. The IBP experts' criteria are robust, easy to apply and have good face validity.

Predicting dementia risk in primary care: development and validation of the Dementia Risk Score using routinely collected data.

PubMed

Walters, K; Hardoon, S; Petersen, I; Iliffe, S; Omar, R Z; Nazareth, I; Rait, G

2016-01-21

Existing dementia risk scores require collection of additional data from patients, limiting their use in practice. Routinely collected healthcare data have the potential to assess dementia risk without the need to collect further information. Our objective was to develop and validate a 5-year dementia risk score derived from primary healthcare data. We used data from general practices in The Health Improvement Network (THIN) database from across the UK, randomly selecting 377 practices for a development cohort and identifying 930,395 patients aged 60-95 years without a recording of dementia, cognitive impairment or memory symptoms at baseline. We developed risk algorithm models for two age groups (60-79 and 80-95 years). An external validation was conducted by validating the model on a separate cohort of 264,224 patients from 95 randomly chosen THIN practices that did not contribute to the development cohort. Our main outcome was 5-year risk of first recorded dementia diagnosis. Potential predictors included sociodemographic, cardiovascular, lifestyle and mental health variables. Dementia incidence was 1.88 (95% CI, 1.83-1.93) and 16.53 (95% CI, 16.15-16.92) per 1000 PYAR for those aged 60-79 (n = 6017) and 80-95 years (n = 7104), respectively. Predictors for those aged 60-79 included age, sex, social deprivation, smoking, BMI, heavy alcohol use, anti-hypertensive drugs, diabetes, stroke/TIA, atrial fibrillation, aspirin, depression. The discrimination and calibration of the risk algorithm were good for the 60-79 years model; D statistic 2.03 (95% CI, 1.95-2.11), C index 0.84 (95% CI, 0.81-0.87), and calibration slope 0.98 (95% CI, 0.93-1.02). The algorithm had a high negative predictive value, but lower positive predictive value at most risk thresholds. Discrimination and calibration were poor for the 80-95 years model. Routinely collected data predicts 5-year risk of recorded diagnosis of dementia for those aged 60-79, but not those aged 80+. This algorithm can identify higher risk populations for dementia in primary care. The risk score has a high negative predictive value and may be most helpful in 'ruling out' those at very low risk from further testing or intensive preventative activities.

Derivation and External Validation of Prediction Models for Advanced Chronic Kidney Disease Following Acute Kidney Injury

PubMed Central

Pannu, Neesh; Hemmelgarn, Brenda R.; Austin, Peter C.; Tan, Zhi; McArthur, Eric; Manns, Braden J.; Tonelli, Marcello; Wald, Ron; Quinn, Robert R.; Ravani, Pietro; Garg, Amit X.

2017-01-01

Importance Some patients will develop chronic kidney disease after a hospitalization with acute kidney injury; however, no risk-prediction tools have been developed to identify high-risk patients requiring follow-up. Objective To derive and validate predictive models for progression of acute kidney injury to advanced chronic kidney disease. Design, Setting, and Participants Data from 2 population-based cohorts of patients with a prehospitalization estimated glomerular filtration rate (eGFR) of more than 45 mL/min/1.73 m2 and who had survived hospitalization with acute kidney injury (defined by a serum creatinine increase during hospitalization > 0.3 mg/dL or > 50% of their prehospitalization baseline), were used to derive and validate multivariable prediction models. The risk models were derived from 9973 patients hospitalized in Alberta, Canada (April 2004-March 2014, with follow-up to March 2015). The risk models were externally validated with data from a cohort of 2761 patients hospitalized in Ontario, Canada (June 2004-March 2012, with follow-up to March 2013). Exposures Demographic, laboratory, and comorbidity variables measured prior to discharge. Main Outcomes and Measures Advanced chronic kidney disease was defined by a sustained reduction in eGFR less than 30 mL/min/1.73 m2 for at least 3 months during the year after discharge. All participants were followed up for up to 1 year. Results The participants (mean [SD] age, 66 [15] years in the derivation and internal validation cohorts and 69 [11] years in the external validation cohort; 40%-43% women per cohort) had a mean (SD) baseline serum creatinine level of 1.0 (0.2) mg/dL and more than 20% had stage 2 or 3 acute kidney injury. Advanced chronic kidney disease developed in 408 (2.7%) of 9973 patients in the derivation cohort and 62 (2.2%) of 2761 patients in the external validation cohort. In the derivation cohort, 6 variables were independently associated with the outcome: older age, female sex, higher baseline serum creatinine value, albuminuria, greater severity of acute kidney injury, and higher serum creatinine value at discharge. In the external validation cohort, a multivariable model including these 6 variables had a C statistic of 0.81 (95% CI, 0.75-0.86) and improved discrimination and reclassification compared with reduced models that included age, sex, and discharge serum creatinine value alone (integrated discrimination improvement, 2.6%; 95% CI, 1.1%-4.0%; categorical net reclassification index, 13.5%; 95% CI, 1.9%-25.1%) or included age, sex, and acute kidney injury stage alone (integrated discrimination improvement, 8.0%; 95% CI, 5.1%-11.0%; categorical net reclassification index, 79.9%; 95% CI, 60.9%-98.9%). Conclusions and Relevance A multivariable model using routine laboratory data was able to predict advanced chronic kidney disease following hospitalization with acute kidney injury. The utility of this model in clinical care requires further research. PMID:29136443

Derivation and External Validation of Prediction Models for Advanced Chronic Kidney Disease Following Acute Kidney Injury.

PubMed

James, Matthew T; Pannu, Neesh; Hemmelgarn, Brenda R; Austin, Peter C; Tan, Zhi; McArthur, Eric; Manns, Braden J; Tonelli, Marcello; Wald, Ron; Quinn, Robert R; Ravani, Pietro; Garg, Amit X

2017-11-14

Some patients will develop chronic kidney disease after a hospitalization with acute kidney injury; however, no risk-prediction tools have been developed to identify high-risk patients requiring follow-up. To derive and validate predictive models for progression of acute kidney injury to advanced chronic kidney disease. Data from 2 population-based cohorts of patients with a prehospitalization estimated glomerular filtration rate (eGFR) of more than 45 mL/min/1.73 m2 and who had survived hospitalization with acute kidney injury (defined by a serum creatinine increase during hospitalization > 0.3 mg/dL or > 50% of their prehospitalization baseline), were used to derive and validate multivariable prediction models. The risk models were derived from 9973 patients hospitalized in Alberta, Canada (April 2004-March 2014, with follow-up to March 2015). The risk models were externally validated with data from a cohort of 2761 patients hospitalized in Ontario, Canada (June 2004-March 2012, with follow-up to March 2013). Demographic, laboratory, and comorbidity variables measured prior to discharge. Advanced chronic kidney disease was defined by a sustained reduction in eGFR less than 30 mL/min/1.73 m2 for at least 3 months during the year after discharge. All participants were followed up for up to 1 year. The participants (mean [SD] age, 66 [15] years in the derivation and internal validation cohorts and 69 [11] years in the external validation cohort; 40%-43% women per cohort) had a mean (SD) baseline serum creatinine level of 1.0 (0.2) mg/dL and more than 20% had stage 2 or 3 acute kidney injury. Advanced chronic kidney disease developed in 408 (2.7%) of 9973 patients in the derivation cohort and 62 (2.2%) of 2761 patients in the external validation cohort. In the derivation cohort, 6 variables were independently associated with the outcome: older age, female sex, higher baseline serum creatinine value, albuminuria, greater severity of acute kidney injury, and higher serum creatinine value at discharge. In the external validation cohort, a multivariable model including these 6 variables had a C statistic of 0.81 (95% CI, 0.75-0.86) and improved discrimination and reclassification compared with reduced models that included age, sex, and discharge serum creatinine value alone (integrated discrimination improvement, 2.6%; 95% CI, 1.1%-4.0%; categorical net reclassification index, 13.5%; 95% CI, 1.9%-25.1%) or included age, sex, and acute kidney injury stage alone (integrated discrimination improvement, 8.0%; 95% CI, 5.1%-11.0%; categorical net reclassification index, 79.9%; 95% CI, 60.9%-98.9%). A multivariable model using routine laboratory data was able to predict advanced chronic kidney disease following hospitalization with acute kidney injury. The utility of this model in clinical care requires further research.

Reliable prediction of clinical outcome in patients with chronic HCV infection and compensated advanced hepatic fibrosis: a validated model using objective and readily available clinical parameters.

PubMed

van der Meer, Adriaan J; Hansen, Bettina E; Fattovich, Giovanna; Feld, Jordan J; Wedemeyer, Heiner; Dufour, Jean-François; Lammert, Frank; Duarte-Rojo, Andres; Manns, Michael P; Ieluzzi, Donatella; Zeuzem, Stefan; Hofmann, W Peter; de Knegt, Robert J; Veldt, Bart J; Janssen, Harry L A

2015-02-01

Reliable tools to predict long-term outcome among patients with well compensated advanced liver disease due to chronic HCV infection are lacking. Risk scores for mortality and for cirrhosis-related complications were constructed with Cox regression analysis in a derivation cohort and evaluated in a validation cohort, both including patients with chronic HCV infection and advanced fibrosis. In the derivation cohort, 100/405 patients died during a median 8.1 (IQR 5.7-11.1) years of follow-up. Multivariate Cox analyses showed age (HR=1.06, 95% CI 1.04 to 1.09, p<0.001), male sex (HR=1.91, 95% CI 1.10 to 3.29, p=0.021), platelet count (HR=0.91, 95% CI 0.87 to 0.95, p<0.001) and log10 aspartate aminotransferase/alanine aminotransferase ratio (HR=1.30, 95% CI 1.12 to 1.51, p=0.001) were independently associated with mortality (C statistic=0.78, 95% CI 0.72 to 0.83). In the validation cohort, 58/296 patients with cirrhosis died during a median of 6.6 (IQR 4.4-9.0) years. Among patients with estimated 5-year mortality risks <5%, 5-10% and >10%, the observed 5-year mortality rates in the derivation cohort and validation cohort were 0.9% (95% CI 0.0 to 2.7) and 2.6% (95% CI 0.0 to 6.1), 8.1% (95% CI 1.8 to 14.4) and 8.0% (95% CI 1.3 to 14.7), 21.8% (95% CI 13.2 to 30.4) and 20.9% (95% CI 13.6 to 28.1), respectively (C statistic in validation cohort = 0.76, 95% CI 0.69 to 0.83). The risk score for cirrhosis-related complications also incorporated HCV genotype (C statistic = 0.80, 95% CI 0.76 to 0.83 in the derivation cohort; and 0.74, 95% CI 0.68 to 0.79 in the validation cohort). Prognosis of patients with chronic HCV infection and compensated advanced liver disease can be accurately assessed with risk scores including readily available objective clinical parameters. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Development and validation of visceral fat quantification as a surrogate marker for differentiation of Crohn's disease and intestinal tuberculosis.

PubMed

Yadav, Dawesh Prakash; Madhusudhan, Kumble Seetharama; Kedia, Saurabh; Sharma, Raju; Pratap Mouli, Venigalla; Bopanna, Sawan; Dhingra, Rajan; Pradhan, Rajesh; Goyal, Sandeep; Sreenivas, Vishnubhatla; Vikram, Naval K; Makharia, Govind; Ahuja, Vineet

2017-02-01

Crohn's disease (CD) and intestinal tuberculosis (ITB) have close phenotypic resemblance. Mesenteric fat (a component of visceral fat [VF]) hypertrophy and fat wrapping, which is visible radiologically as fibrofatty proliferation, is seen more commonly in CD than in ITB. The present study was conducted to study the role of VF in differentiating CD and ITB. Visceral fat area and subcutaneous (SC) fat area were measured on computed tomography in two cohorts (development and validation). VF/SC ratio was also calculated for all patients. In the development cohort, retrospective data collection was carried out for 75 patients with CD and ITB who were on follow-up from January 2012 to November 2014. In the validation cohort, 82 patients were recruited prospectively from December 2014 to December 2015 and were diagnosed as CD or ITB according to standard diagnostic criteria. Visceral fat area and VF/SC ratio were significantly higher in CD patients (n = 42: development, n = 46: validation) than in ITB patients (n = 33: development, n = 36: validation) in both the development (106.2 ± 63.5 vs 37.3 ± 22, P = <0.001; 1.1 ± 0.57 vs 0.43 ± 0.24, P = <0.001) and validation cohorts (102.2 ± 69.8 vs 55.8 ± 44.9, P = 0.01; 1.2 ± 0.68 vs 0.56 ± 0.33, P = <0.001). A cut-off of 0.63 for VF/SC ratio in the development cohort had a high sensitivity (82%) and specificity (81%) in differentiating CD and ITB. Similar sensitivity (81%) and specificity (78%) were seen when this cut-off was applied in the validation cohort. The VF/SC ratio is a simple, cost-effective, non-invasive and single objective parameter with a good sensitivity and specificity to differentiate CD and ITB. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Evaluation of a methodology to validate National Death Index retrieval results among a cohort of U.S. service members.

PubMed

Skopp, Nancy A; Smolenski, Derek J; Schwesinger, Daniel A; Johnson, Christopher J; Metzger-Abamukong, Melinda J; Reger, Mark A

2017-06-01

Accurate knowledge of the vital status of individuals is critical to the validity of mortality research. National Death Index (NDI) and NDI-Plus are comprehensive epidemiological resources for mortality ascertainment and cause of death data that require additional user validation. Currently, there is a gap in methods to guide validation of NDI search results rendered for active duty service members. The purpose of this research was to adapt and evaluate the CDC National Program of Cancer Registries (NPCR) algorithm for mortality ascertainment in a large military cohort. We adapted and applied the NPCR algorithm to a cohort of 7088 service members on active duty at the time of death at some point between 2001 and 2009. We evaluated NDI validity and NDI-Plus diagnostic agreement against the Department of Defense's Armed Forces Medical Examiner System (AFMES). The overall sensitivity of the NDI to AFMES records after the application of the NPCR algorithm was 97.1%. Diagnostic estimates of measurement agreement between the NDI-Plus and the AFMES cause of death groups were high. The NDI and NDI-Plus can be successfully used with the NPCR algorithm to identify mortality and cause of death among active duty military cohort members who die in the United States. Published by Elsevier Inc.

Independent surgical validation of the new prostate cancer grade-grouping system.

PubMed

Spratt, Daniel E; Cole, Adam I; Palapattu, Ganesh S; Weizer, Alon Z; Jackson, William C; Montgomery, Jeffrey S; Dess, Robert T; Zhao, Shuang G; Lee, Jae Y; Wu, Angela; Kunju, Lakshmi P; Talmich, Emily; Miller, David C; Hollenbeck, Brent K; Tomlins, Scott A; Feng, Felix Y; Mehra, Rohit; Morgan, Todd M

2016-11-01

To report the independent prognostic impact of the new prostate cancer grade-grouping system in a large external validation cohort of patients treated with radical prostatectomy (RP). Between 1994 and 2013, 3 694 consecutive men were treated with RP at a single institution. To investigate the performance of and validate the grade-grouping system, biochemical recurrence-free survival (bRFS) rates were assessed using Kaplan-Meier tests, Cox-regression modelling, and discriminatory comparison analyses. Separate analyses were performed based on biopsy and RP grade. The median follow-up was 52.7 months. The 5-year actuarial bRFS for biopsy grade groups 1-5 were 94.2%, 89.2%, 73.1%, 63.1%, and 54.7%, respectively (P < 0.001). Similarly, the 5-year actuarial bRFS based on RP grade groups was 96.1%, 93.0%, 74.0%, 64.4%, and 49.9% for grade groups 1-5, respectively (P < 0.001). The adjusted hazard ratios for bRFS relative to biopsy grade group 1 were 1.98, 4.20, 5.57, and 9.32 for groups 2, 3, 4, and 5, respectively (P < 0.001), and for RP grade groups were 2.09, 5.27, 5.86, and 10.42 (P < 0.001). The five-grade-group system had a higher prognostic discrimination compared with the commonly used three-tier system (Gleason score 6 vs 7 vs 8-10). In an independent surgical cohort, we have validated the prognostic benefit of the new prostate cancer grade-grouping system for bRFS, and shown that the benefit is maintained after adjusting for important clinicopathological variables. The greater predictive accuracy of the new system will improve risk stratification in the clinical setting and aid in patient counselling. © 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.

The factor structure of the Buss and Plomin EAS Temperament Survey (parental ratings) in a Dutch sample of elementary school children.

PubMed

Boer, F; Westenberg, P M

1994-06-01

The psychometric properties of the Buss and Plomin (1984) EAS Temperament Survey for Children (Parental Ratings) were examined in a sample of Dutch children between 4 and 13 years of age. Ratings were obtained from 230 mothers and 172 fathers. The findings presented here provide the lacking cross-validation of the original analyses by Rowe and Plomin (1977): Emotionality, activity, and shyness were independent temperaments, regardless of age and gender. The factorial position of the yet experimental Sociability scale is more ambiguous: Sociability was significantly related to both shyness and activity but was more strongly associated with shyness in the youngest age cohort and most strongly with activity in the oldest cohort. This age trend, combined with a positive association with activity, supports the premise that sociability cannot be equated to nonshyness and justifies the inclusion of a separate Sociability scale in the EAS. All four EAS scales are reliable in terms of internal consistency and interrater agreement, but one modification of the Sociability scale is needed.

Electronic Versus Manual Data Processing: Evaluating the Use of Electronic Health Records in Out-of-Hospital Clinical Research

PubMed Central

Newgard, Craig D.; Zive, Dana; Jui, Jonathan; Weathers, Cody; Daya, Mohamud

2011-01-01

Objectives To compare case ascertainment, agreement, validity, and missing values for clinical research data obtained, processed, and linked electronically from electronic health records (EHR), compared to “manual” data processing and record abstraction in a cohort of out-ofhospital trauma patients. Methods This was a secondary analysis of two sets of data collected for a prospective, population-based, out-of-hospital trauma cohort evaluated by 10 emergency medical services (EMS) agencies transporting to 16 hospitals, from January 1, 2006 through October 2, 2007. Eighteen clinical, operational, procedural, and outcome variables were collected and processed separately and independently using two parallel data processing strategies, by personnel blinded to patients in the other group. The electronic approach included electronic health record data exports from EMS agencies, reformatting and probabilistic linkage to outcomes from local trauma registries and state discharge databases. The manual data processing approach included chart matching, data abstraction, and data entry by a trained abstractor. Descriptive statistics, measures of agreement, and validity were used to compare the two approaches to data processing. Results During the 21-month period, 418 patients underwent both data processing methods and formed the primary cohort. Agreement was good to excellent (kappa 0.76 to 0.97; intraclass correlation coefficient 0.49 to 0.97), with exact agreement in 67% to 99% of cases, and a median difference of zero for all continuous and ordinal variables. The proportions of missing out-of-hospital values were similar between the two approaches, although electronic processing generated more missing outcomes (87 out of 418, 21%, 95% CI = 17% to 25%) than the manual approach (11 out of 418, 3%, 95% CI = 1% to 5%). Case ascertainment of eligible injured patients was greater using electronic methods (n = 3,008) compared to manual methods (n = 629). Conclusions In this sample of out-of-hospital trauma patients, an all-electronic data processing strategy identified more patients and generated values with good agreement and validity compared to traditional data collection and processing methods. PMID:22320373

Long-Acting β-Agonist in Combination or Separate Inhaler as Step-Up Therapy for Children with Uncontrolled Asthma Receiving Inhaled Corticosteroids.

PubMed

Turner, Steve; Richardson, Kathryn; Murray, Clare; Thomas, Mike; Hillyer, Elizabeth V; Burden, Anne; Price, David B

Adding a long-acting β 2 -agonist (LABA) to inhaled corticosteroids (ICS) using a fixed-dose combination (FDC) inhaler is the UK guideline recommendation for children aged more than 4 years with uncontrolled asthma. The evidence of benefit of adding an FDC inhaler over a separate LABA inhaler is limited. The objective of this study was to compare the effectiveness of a LABA added as an FDC inhaler, and as a separate inhaler, in children with uncontrolled asthma. Two UK primary care databases were used to create a matched cohort study with a 2-year follow-up period. We included children prescribed their first step-up from ICS monotherapy. Two cohorts were formed for children receiving an add-on LABA as an FDC inhaler, or a separate LABA inhaler. Matching variables and confounders were identified by comparing characteristics during a baseline year of follow-up. Outcomes were examined during the subsequent year. The primary outcome was an adjusted odds ratio for overall asthma control (defined as follows: no asthma-related hospital admission or emergency room visit, prescription for oral corticosteroids or antibiotic with evidence of respiratory consultation, and ≤2 puffs of short-acting β-agonist daily). The final study consisted of 1330 children in each cohort (mean age 9 years; 59% male). In the separate ICS+LABA cohort, the odds of achieving overall asthma control were lower (adjusted odds ratio, 0.77 [95% confidence interval, 0.66-0.91]; P = .001) compared with the FDC cohort. The study demonstrates a small but significant benefit in achieving asthma control from an add-on LABA as an FDC, compared with a separate inhaler and this supports current guideline recommendations. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Introducing a novel highly prognostic grading scheme based on tumour budding and cell nest size for squamous cell carcinoma of the uterine cervix.

PubMed

Jesinghaus, Moritz; Strehl, Johanna; Boxberg, Melanie; Brühl, Frido; Wenzel, Adrian; Konukiewitz, Björn; Schlitter, Anna M; Steiger, Katja; Warth, Arne; Schnelzer, Andreas; Kiechle, Marion; Beckmann, Matthias W; Noske, Aurelia; Hartmann, Arndt; Mehlhorn, Grit; Koch, Martin C; Weichert, Wilko

2018-04-01

A novel histopathological grading system based on tumour budding and cell nest size has recently been shown to outperform conventional (WHO-based) grading algorithms in several tumour entities such as lung, oral, and oesophageal squamous cell carcinoma (SCC) in terms of prognostic patient stratification. Here, we tested the prognostic value of this innovative grading approach in two completely independent cohorts of SCC of the uterine cervix. To improve morphology-based grading, we investigated tumour budding activity and cell nest size as well as several other histomorphological factors (e.g., keratinization, nuclear size, mitotic activity) in a test cohort (n = 125) and an independent validation cohort (n = 122) of cervical SCC. All parameters were correlated with clinicopathological factors and patient outcome. Small cell nest size and high tumour budding activity were strongly associated with a dismal patient prognosis (p < 0.001 for overall survival [OS], disease-specific survival, and disease-free survival; test cohort) in both cohorts of cervical SCC. A novel grading algorithm combining these two parameters proved to be a highly effective, stage-independent prognosticator in both cohorts (OS: p < 0.001, test cohort; p = 0.001, validation cohort). In the test cohort, multivariate statistical analysis of the novel grade revealed that the hazard ratio (HR) for OS was 2.3 for G2 and 5.1 for G3 tumours compared to G1 neoplasms (p = 0.010). In the validation cohort, HR for OS was 3.0 for G2 and 7.2 for G3 tumours (p = 0.012). In conclusion, our novel grading algorithm incorporating cell nest size and tumour budding allows strongly prognostic histopathological grading of cervical SCC superior to WHO-based grading. Therefore, our data can be regarded as a cross-organ validation of previous results demonstrated for oesophageal, lung, and oral SCC. We suggest this grading algorithm as an additional morphology-based parameter for the routine diagnostic assessment of this tumour entity. © 2018 The Authors The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.

Health Assessment Questionnaire disability progression in early rheumatoid arthritis: Systematic review and analysis of two inception cohorts

PubMed Central

Norton, Sam; Fu, Bo; Scott, David L.; Deighton, Chris; Symmons, Deborah P.M.; Wailoo, Allan J.; Tosh, Jonathan; Lunt, Mark; Davies, Rebecca; Young, Adam; Verstappen, Suzanne M.M

2014-01-01

Objective The Health Assessment Questionnaire is widely used for patients with inflammatory polyarthritis (IP) and its subset, rheumatoid arthritis (RA). In this study, we evaluated the progression of HAQ scores in RA (i) by systematically reviewing the published literature on the methods used to assess changes in functional disability over time and (ii) to study in detail HAQ progression in two large prospective observational studies from the UK. Methods Data from two large inception cohorts, ERAS and NOAR, were studied to determine trajectories of HAQ progression over time by applying latent class growth models (LCGMs) to each dataset separately. Age, sex, baseline DAS28, symptom duration, rheumatoid factor, fulfilment of the 1987 ACR criteria and socio-economic status (SES) were included as potential predictors of HAQ trajectory subgroup membership. Results The literature search identified 49 studies showing that HAQ progression has mainly been based on average changes in the total study population. In the HAQ progression study, a LCGM with four HAQ trajectory subgroups was selected as providing the best fit in both cohorts. In both the cohorts, older age, female sex, longer symptom duration, fulfilment of the 1987 ACR criteria, higher DAS28 and lower SES were associated with increased likelihood of membership of subgroups with worse HAQ progression. Conclusion Four distinct HAQ trajectory subgroups were derived from the ERAS and NOAR cohorts. The fact that the subgroups identified were nearly identical supports their validity. Identifying distinct groups of patients who are at risk of poor functional outcome may help to target therapy to those who are most likely to benefit. PMID:24925692

Development and validation of a gene expression-based signature to predict distant metastasis in locoregionally advanced nasopharyngeal carcinoma: a retrospective, multicentre, cohort study.

PubMed

Tang, Xin-Ran; Li, Ying-Qin; Liang, Shao-Bo; Jiang, Wei; Liu, Fang; Ge, Wen-Xiu; Tang, Ling-Long; Mao, Yan-Ping; He, Qing-Mei; Yang, Xiao-Jing; Zhang, Yuan; Wen, Xin; Zhang, Jian; Wang, Ya-Qin; Zhang, Pan-Pan; Sun, Ying; Yun, Jing-Ping; Zeng, Jing; Li, Li; Liu, Li-Zhi; Liu, Na; Ma, Jun

2018-03-01

Gene expression patterns can be used as prognostic biomarkers in various types of cancers. We aimed to identify a gene expression pattern for individual distant metastatic risk assessment in patients with locoregionally advanced nasopharyngeal carcinoma. In this multicentre, retrospective, cohort analysis, we included 937 patients with locoregionally advanced nasopharyngeal carcinoma from three Chinese hospitals: the Sun Yat-sen University Cancer Center (Guangzhou, China), the Affiliated Hospital of Guilin Medical University (Guilin, China), and the First People's Hospital of Foshan (Foshan, China). Using microarray analysis, we profiled mRNA gene expression between 24 paired locoregionally advanced nasopharyngeal carcinoma tumours from patients at Sun Yat-sen University Cancer Center with or without distant metastasis after radical treatment. Differentially expressed genes were examined using digital expression profiling in a training cohort (Guangzhou training cohort; n=410) to build a gene classifier using a penalised regression model. We validated the prognostic accuracy of this gene classifier in an internal validation cohort (Guangzhou internal validation cohort, n=204) and two external independent cohorts (Guilin cohort, n=165; Foshan cohort, n=158). The primary endpoint was distant metastasis-free survival. Secondary endpoints were disease-free survival and overall survival. We identified 137 differentially expressed genes between metastatic and non-metastatic locoregionally advanced nasopharyngeal carcinoma tissues. A distant metastasis gene signature for locoregionally advanced nasopharyngeal carcinoma (DMGN) that consisted of 13 genes was generated to classify patients into high-risk and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter distant metastasis-free survival (hazard ratio [HR] 4·93, 95% CI 2·99-8·16; p<0·0001), disease-free survival (HR 3·51, 2·43-5·07; p<0·0001), and overall survival (HR 3·22, 2·18-4·76; p<0·0001) than patients with low-risk scores. The prognostic accuracy of DMGN was validated in the internal and external cohorts. Furthermore, among patients with low-risk scores in the combined training and internal cohorts, concurrent chemotherapy improved distant metastasis-free survival compared with those patients who did not receive concurrent chemotherapy (HR 0·40, 95% CI 0·19-0·83; p=0·011), whereas patients with high-risk scores did not benefit from concurrent chemotherapy (HR 1·03, 0·71-1·50; p=0·876). This was also validated in the two external cohorts combined. We developed a nomogram based on the DMGN and other variables that predicted an individual's risk of distant metastasis, which was strengthened by adding Epstein-Barr virus DNA status. The DMGN is a reliable prognostic tool for distant metastasis in patients with locoregionally advanced nasopharyngeal carcinoma and might be able to predict which patients benefit from concurrent chemotherapy. It has the potential to guide treatment decisions for patients at different risk of distant metastasis. The National Natural Science Foundation of China, the National Science & Technology Pillar Program during the Twelfth Five-year Plan Period, the Natural Science Foundation of Guang Dong Province, the National Key Research and Development Program of China, the Innovation Team Development Plan of the Ministry of Education, the Health & Medical Collaborative Innovation Project of Guangzhou City, China, and the Program of Introducing Talents of Discipline to Universities. Copyright © 2018 Elsevier Ltd. All rights reserved.

A microRNA-based prediction model for lymph node metastasis in hepatocellular carcinoma.

PubMed

Zhang, Li; Xiang, Zuo-Lin; Zeng, Zhao-Chong; Fan, Jia; Tang, Zhao-You; Zhao, Xiao-Mei

2016-01-19

We developed an efficient microRNA (miRNA) model that could predict the risk of lymph node metastasis (LNM) in hepatocellular carcinoma (HCC). We first evaluated a training cohort of 192 HCC patients after hepatectomy and found five LNM associated predictive factors: vascular invasion, Barcelona Clinic Liver Cancer stage, miR-145, miR-31, and miR-92a. The five statistically independent factors were used to develop a predictive model. The predictive value of the miRNA-based model was confirmed in a validation cohort of 209 consecutive HCC patients. The prediction model was scored for LNM risk from 0 to 8. The cutoff value 4 was used to distinguish high-risk and low-risk groups. The model sensitivity and specificity was 69.6 and 80.2%, respectively, during 5 years in the validation cohort. And the area under the curve (AUC) for the miRNA-based prognostic model was 0.860. The 5-year positive and negative predictive values of the model in the validation cohort were 30.3 and 95.5%, respectively. Cox regression analysis revealed that the LNM hazard ratio of the high-risk versus low-risk groups was 11.751 (95% CI, 5.110-27.021; P < 0.001) in the validation cohort. In conclusion, the miRNA-based model is reliable and accurate for the early prediction of LNM in patients with HCC.

Risk factors and nomogram for pancreatic pseudocysts in chronic pancreatitis: A cohort of 1998 patients.

PubMed

Hao, Lu; Pan, Jun; Wang, Dan; Bi, Ya-Wei; Ji, Jun-Tao; Xin, Lei; Liao, Zhuan; Du, Ting-Ting; Lin, Jin-Huan; Zhang, Di; Zeng, Xiang-Peng; Ye, Bo; Zou, Wen-Bin; Chen, Hui; Xie, Ting; Li, Bai-Rong; Zheng, Zhao-Hong; Hu, Liang-Hao; Li, Zhao-Shen

2017-07-01

Pancreatic pseudocyst is a common complication of chronic pancreatitis. The identification of risk factors and development of a nomogram for pancreatic pseudocysts in chronic pancreatitis patients may contribute to the early diagnosis and intervention of pancreatic pseudocysts. Patients with chronic pancreatitis admitted to our center from January 2000 to December 2013 were enrolled. Cumulative rates of pancreatic pseudocysts after the onset of chronic pancreatitis and after the diagnosis of chronic pancreatitis were calculated. Patients were randomly assigned, in a 2:1 ratio, to the training and validation cohort. Based on the training cohort, risk factors were identified through Cox proportional hazards regression model, and nomogram was developed. Internal and external validations were performed based on the training and validation cohort, respectively. With a total of 1998 patients, pancreatic pseudocysts were detected in 228 (11.41%) patients. Age at the onset of chronic pancreatitis, smoking, and severe acute pancreatitis were identified risk factors for pancreatic pseudocysts development while steatorrhea and pancreatic stones were protective factors. Incorporating these five factors, the nomogram achieved good concordance indexes of 0.735 and 0.628 in the training and validation cohorts, respectively, with well-fitted calibration curves. The nomogram achieved an individualized prediction of pancreatic pseudocysts development in chronic pancreatitis. It may help the early diagnosis and management of pancreatic pseudocysts. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

A prospectively validated nomogram for predicting the risk of chemotherapy-induced febrile neutropenia: a multicenter study.

PubMed

Bozcuk, H; Yıldız, M; Artaç, M; Kocer, M; Kaya, Ç; Ulukal, E; Ay, S; Kılıç, M P; Şimşek, E H; Kılıçkaya, P; Uçar, S; Coskun, H S; Savas, B

2015-06-01

There is clinical need to predict risk of febrile neutropenia before a specific cycle of chemotherapy in cancer patients. Data on 3882 chemotherapy cycles in 1089 consecutive patients with lung, breast, and colon cancer from four teaching hospitals were used to construct a predictive model for febrile neutropenia. A final nomogram derived from the multivariate predictive model was prospectively confirmed in a second cohort of 960 consecutive cases and 1444 cycles. The following factors were used to construct the nomogram: previous history of febrile neutropenia, pre-cycle lymphocyte count, type of cancer, cycle of current chemotherapy, and patient age. The predictive model had a concordance index of 0.95 (95 % confidence interval (CI) = 0.91-0.99) in the derivation cohort and 0.85 (95 % CI = 0.80-0.91) in the external validation cohort. A threshold of 15 % for the risk of febrile neutropenia in the derivation cohort was associated with a sensitivity of 0.76 and specificity of 0.98. These figures were 1.00 and 0.49 in the validation cohort if a risk threshold of 50 % was chosen. This nomogram is helpful in the prediction of febrile neutropenia after chemotherapy in patients with lung, breast, and colon cancer. Usage of this nomogram may help decrease the morbidity and mortality associated with febrile neutropenia and deserves further validation.

A new model of wheezing severity in young children using the validated ISAAC wheezing module: A latent variable approach with validation in independent cohorts.

PubMed

Brunwasser, Steven M; Gebretsadik, Tebeb; Gold, Diane R; Turi, Kedir N; Stone, Cosby A; Datta, Soma; Gern, James E; Hartert, Tina V

2018-01-01

The International Study of Asthma and Allergies in Children (ISAAC) Wheezing Module is commonly used to characterize pediatric asthma in epidemiological studies, including nearly all airway cohorts participating in the Environmental Influences on Child Health Outcomes (ECHO) consortium. However, there is no consensus model for operationalizing wheezing severity with this instrument in explanatory research studies. Severity is typically measured using coarsely-defined categorical variables, reducing power and potentially underestimating etiological associations. More precise measurement approaches could improve testing of etiological theories of wheezing illness. We evaluated a continuous latent variable model of pediatric wheezing severity based on four ISAAC Wheezing Module items. Analyses included subgroups of children from three independent cohorts whose parents reported past wheezing: infants ages 0-2 in the INSPIRE birth cohort study (Cohort 1; n = 657), 6-7-year-old North American children from Phase One of the ISAAC study (Cohort 2; n = 2,765), and 5-6-year-old children in the EHAAS birth cohort study (Cohort 3; n = 102). Models were estimated using structural equation modeling. In all cohorts, covariance patterns implied by the latent variable model were consistent with the observed data, as indicated by non-significant χ2 goodness of fit tests (no evidence of model misspecification). Cohort 1 analyses showed that the latent factor structure was stable across time points and child sexes. In both cohorts 1 and 3, the latent wheezing severity variable was prospectively associated with wheeze-related clinical outcomes, including physician asthma diagnosis, acute corticosteroid use, and wheeze-related outpatient medical visits when adjusting for confounders. We developed an easily applicable continuous latent variable model of pediatric wheezing severity based on items from the well-validated ISAAC Wheezing Module. This model prospectively associates with asthma morbidity, as demonstrated in two ECHO birth cohort studies, and provides a more statistically powerful method of testing etiologic hypotheses of childhood wheezing illness and asthma.

Development of an Unrelated Donor Selection Score Predictive of Survival after HCT: Donor Age Matters Most.

PubMed

Shaw, Bronwen E; Logan, Brent R; Spellman, Stephen R; Marsh, Steven G E; Robinson, James; Pidala, Joseph; Hurley, Carolyn; Barker, Juliet; Maiers, Martin; Dehn, Jason; Wang, Hailin; Haagenson, Mike; Porter, David; Petersdorf, Effie W; Woolfrey, Ann; Horowitz, Mary M; Verneris, Michael; Hsu, Katharine C; Fleischhauer, Katharina; Lee, Stephanie J

2018-05-01

Donor factors, in addition to HLA matching status, have been associated with recipient survival in unrelated donor (URD) hematopoietic cell transplantation (HCT); however, there is no hierarchical algorithm that weights the characteristics of individual donors against each other in a quantitative manner to facilitate donor selection. The goal of this study was to develop and validate a donor selection score that prioritizes donor characteristics associated with better survival in 8/8 HLA-matched URDs. Two separate patient/donor cohorts, the first receiving HCT between 1999 and 2011 (n = 5952, c1), and the second between 2012 and 2014 (n = 4510, c2) were included in the analysis. Both cohorts were randomly spilt, 2:1, into training and testing sets. Despite studying over 10,000 URD transplants, we were unable to validate a donor selection score. The only donor characteristic associated with better survival was younger age, with 2-year survival being 3% better when a donor 10 years younger is selected. These results support previous studies suggesting prioritization of a younger 8/8 HLA-matched donor. This large dataset also shows that none of the other donor clinical factors tested were reproducibly associated with survival, and hence flexibility in selecting URDs based on other characteristics is justified. These data support a simplified URD selection process and have significant implications for URD registries. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

26 CFR 1.1041-2 - Redemptions of stock.

Code of Federal Regulations, 2010 CFR

2010-04-01

... paragraph (a)(2) of this section, if a divorce or separation instrument, or a valid written agreement... of paragraph (a)(1) of this section, if a divorce or separation instrument, or a valid written... paragraph (c), a divorce or separation instrument must be effective, or a valid written agreement must be...

26 CFR 1.1041-2 - Redemptions of stock.

Code of Federal Regulations, 2014 CFR

2014-04-01

... paragraph (a)(2) of this section, if a divorce or separation instrument, or a valid written agreement... of paragraph (a)(1) of this section, if a divorce or separation instrument, or a valid written... paragraph (c), a divorce or separation instrument must be effective, or a valid written agreement must be...

26 CFR 1.1041-2 - Redemptions of stock.

Code of Federal Regulations, 2013 CFR

2013-04-01

... paragraph (a)(2) of this section, if a divorce or separation instrument, or a valid written agreement... of paragraph (a)(1) of this section, if a divorce or separation instrument, or a valid written... paragraph (c), a divorce or separation instrument must be effective, or a valid written agreement must be...

26 CFR 1.1041-2 - Redemptions of stock.

Code of Federal Regulations, 2011 CFR

2011-04-01

... paragraph (a)(2) of this section, if a divorce or separation instrument, or a valid written agreement... of paragraph (a)(1) of this section, if a divorce or separation instrument, or a valid written... paragraph (c), a divorce or separation instrument must be effective, or a valid written agreement must be...

26 CFR 1.1041-2 - Redemptions of stock.

Code of Federal Regulations, 2012 CFR

2012-04-01

... paragraph (a)(2) of this section, if a divorce or separation instrument, or a valid written agreement... of paragraph (a)(1) of this section, if a divorce or separation instrument, or a valid written... paragraph (c), a divorce or separation instrument must be effective, or a valid written agreement must be...

Proteomic signatures in plasma during early acute renal allograft rejection.

PubMed

Freue, Gabriela V Cohen; Sasaki, Mayu; Meredith, Anna; Günther, Oliver P; Bergman, Axel; Takhar, Mandeep; Mui, Alice; Balshaw, Robert F; Ng, Raymond T; Opushneva, Nina; Hollander, Zsuzsanna; Li, Guiyun; Borchers, Christoph H; Wilson-McManus, Janet; McManus, Bruce M; Keown, Paul A; McMaster, W Robert

2010-09-01

Acute graft rejection is an important clinical problem in renal transplantation and an adverse predictor for long term graft survival. Plasma biomarkers may offer an important option for post-transplant monitoring and permit timely and effective therapeutic intervention to minimize graft damage. This case-control discovery study (n = 32) used isobaric tagging for relative and absolute protein quantification (iTRAQ) technology to quantitate plasma protein relative concentrations in precise cohorts of patients with and without biopsy-confirmed acute rejection (BCAR). Plasma samples were depleted of the 14 most abundant plasma proteins to enhance detection sensitivity. A total of 18 plasma proteins that encompassed processes related to inflammation, complement activation, blood coagulation, and wound repair exhibited significantly different relative concentrations between patient cohorts with and without BCAR (p value <0.05). Twelve proteins with a fold-change >or=1.15 were selected for diagnostic purposes: seven were increased (titin, lipopolysaccharide-binding protein, peptidase inhibitor 16, complement factor D, mannose-binding lectin, protein Z-dependent protease and beta(2)-microglobulin) and five were decreased (kininogen-1, afamin, serine protease inhibitor, phosphatidylcholine-sterol acyltransferase, and sex hormone-binding globulin) in patients with BCAR. The first three principal components of these proteins showed clear separation of cohorts with and without BCAR. Performance improved with the inclusion of sequential proteins, reaching a primary asymptote after the first three (titin, kininogen-1, and lipopolysaccharide-binding protein). Longitudinal monitoring over the first 3 months post-transplant based on ratios of these three proteins showed clear discrimination between the two patient cohorts at time of rejection. The score then declined to baseline following treatment and resolution of the rejection episode and remained comparable between cases and controls throughout the period of quiescent follow-up. Results were validated using ELISA where possible, and initial cross-validation estimated a sensitivity of 80% and specificity of 90% for classification of BCAR based on a four-protein ELISA classifier. This study provides evidence that protein concentrations in plasma may provide a relevant measure for the occurrence of BCAR and offers a potential tool for immunologic monitoring.

A Simple, Evidence-Based Approach to Help Guide Diagnosis of Heart Failure with Preserved Ejection Fraction.

PubMed

Reddy, Yogesh N V; Carter, Rickey E; Obokata, Masaru; Redfield, Margaret M; Borlaug, Barry A

2018-05-23

Background -Diagnosis of heart failure with preserved ejection fraction (HFpEF) is challenging in euvolemic patients with dyspnea, and no evidence-based criteria are available. We sought to develop and then validate non-invasive diagnostic criteria that could be used to estimate the likelihood that HFpEF is present among patients with unexplained dyspnea in order to guide further testing. Methods -Consecutive patients with unexplained dyspnea referred for invasive hemodynamic exercise testing were retrospectively evaluated. Diagnosis of HFpEF (case) or non-cardiac dyspnea (control) was ascertained by invasive hemodynamic exercise testing. Logistic regression was performed to evaluate the ability of clinical findings to discriminate cases from controls. A scoring system was developed and then validated in a separate test cohort. Results -The derivation cohort included 414 consecutive patients (267 HFpEF and 147 controls, HFpEF prevalence 64%). The test cohort included 100 consecutive patients (61 HFpEF, prevalence 61%). Obesity, atrial fibrillation, age>60 years, treatment with 2 or more antihypertensives, echocardiographic E/e' ratio>9 and echocardiographic pulmonary artery systolic pressure>35 mmHg were selected as the final set of predictive variables. A weighted score based on these six variables was used to create a composite score (H 2 FPEF score) ranging from 0-9. The odds of HFpEF doubled for each 1 unit score increase [OR 1.98 [1.74-2.30], p<0.0001], with an AUC of 0.841 (p<0.0001). The H 2 FPEF score was superior to a currently-used algorithm based upon expert consensus (increase in AUC of +0.169 [+0.120 to +0.217], p<0.0001). Performance in the independent test cohort was maintained [AUC 0.886, p<0.0001]. Conclusions -The H 2 FPEF score, which relies upon simple clinical characteristics and echocardiography, enables discrimination of HFpEF from non-cardiac causes of dyspnea, and can assist in determination of the need for further diagnostic testing in the evaluation of patients with unexplained exertional dyspnea.

Proteomic Signatures in Plasma during Early Acute Renal Allograft Rejection*

PubMed Central

Freue, Gabriela V. Cohen; Sasaki, Mayu; Meredith, Anna; Günther, Oliver P.; Bergman, Axel; Takhar, Mandeep; Mui, Alice; Balshaw, Robert F.; Ng, Raymond T.; Opushneva, Nina; Hollander, Zsuzsanna; Li, Guiyun; Borchers, Christoph H.; Wilson-McManus, Janet; McManus, Bruce M.; Keown, Paul A.; McMaster, W. Robert

2010-01-01

Acute graft rejection is an important clinical problem in renal transplantation and an adverse predictor for long term graft survival. Plasma biomarkers may offer an important option for post-transplant monitoring and permit timely and effective therapeutic intervention to minimize graft damage. This case-control discovery study (n = 32) used isobaric tagging for relative and absolute protein quantification (iTRAQ) technology to quantitate plasma protein relative concentrations in precise cohorts of patients with and without biopsy-confirmed acute rejection (BCAR). Plasma samples were depleted of the 14 most abundant plasma proteins to enhance detection sensitivity. A total of 18 plasma proteins that encompassed processes related to inflammation, complement activation, blood coagulation, and wound repair exhibited significantly different relative concentrations between patient cohorts with and without BCAR (p value <0.05). Twelve proteins with a fold-change ≥1.15 were selected for diagnostic purposes: seven were increased (titin, lipopolysaccharide-binding protein, peptidase inhibitor 16, complement factor D, mannose-binding lectin, protein Z-dependent protease and β2-microglobulin) and five were decreased (kininogen-1, afamin, serine protease inhibitor, phosphatidylcholine-sterol acyltransferase, and sex hormone-binding globulin) in patients with BCAR. The first three principal components of these proteins showed clear separation of cohorts with and without BCAR. Performance improved with the inclusion of sequential proteins, reaching a primary asymptote after the first three (titin, kininogen-1, and lipopolysaccharide-binding protein). Longitudinal monitoring over the first 3 months post-transplant based on ratios of these three proteins showed clear discrimination between the two patient cohorts at time of rejection. The score then declined to baseline following treatment and resolution of the rejection episode and remained comparable between cases and controls throughout the period of quiescent follow-up. Results were validated using ELISA where possible, and initial cross-validation estimated a sensitivity of 80% and specificity of 90% for classification of BCAR based on a four-protein ELISA classifier. This study provides evidence that protein concentrations in plasma may provide a relevant measure for the occurrence of BCAR and offers a potential tool for immunologic monitoring. PMID:20501940

Clinical prediction models for young febrile infants at the emergency department: an international validation study.

PubMed

Vos-Kerkhof, Evelien de; Gomez, Borja; Milcent, Karen; Steyerberg, Ewout W; Nijman, Ruud Gerard; Smit, Frank J; Mintegi, Santiago; Moll, Henriette A; Gajdos, Vincent; Oostenbrink, Rianne

2018-05-24

To assess the diagnostic value of existing clinical prediction models (CPM; ie, statistically derived) in febrile young infants at risk for serious bacterial infections. A systematic literature review identified eight CPMs for predicting serious bacterial infections in febrile children. We validated these CPMs on four validation cohorts of febrile children in Spain (age <3 months), France (age <3 months) and two cohorts in the Netherlands (age 1-3 months and >3-12 months). We evaluated the performance of the CPMs by sensitivity/specificity, area under the receiver operating characteristic curve (AUC) and calibration studies. The original cohorts in which the prediction rules were developed (derivation cohorts) ranged from 381 to 15 781 children, with a prevalence of serious bacterial infections varying from 0.8% to 27% and spanned an age range of 0-16 years. All CPMs originally performed moderately to very well (AUC 0.60-0.93). The four validation cohorts included 159-2204 febrile children, with a median age range of 1.8 (1.2-2.4) months for the three cohorts <3 months and 8.4 (6.0-9.6) months for the cohort >3-12 months of age. The prevalence of serious bacterial infections varied between 15.1% and 17.2% in the three cohorts <3 months and was 9.8% for the cohort >3-12 months of age. Although discriminative values varied greatly, best performance was observed for four CPMs including clinical signs and symptoms, urine dipstick analyses and laboratory markers with AUC ranging from 0.68 to 0.94 in the three cohorts <3 months (ranges sensitivity: 0.48-0.94 and specificity: 0.71-0.97). For the >3-12 months' cohort AUC ranges from 0.80 to 0.89 (ranges sensitivity: 0.70-0.82 and specificity: 0.78-0.90). In general, the specificities exceeded sensitivities in our cohorts, in contrast to derivation cohorts with high sensitivities, although this effect was stronger in infants <3 months than in infants >3-12 months. We identified four CPMs, including clinical signs and symptoms, urine dipstick analysis and laboratory markers, which can aid clinicians in identifying serious bacterial infections. We suggest clinicians should use CPMs as an adjunctive clinical tool when assessing the risk of serious bacterial infections in febrile young infants. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Apparent and internal validity of a Monte Carlo-Markov model for cardiovascular disease in a cohort follow-up study.

PubMed

Nijhuis, Rogier L; Stijnen, Theo; Peeters, Anna; Witteman, Jacqueline C M; Hofman, Albert; Hunink, M G Myriam

2006-01-01

To determine the apparent and internal validity of the Rotterdam Ischemic heart disease & Stroke Computer (RISC) model, a Monte Carlo-Markov model, designed to evaluate the impact of cardiovascular disease (CVD) risk factors and their modification on life expectancy (LE) and cardiovascular disease-free LE (DFLE) in a general population (hereinafter, these will be referred to together as (DF)LE). The model is based on data from the Rotterdam Study, a cohort follow-up study of 6871 subjects aged 55 years and older who visited the research center for risk factor assessment at baseline (1990-1993) and completed a follow-up visit 7 years later (original cohort). The transition probabilities and risk factor trends used in the RISC model were based on data from 3501 subjects (the study cohort). To validate the RISC model, the number of simulated CVD events during 7 years' follow-up were compared with the observed number of events in the study cohort and the original cohort, respectively, and simulated (DF)LEs were compared with the (DF)LEs calculated from multistate life tables. Both in the study cohort and in the original cohort, the simulated distribution of CVD events was consistent with the observed number of events (CVD deaths: 7.1% v. 6.6% and 7.4% v. 7.6%, respectively; non-CVD deaths: 11.2% v. 11.5% and 12.9% v. 13.0%, respectively). The distribution of (DF)LEs estimated with the RISC model consistently encompassed the (DF)LEs calculated with multistate life tables. The simulated events and (DF)LE estimates from the RISC model are consistent with observed data from a cohort follow-up study.

[The Amsterdam wrist rules: the multicenter prospective derivation and external validation of a clinical decision rule for the use of radiography in acute wrist trauma].

PubMed

Walenkamp, Monique M J; Bentohami, Abdelali; Slaar, Annelie; Beerekamp, M S H Suzan; Maas, Mario; Jager, L C Cara; Sosef, Nico L; van Velde, Romuald; Ultee, Jan M; Steyerberg, Ewout W; Goslings, J C Carel; Schep, Niels W L

2016-01-01

Although only 39% of patients with wrist trauma have sustained a fracture, the majority of patients is routinely referred for radiography. The purpose of this study was to derive and externally validate a clinical decision rule that selects patients with acute wrist trauma in the Emergency Department (ED) for radiography. This multicenter prospective study consisted of three components: (1) derivation of a clinical prediction model for detecting wrist fractures in patients following wrist trauma; (2) external validation of this model; and (3) design of a clinical decision rule. The study was conducted in the EDs of five Dutch hospitals: one academic hospital (derivation cohort) and four regional hospitals (external validation cohort). We included all adult patients with acute wrist trauma. The main outcome was fracture of the wrist (distal radius, distal ulna or carpal bones) diagnosed on conventional X-rays. A total of 882 patients were analyzed; 487 in the derivation cohort and 395 in the validation cohort. We derived a clinical prediction model with eight variables: age; sex, swelling of the wrist; swelling of the anatomical snuffbox, visible deformation; distal radius tender to palpation; pain on radial deviation and painful axial compression of the thumb. The Area Under the Curve at external validation of this model was 0.81 (95% CI: 0.77-0.85). The sensitivity and specificity of the Amsterdam Wrist Rules (AWR) in the external validation cohort were 98% (95% CI: 95-99%) and 21% (95% CI: 15%-28). The negative predictive value was 90% (95% CI: 81-99%). The Amsterdam Wrist Rules is a clinical prediction rule with a high sensitivity and negative predictive value for fractures of the wrist. Although external validation showed low specificity and 100 % sensitivity could not be achieved, the Amsterdam Wrist Rules can provide physicians in the Emergency Department with a useful screening tool to select patients with acute wrist trauma for radiography. The upcoming implementation study will further reveal the impact of the Amsterdam Wrist Rules on the anticipated reduction of X-rays requested, missed fractures, Emergency Department waiting times and health care costs.

Clinical prognostic rules for severe acute respiratory syndrome in low- and high-resource settings.

PubMed

Cowling, Benjamin J; Muller, Matthew P; Wong, Irene O L; Ho, Lai-Ming; Lo, Su-Vui; Tsang, Thomas; Lam, Tai Hing; Louie, Marie; Leung, Gabriel M

2006-07-24

An accurate prognostic model for patients with severe acute respiratory syndrome (SARS) could provide a practical clinical decision aid. We developed and validated prognostic rules for both high- and low-resource settings based on data available at the time of admission. We analyzed data on all 1755 and 291 patients with SARS in Hong Kong (derivation cohort) and Toronto (validation cohort), respectively, using a multivariable logistic scoring method with internal and external validation. Scores were assigned on the basis of patient history in a basic model, and a full model additionally incorporated radiological and laboratory results. The main outcome measure was death. Predictors for mortality in the basic model included older age, male sex, and the presence of comorbid conditions. Additional predictors in the full model included haziness or infiltrates on chest radiography, less than 95% oxygen saturation on room air, high lactate dehydrogenase level, and high neutrophil and low platelet counts. The basic model had an area under the receiver operating characteristic (ROC) curve of 0.860 in the derivation cohort, which was maintained on external validation with an area under the ROC curve of 0.882. The full model improved discrimination with areas under the ROC curve of 0.877 and 0.892 in the derivation and validation cohorts, respectively. The model performs well and could be useful in assessing prognosis for patients who are infected with re-emergent SARS.

A Molecular Host Response Assay to Discriminate Between Sepsis and Infection-Negative Systemic Inflammation in Critically Ill Patients: Discovery and Validation in Independent Cohorts

PubMed Central

McHugh, Leo; Seldon, Therese A.; Brandon, Roslyn A.; Kirk, James T.; Rapisarda, Antony; Sutherland, Allison J.; Presneill, Jeffrey J.; Venter, Deon J.; Lipman, Jeffrey; Thomas, Mervyn R.; Klein Klouwenberg, Peter M. C.; van Vught, Lonneke; Scicluna, Brendon; Bonten, Marc; Cremer, Olaf L.; Schultz, Marcus J.; van der Poll, Tom; Yager, Thomas D.; Brandon, Richard B.

2015-01-01

Background Systemic inflammation is a whole body reaction having an infection-positive (i.e., sepsis) or infection-negative origin. It is important to distinguish between these two etiologies early and accurately because this has significant therapeutic implications for critically ill patients. We hypothesized that a molecular classifier based on peripheral blood RNAs could be discovered that would (1) determine which patients with systemic inflammation had sepsis, (2) be robust across independent patient cohorts, (3) be insensitive to disease severity, and (4) provide diagnostic utility. The goal of this study was to identify and validate such a molecular classifier. Methods and Findings We conducted an observational, non-interventional study of adult patients recruited from tertiary intensive care units (ICUs). Biomarker discovery utilized an Australian cohort (n = 105) consisting of 74 cases (sepsis patients) and 31 controls (post-surgical patients with infection-negative systemic inflammation) recruited at five tertiary care settings in Brisbane, Australia, from June 3, 2008, to December 22, 2011. A four-gene classifier combining CEACAM4, LAMP1, PLA2G7, and PLAC8 RNA biomarkers was identified. This classifier, designated SeptiCyte Lab, was validated using reverse transcription quantitative PCR and receiver operating characteristic (ROC) curve analysis in five cohorts (n = 345) from the Netherlands. Patients for validation were selected from the Molecular Diagnosis and Risk Stratification of Sepsis study (ClinicalTrials.gov, NCT01905033), which recruited ICU patients from the Academic Medical Center in Amsterdam and the University Medical Center Utrecht. Patients recruited from November 30, 2012, to August 5, 2013, were eligible for inclusion in the present study. Validation cohort 1 (n = 59) consisted entirely of unambiguous cases and controls; SeptiCyte Lab gave an area under curve (AUC) of 0.95 (95% CI 0.91–1.00) in this cohort. ROC curve analysis of an independent, more heterogeneous group of patients (validation cohorts 2–5; 249 patients after excluding 37 patients with an infection likelihood of “possible”) gave an AUC of 0.89 (95% CI 0.85–0.93). Disease severity, as measured by Sequential Organ Failure Assessment (SOFA) score or Acute Physiology and Chronic Health Evaluation (APACHE) IV score, was not a significant confounding variable. The diagnostic utility of SeptiCyte Lab was evaluated by comparison to various clinical and laboratory parameters available to a clinician within 24 h of ICU admission. SeptiCyte Lab was significantly better at differentiating cases from controls than all tested parameters, both singly and in various logistic combinations, and more than halved the diagnostic error rate compared to procalcitonin in all tested cohorts and cohort combinations. Limitations of this study relate to (1) cohort compositions that do not perfectly reflect the composition of the intended use population, (2) potential biases that could be introduced as a result of the current lack of a gold standard for diagnosing sepsis, and (3) lack of a complete, unbiased comparison to C-reactive protein. Conclusions SeptiCyte Lab is a rapid molecular assay that may be clinically useful in managing ICU patients with systemic inflammation. Further study in population-based cohorts is needed to validate this assay for clinical use. PMID:26645559

Evaluation of community-acquired sepsis by PIRO system in the emergency department.

PubMed

Chen, Yun-Xia; Li, Chun-Sheng

2013-09-01

The predisposition, infection/insult, response, and organ dysfunction (PIRO) staging system for septic patients allows grouping of heterogeneous patients into homogeneous subgroups. The purposes of this single-center, prospective, observational cohort study were to create a PIRO system for patients with community-acquired sepsis (CAS) presenting to the emergency department (ED) and assess its prognostic and stratification capabilities. Septic patients were enrolled and allocated to derivation (n = 831) or validation (n = 860) cohorts according to their enrollment dates. The derivation cohort was used to identify independent predictors of mortality and create a PIRO system by binary logistic regression analysis, and the prognostic performance of PIRO was investigated in the validation cohort by receiver operator characteristic (ROC) curve. Ten independent predictors of 28-day mortality were identified. The PIRO system combined the components of predisposition (age, chronic obstructive pulmonary disease, hypoalbuminemia), infection (central nervous system infection), response (temperature, procalcitonin), and organ dysfunction (brain natriuretic peptide, troponin I, mean arterial pressure, Glasgow coma scale score). The area under the ROC of PIRO was 0.833 for the derivation cohort and 0.813 for the validation cohort. There was a stepwise increase in 28-day mortality with increasing PIRO score and the differences between the low- (PIRO 0-10), intermediate- (11-20), and high- (>20) risk groups were very significant in both cohorts (p < 0.01). The present study demonstrates that this PIRO system is valuable for prognosis and risk stratification in patients with CAS in the ED.

External validation of preexisting first trimester preeclampsia prediction models.

PubMed

Allen, Rebecca E; Zamora, Javier; Arroyo-Manzano, David; Velauthar, Luxmilar; Allotey, John; Thangaratinam, Shakila; Aquilina, Joseph

2017-10-01

To validate the increasing number of prognostic models being developed for preeclampsia using our own prospective study. A systematic review of literature that assessed biomarkers, uterine artery Doppler and maternal characteristics in the first trimester for the prediction of preeclampsia was performed and models selected based on predefined criteria. Validation was performed by applying the regression coefficients that were published in the different derivation studies to our cohort. We assessed the models discrimination ability and calibration. Twenty models were identified for validation. The discrimination ability observed in derivation studies (Area Under the Curves) ranged from 0.70 to 0.96 when these models were validated against the validation cohort, these AUC varied importantly, ranging from 0.504 to 0.833. Comparing Area Under the Curves obtained in the derivation study to those in the validation cohort we found statistically significant differences in several studies. There currently isn't a definitive prediction model with adequate ability to discriminate for preeclampsia, which performs as well when applied to a different population and can differentiate well between the highest and lowest risk groups within the tested population. The pre-existing large number of models limits the value of further model development and future research should be focussed on further attempts to validate existing models and assessing whether implementation of these improves patient care. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Epigenome-wide DNA methylation analysis in siblings and monozygotic twins discordant for sporadic Parkinson's disease revealed different epigenetic patterns in peripheral blood mononuclear cells.

PubMed

Kaut, Oliver; Schmitt, Ina; Tost, Jörg; Busato, Florence; Liu, Yi; Hofmann, Per; Witt, Stephanie H; Rietschel, Marcella; Fröhlich, Holger; Wüllner, Ullrich

2017-01-01

Numerous studies have elucidated the genetics of Parkinson's disease; however, the aetiology of the majority of sporadic cases has not yet been resolved. We hypothesized that epigenetic variations could be associated with PD and evaluated the DNA methylation pattern in PD patients compared to brothers or twins without PD. The methylation of DNA from peripheral blood mononuclear cells of 62 discordant siblings including 24 monozygotic twins was characterized with Illumina DNA Methylation 450K bead arrays and subsequently validated in two independent cohorts: 221 PD vs. 227 healthy individuals (cohort 1) applying Illumina's VeraCode and 472 PD patients vs. 487 controls (cohort 2) using pyrosequencing. We choose a delta beta of >15 % and selected 62 differentially methylated CpGs in 51 genes from the discordant siblings. Among them, three displayed multiple CpGs per gene: microRNA 886 (MIR886, 10 CpGs), phosphodiesterase 4D (PDE4D, 2 CpGs) and tripartite motif-containing 34 (TRIM34, 2 CpGs). PDE4D was confirmed in both cohorts (p value 2.44e-05). In addition, for biomarker construction, we used the penalized logistic regression model, resulting in a signature of eight CpGs with an AUC of 0.77. Our findings suggest that a distinct level of PD susceptibility stems from individual, epigenetic modifications of specific genes. We identified a signature of CpGs in blood cells that could separate control from disease with a reasonable discriminatory power, holding promise for future epigenetically based biomarker development.

Characterizing Heterogeneity within Head and Neck Lesions Using Cluster Analysis of Multi-Parametric MRI Data

PubMed Central

Borri, Marco; Schmidt, Maria A.; Powell, Ceri; Koh, Dow-Mu; Riddell, Angela M.; Partridge, Mike; Bhide, Shreerang A.; Nutting, Christopher M.; Harrington, Kevin J.; Newbold, Katie L.; Leach, Martin O.

2015-01-01

Purpose To describe a methodology, based on cluster analysis, to partition multi-parametric functional imaging data into groups (or clusters) of similar functional characteristics, with the aim of characterizing functional heterogeneity within head and neck tumour volumes. To evaluate the performance of the proposed approach on a set of longitudinal MRI data, analysing the evolution of the obtained sub-sets with treatment. Material and Methods The cluster analysis workflow was applied to a combination of dynamic contrast-enhanced and diffusion-weighted imaging MRI data from a cohort of squamous cell carcinoma of the head and neck patients. Cumulative distributions of voxels, containing pre and post-treatment data and including both primary tumours and lymph nodes, were partitioned into k clusters (k = 2, 3 or 4). Principal component analysis and cluster validation were employed to investigate data composition and to independently determine the optimal number of clusters. The evolution of the resulting sub-regions with induction chemotherapy treatment was assessed relative to the number of clusters. Results The clustering algorithm was able to separate clusters which significantly reduced in voxel number following induction chemotherapy from clusters with a non-significant reduction. Partitioning with the optimal number of clusters (k = 4), determined with cluster validation, produced the best separation between reducing and non-reducing clusters. Conclusion The proposed methodology was able to identify tumour sub-regions with distinct functional properties, independently separating clusters which were affected differently by treatment. This work demonstrates that unsupervised cluster analysis, with no prior knowledge of the data, can be employed to provide a multi-parametric characterization of functional heterogeneity within tumour volumes. PMID:26398888

Identification of men with low-risk biopsy-confirmed prostate cancer as candidates for active surveillance.

PubMed

Lin, Daniel W; Crawford, E David; Keane, Thomas; Evans, Brent; Reid, Julia; Rajamani, Saradha; Brown, Krystal; Gutin, Alexander; Tward, Jonathan; Scardino, Peter; Brawer, Michael; Stone, Steven; Cuzick, Jack

2018-06-01

A combined clinical cell-cycle risk (CCR) score that incorporates prognostic molecular and clinical information has been recently developed and validated to improve prostate cancer mortality (PCM) risk stratification over clinical features alone. As clinical features are currently used to select men for active surveillance (AS), we developed and validated a CCR score threshold to improve the identification of men with low-risk disease who are appropriate for AS. The score threshold was selected based on the 90th percentile of CCR scores among men who might typically be considered for AS based on NCCN low/favorable-intermediate risk criteria (CCR = 0.8). The threshold was validated using 10-year PCM in an unselected, conservatively managed cohort and in the subset of the same cohort after excluding men with high-risk features. The clinical effect was evaluated in a contemporary clinical cohort. In the unselected validation cohort, men with CCR scores below the threshold had a predicted mean 10-year PCM of 2.7%, and the threshold significantly dichotomized low- and high-risk disease (P = 1.2 × 10 -5 ). After excluding high-risk men from the validation cohort, men with CCR scores below the threshold had a predicted mean 10-year PCM of 2.3%, and the threshold significantly dichotomized low- and high-risk disease (P = 0.020). There were no prostate cancer-specific deaths in men with CCR scores below the threshold in either analysis. The proportion of men in the clinical testing cohort identified as candidates for AS was substantially higher using the threshold (68.8%) compared to clinicopathologic features alone (42.6%), while mean 10-year predicted PCM risks remained essentially identical (1.9% vs. 2.0%, respectively). The CCR score threshold appropriately dichotomized patients into low- and high-risk groups for 10-year PCM, and may enable more appropriate selection of patients for AS. Copyright © 2018 Elsevier Inc. All rights reserved.

Derivation and Internal Validation of a Clinical Prediction Tool for 30-Day Mortality in Lower Gastrointestinal Bleeding.

PubMed

Sengupta, Neil; Tapper, Elliot B

2017-05-01

There are limited data to predict which patients with lower gastrointestinal bleeding are at risk for adverse outcomes. We aimed to develop a clinical tool based on admission variables to predict 30-day mortality in lower gastrointestinal bleeding. We used a validated machine learning algorithm to identify adult patients hospitalized with lower gastrointestinal bleeding at an academic medical center between 2008 and 2015. The cohort was split randomly into derivation and validation cohorts. In the derivation cohort, we used multiple logistic regression on all candidate admission variables to create a prediction model for 30-day mortality, using area under the receiving operator characteristic curve and misclassification rate to estimate prediction accuracy. Regression coefficients were used to derive an integer score, and mortality risk associated with point totals was assessed. In the derivation cohort (n = 4044), 8 variables were most associated with 30-day mortality: age, dementia, metastatic cancer, chronic kidney disease, chronic pulmonary disease, anticoagulant use, admission hematocrit, and albumin. The model yielded a misclassification rate of 0.06 and area under the curve of 0.81. The integer score ranged from -10 to 26 in the derivation cohort, with a misclassification rate of 0.11 and area under the curve of 0.74. In the validation cohort (n = 2060), the score had an area under the curve of 0.72 with a misclassification rate of 0.12. After dividing the score into 4 quartiles of risk, 30-day mortality in the derivation and validation sets was 3.6% and 4.4% in quartile 1, 4.9% and 7.3% in quartile 2, 9.9% and 9.1% in quartile 3, and 24% and 26% in quartile 4, respectively. A clinical tool can be used to predict 30-day mortality in patients hospitalized with lower gastrointestinal bleeding. Copyright © 2017 Elsevier Inc. All rights reserved.

Overcoming intratumoural heterogeneity for reproducible molecular risk stratification: a case study in advanced kidney cancer.

PubMed

Lubbock, Alexander L R; Stewart, Grant D; O'Mahony, Fiach C; Laird, Alexander; Mullen, Peter; O'Donnell, Marie; Powles, Thomas; Harrison, David J; Overton, Ian M

2017-06-26

Metastatic clear cell renal cell cancer (mccRCC) portends a poor prognosis and urgently requires better clinical tools for prognostication as well as for prediction of response to treatment. Considerable investment in molecular risk stratification has sought to overcome the performance ceiling encountered by methods restricted to traditional clinical parameters. However, replication of results has proven challenging, and intratumoural heterogeneity (ITH) may confound attempts at tissue-based stratification. We investigated the influence of confounding ITH on the performance of a novel molecular prognostic model, enabled by pathologist-guided multiregion sampling (n = 183) of geographically separated mccRCC cohorts from the SuMR trial (development, n = 22) and the SCOTRRCC study (validation, n = 22). Tumour protein levels quantified by reverse phase protein array (RPPA) were investigated alongside clinical variables. Regularised wrapper selection identified features for Cox multivariate analysis with overall survival as the primary endpoint. The optimal subset of variables in the final stratification model consisted of N-cadherin, EPCAM, Age, mTOR (NEAT). Risk groups from NEAT had a markedly different prognosis in the validation cohort (log-rank p = 7.62 × 10 -7 ; hazard ratio (HR) 37.9, 95% confidence interval 4.1-353.8) and 2-year survival rates (accuracy = 82%, Matthews correlation coefficient = 0.62). Comparisons with established clinico-pathological scores suggest favourable performance for NEAT (Net reclassification improvement 7.1% vs International Metastatic Database Consortium score, 25.4% vs Memorial Sloan Kettering Cancer Center score). Limitations include the relatively small cohorts and associated wide confidence intervals on predictive performance. Our multiregion sampling approach enabled investigation of NEAT validation when limiting the number of samples analysed per tumour, which significantly degraded performance. Indeed, sample selection could change risk group assignment for 64% of patients, and prognostication with one sample per patient performed only slightly better than random expectation (median logHR = 0.109). Low grade tissue was associated with 3.5-fold greater variation in predicted risk than high grade (p = 0.044). This case study in mccRCC quantitatively demonstrates the critical importance of tumour sampling for the success of molecular biomarker studies research where ITH is a factor. The NEAT model shows promise for mccRCC prognostication and warrants follow-up in larger cohorts. Our work evidences actionable parameters to guide sample collection (tumour coverage, size, grade) to inform the development of reproducible molecular risk stratification methods.

Development and validation of an ICD-10-based disability predictive index for patients admitted to hospitals with trauma.

PubMed

Wada, Tomoki; Yasunaga, Hideo; Yamana, Hayato; Matsui, Hiroki; Fushimi, Kiyohide; Morimura, Naoto

2018-03-01

There was no established disability predictive measurement for patients with trauma that could be used in administrative claims databases. The aim of the present study was to develop and validate a diagnosis-based disability predictive index for severe physical disability at discharge using the International Classification of Diseases, 10th revision (ICD-10) coding. This retrospective observational study used the Diagnosis Procedure Combination database in Japan. Patients who were admitted to hospitals with trauma and discharged alive from 01 April 2010 to 31 March 2015 were included. Pediatric patients under 15 years old were excluded. Data for patients admitted to hospitals from 01 April 2010 to 31 March 2013 was used for development of a disability predictive index (derivation cohort), while data for patients admitted to hospitals from 01 April 2013 to 31 March 2015 was used for the internal validation (validation cohort). The outcome of interest was severe physical disability defined as the Barthel Index score of <60 at discharge. Trauma-related ICD-10 codes were categorized into 36 injury groups with reference to the categorization used in the Global Burden of Diseases study 2013. A multivariable logistic regression analysis was performed for the outcome using the injury groups and patient baseline characteristics including patient age, sex, and Charlson Comorbidity Index (CCI) score in the derivation cohort. A score corresponding to a regression coefficient was assigned to each injury group. The disability predictive index for each patient was defined as the sum of the scores. The predictive performance of the index was validated using the receiver operating characteristic curve analysis in the validation cohort. The derivation cohort included 1,475,158 patients, while the validation cohort included 939,659 patients. Of the 939,659 patients, 235,382 (25.0%) were discharged with severe physical disability. The c-statistics of the disability predictive index was 0.795 (95% confidence interval [CI] 0.794-0.795), while that of a model using the disability predictive index and patient baseline characteristics was 0.856 (95% CI 0.855-0.857). Severe physical disability at discharge may be well predicted with patient age, sex, CCI score, and the diagnosis-based disability predictive index in patients admitted to hospitals with trauma. Copyright © 2018 Elsevier Ltd. All rights reserved.

Development and validation of a clinical risk score for predicting drug-resistant bacterial pneumonia in older Chinese patients.

PubMed

Ma, Hon Ming; Ip, Margaret; Woo, Jean; Hui, David S C

2014-05-01

Health care-associated pneumonia (HCAP) and drug-resistant bacterial pneumonia may not share identical risk factors. We have shown that bronchiectasis, recent hospitalization and severe pneumonia (confusion, blood urea level, respiratory rate, low blood pressure and 65 year old (CURB-65) score ≥ 3) were independent predictors of pneumonia caused by potentially drug-resistant (PDR) pathogens. This study aimed to develop and validate a clinical risk score for predicting drug-resistant bacterial pneumonia in older patients. We derived a risk score by assigning a weighting to each of these risk factors as follows: 14, bronchiectasis; 5, recent hospitalization; 2, severe pneumonia. A 0.5 point was defined for the presence of other risk factors for HCAP. We compared the areas under the receiver-operating characteristics curve (AUROC) of our risk score and the HCAP definition in predicting PDR pathogens in two cohorts of older patients hospitalized with non-nosocomial pneumonia. The derivation and validation cohorts consisted of 354 and 96 patients with bacterial pneumonia, respectively. PDR pathogens were isolated in 48 and 21 patients in the derivation and validation cohorts, respectively. The AUROCs of our risk score and the HCAP definition were 0.751 and 0.650, respectively, in the derivation cohort, and were 0.782 and 0.671, respectively, in the validation cohort. The differences between our risk score and the HCAP definition reached statistical significance. A score ≥ 2.5 had the best balance between sensitivity and specificity. Our risk score outperformed the HCAP definition to predict pneumonia caused by PDR pathogens. A history of bronchiectasis or recent hospitalization is the major indication of starting empirical broad-spectrum antibiotics. © 2014 Asian Pacific Society of Respirology.

Development and validation of multivariable predictive model for thromboembolic events in lymphoma patients.

PubMed

Antic, Darko; Milic, Natasa; Nikolovski, Srdjan; Todorovic, Milena; Bila, Jelena; Djurdjevic, Predrag; Andjelic, Bosko; Djurasinovic, Vladislava; Sretenovic, Aleksandra; Vukovic, Vojin; Jelicic, Jelena; Hayman, Suzanne; Mihaljevic, Biljana

2016-10-01

Lymphoma patients are at increased risk of thromboembolic events but thromboprophylaxis in these patients is largely underused. We sought to develop and validate a simple model, based on individual clinical and laboratory patient characteristics that would designate lymphoma patients at risk for thromboembolic event. The study population included 1,820 lymphoma patients who were treated in the Lymphoma Departments at the Clinics of Hematology, Clinical Center of Serbia and Clinical Center Kragujevac. The model was developed using data from a derivation cohort (n = 1,236), and further assessed in the validation cohort (n = 584). Sixty-five patients (5.3%) in the derivation cohort and 34 (5.8%) patients in the validation cohort developed thromboembolic events. The variables independently associated with risk for thromboembolism were: previous venous and/or arterial events, mediastinal involvement, BMI>30 kg/m(2) , reduced mobility, extranodal localization, development of neutropenia and hemoglobin level < 100g/L. Based on the risk model score, the population was divided into the following risk categories: low (score 0-1), intermediate (score 2-3), and high (score >3). For patients classified at risk (intermediate and high-risk scores), the model produced negative predictive value of 98.5%, positive predictive value of 25.1%, sensitivity of 75.4%, and specificity of 87.5%. A high-risk score had positive predictive value of 65.2%. The diagnostic performance measures retained similar values in the validation cohort. Developed prognostic Thrombosis Lymphoma - ThroLy score is more specific for lymphoma patients than any other available score targeting thrombosis in cancer patients. Am. J. Hematol. 91:1014-1019, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Validation of SAPS3 admission score and its customization for use in Korean intensive care unit patients: a prospective multicentre study.

PubMed

Lim, So Yeon; Koh, Shin Ok; Jeon, Kyeongman; Na, Sungwon; Lim, Chae-Man; Choi, Won-Il; Lee, Young-Joo; Kim, Seok Chan; Chon, Gyu Rak; Kim, Je Hyeong; Kim, Jae Yeol; Lim, Jaemin; Rhee, Chin Kook; Park, Sunghoon; Kim, Ho Cheol; Lee, Jin Hwa; Lee, Ji Hyun; Park, Jisook; Koh, Younsuck; Suh, Gee Young

2013-08-01

To externally validate the simplified acute physiology score 3 (SAPS3) and to customize it for use in Korean intensive care unit (ICU) patients. This is a prospective multicentre cohort study involving 22 ICUs from 15 centres throughout Korea. The study population comprised patients who were consecutively admitted to participating ICUs from 1 July 2010 to 31 January 2011. A total of 4617 patients were enrolled. ICU mortality was 14.3%, and hospital mortality was 20.6%. The patients were randomly assigned into one of two cohorts: a development (n = 2309) or validation (n = 2308) cohort. In the development cohort, the general SAPS3 had good discrimination (area under the receiver operating characteristics curve = 0.829), but poor calibration (Hosmer-Lemeshow goodness-of-fit test H = 123.06, P < 0.001, C = 118.45, P < 0.001). The Australasia SAPS3 did not improve calibration (H = 73.53, P < 0.001, C = 70.52, P < 0.001). Customization was achieved by altering the logit of the original SAPS3 equation. The new equation for Korean ICU patients was validated in the validation cohort, and demonstrated both good discrimination (area under the receiver operating characteristics curve = 0.835) and good calibration (H = 4.61, P = 0.799, C = 5.67, P = 0.684). General and regional Australasia SAPS3 admission scores showed poor calibration for use in Korean ICU patients, but the prognostic power of the SAPS3 was significantly improved by customization. Prediction models should be customized before being used to predict mortality in different regions of the world. © 2013 The Authors. Respirology © 2013 Asian Pacific Society of Respirology.

Small RNA-seq during acute maximal exercise reveal RNAs involved in vascular inflammation and cardiometabolic health: brief report.

PubMed

Shah, Ravi; Yeri, Ashish; Das, Avash; Courtright-Lim, Amanda; Ziegler, Olivia; Gervino, Ernest; Ocel, Jeffrey; Quintero-Pinzon, Pablo; Wooster, Luke; Bailey, Cole Shields; Tanriverdi, Kahraman; Beaulieu, Lea M; Freedman, Jane E; Ghiran, Ionita; Lewis, Gregory D; Van Keuren-Jensen, Kendall; Das, Saumya

2017-12-01

Exercise improves cardiometabolic and vascular function, although the mechanisms remain unclear. Our objective was to demonstrate the diversity of circulating extracellular RNA (ex-RNA) release during acute exercise in humans and its relevance to exercise-mediated benefits on vascular inflammation. We performed plasma small RNA sequencing in 26 individuals undergoing symptom-limited maximal treadmill exercise, with replication of our top candidate miRNA in a separate cohort of 59 individuals undergoing bicycle ergometry. We found changes in miRNAs and other ex-RNAs with exercise (e.g., Y RNAs and tRNAs) implicated in cardiovascular disease. In two independent cohorts of acute maximal exercise, we identified miR-181b-5p as a key ex-RNA increased in plasma after exercise, with validation in a separate cohort. In a mouse model of acute exercise, we found significant increases in miR-181b-5p expression in skeletal muscle after acute exercise in young (but not older) mice. Previous work revealed a strong role for miR-181b-5p in vascular inflammation in obesity, insulin resistance, sepsis, and cardiovascular disease. We conclude that circulating ex-RNAs were altered in plasma after acute exercise target pathways involved in inflammation, including miR-181b-5p. Further investigation into the role of known (e.g., miRNA) and novel (e.g., Y RNAs) RNAs is warranted to uncover new mechanisms of vascular inflammation on exercise-mediated benefits on health. NEW & NOTEWORTHY How exercise provides benefits to cardiometabolic health remains unclear. We performed RNA sequencing in plasma during exercise to identify the landscape of small noncoding circulating transcriptional changes. Our results suggest a link between inflammation and exercise, providing rich data on circulating noncoding RNAs for future studies by the scientific community. Copyright © 2017 the American Physiological Society.

The effects of common medical interventions on pain, back function, and work resumption in patients with chronic low back pain: A prospective 2-year cohort study in six countries.

PubMed

Hansson, T H; Hansson, E K

2000-12-01

A prospective cohort study with identical questionnaires and inclusion criteria was performed. To compare in six different countries the frequencies and effects of the common medical interventions used for patients with low back pain who are work incapacitated. Low back pain is a huge problem with increasing costs for health care, industry, and society. Cohorts of employed men and women ages 18 to 59 years who had been sick-listed (100%) for a minimum of 90 days because of low back pain were recruited in Denmark, Germany, Israel, Sweden, the Netherlands, and the United States. The subjects received three separate questionnaires with identical questions after 90 days, 1 year, and 2 years. The questionnaires included separate questions about background factors, treatment, and the like, as well as validated scales such as the Hannover Activities of Daily Living, von Korff pain score, Short Form-36, and Karasek-Theorell. Working status was obtained from registers. Main outcome measures were working/not working, back function, and pain. All three questionnaires were completed by 2080 subjects in the six countries. With few exceptions, there were great similarities in the appointments, examinations, and treatments in the different countries. Considerable differences were found between the back surgery rates, which ranged from 6% in Sweden to 32% in the United States during the first 90 days of the study. Very few of the interventions had any noticeable positive effects on work resumption, pain, or back function. Back surgery in Sweden was a striking exception, positively affecting all three outcome measures. The frequencies of work resumption within the first year ranged from 73% in the Netherlands to 32% in Denmark. Almost none of the commonly occurring and frequently practiced medical interventions for patients who are sick-listed because of low back pain had any positive effects on either the recorded health measures or work resumption.

Applying Classification Trees to Hospital Administrative Data to Identify Patients with Lower Gastrointestinal Bleeding

PubMed Central

Siddique, Juned; Ruhnke, Gregory W.; Flores, Andrea; Prochaska, Micah T.; Paesch, Elizabeth; Meltzer, David O.; Whelan, Chad T.

2015-01-01

Background Lower gastrointestinal bleeding (LGIB) is a common cause of acute hospitalization. Currently, there is no accepted standard for identifying patients with LGIB in hospital administrative data. The objective of this study was to develop and validate a set of classification algorithms that use hospital administrative data to identify LGIB. Methods Our sample consists of patients admitted between July 1, 2001 and June 30, 2003 (derivation cohort) and July 1, 2003 and June 30, 2005 (validation cohort) to the general medicine inpatient service of the University of Chicago Hospital, a large urban academic medical center. Confirmed cases of LGIB in both cohorts were determined by reviewing the charts of those patients who had at least 1 of 36 principal or secondary International Classification of Diseases, Ninth revision, Clinical Modification (ICD-9-CM) diagnosis codes associated with LGIB. Classification trees were used on the data of the derivation cohort to develop a set of decision rules for identifying patients with LGIB. These rules were then applied to the validation cohort to assess their performance. Results Three classification algorithms were identified and validated: a high specificity rule with 80.1% sensitivity and 95.8% specificity, a rule that balances sensitivity and specificity (87.8% sensitivity, 90.9% specificity), and a high sensitivity rule with 100% sensitivity and 91.0% specificity. Conclusion These classification algorithms can be used in future studies to evaluate resource utilization and assess outcomes associated with LGIB without the use of chart review. PMID:26406318

Calibration power of the Braden scale in predicting pressure ulcer development.

PubMed

Chen, Hong-Lin; Cao, Ying-Juan; Wang, Jing; Huai, Bao-Sha

2016-11-02

Calibration is the degree of correspondence between the estimated probability produced by a model and the actual observed probability. The aim of this study was to investigate the calibration power of the Braden scale in predicting pressure ulcer development (PU). A retrospective analysis was performed among consecutive patients in 2013. The patients were separated into training a group and a validation group. The predicted incidence was calculated using a logistic regression model in the training group and the Hosmer-Lemeshow test was used for assessing the goodness of fit. In the validation cohort, the observed and the predicted incidence were compared by the Chi-square (χ 2 ) goodness of fit test for calibration power. We included 2585 patients in the study, of these 78 patients (3.0%) developed a PU. Between the training and validation groups the patient characteristics were non-significant (p>0.05). In the training group, the logistic regression model for predicting pressure ulcer was Logit(P) = -0.433*Braden score+2.616. The Hosmer-Lemeshow test showed no goodness fit (χ 2 =13.472; p=0.019). In the validation group, the predicted pressure ulcer incidence also did not fit well with the observed incidence (χ 2 =42.154, p=0.000 by Braden scores; and χ 2 =17.223, p=0.001 by Braden scale risk classification). The Braden scale has low calibration power in predicting PU formation.

Surrogate clinical endpoints to predict overall survival in non-small cell lung cancer trials-are we in a new era?

PubMed

Clarke, Jeffrey M; Wang, Xiaofei; Ready, Neal E

2015-12-01

Surrogate endpoints for clinical trials in oncology offer an alternative metric for measuring clinical benefit, allowing for shorter trial duration, smaller patient cohorts, and single arm design. The correlation of surrogate endpoints with overall survival (OS) in therapeutic studies is a central consideration to their validity. The Food and Drug Administration (FDA) recently published an analysis of fourteen clinical trials in advanced non-small cell lung cancer (NSCLC), and discovered a strong association between response rate and progression free survival. Furthermore, a correlation between response rate and OS is demonstrated when analyzing the experimental treatment arm separately, minimizing bias from patient crossover. We also highlight multiple, important considerations when using response as an endpoint in clinical trials involving NSCLC patients.

Exercise barriers self-efficacy: development and validation of a subcale for individuals with cancer-related lymphedema.

PubMed

Buchan, Jena; Janda, Monika; Box, Robyn; Rogers, Laura; Hayes, Sandi

2015-03-18

No tool exists to measure self-efficacy for overcoming lymphedema-related exercise barriers in individuals with cancer-related lymphedema. However, an existing scale measures confidence to overcome general exercise barriers in cancer survivors. Therefore, the purpose of this study was to develop, validate and assess the reliability of a subscale, to be used in conjunction with the general barriers scale, for determining exercise barriers self-efficacy in individuals facing lymphedema-related exercise barriers. A lymphedema-specific exercise barriers self-efficacy subscale was developed and validated using a cohort of 106 cancer survivors with cancer-related lymphedema, from Brisbane, Australia. An initial ten-item lymphedema-specific barrier subscale was developed and tested, with participant feedback and principal components analysis results used to guide development of the final version. Validity and test-retest reliability analyses were conducted on the final subscale. The final lymphedema-specific subscale contained five items. Principal components analysis revealed these items loaded highly (>0.75) on a separate factor when tested with a well-established nine-item general barriers scale. The final five-item subscale demonstrated good construct and criterion validity, high internal consistency (Cronbach's alpha = 0.93) and test-retest reliability (ICC = 0.67, p < 0.01). A valid and reliable lymphedema-specific subscale has been developed to assess exercise barriers self-efficacy in individuals with cancer-related lymphedema. This scale can be used in conjunction with an existing general exercise barriers scale to enhance exercise adherence in this understudied patient group.

Parental separation in childhood and adult smoking in the 1958 British birth cohort.

PubMed

Martindale, Sarah E; Lacey, Rebecca E

2017-08-01

Parental separation or divorce is a known risk factor for poorer adult health. One mechanism may operate through the uptake of risky health behaviours, such as smoking. This study investigated the association between parental separation and adult smoking in a large British birth cohort and also examined potential socioeconomic, relational and psychosocial mediators. Differences by gender and timing of parental separation were also assessed. Multiply imputed data on 11 375 participants of the National Child Development Study (the 1958 British birth cohort) were used. A series of multinomial logistic regression models were estimated to investigate the association between parental separation (0-16 years) and adult smoking status (age 42), and the role of potential socioeconomic, relational and psychosocial mediators. Parental separation in childhood was associated with an increased risk of being a current (RRR = 2.14, 95% CI: 1.77, 2.60) or ex-smoker (RRR = 1.50, 95% CI: 1.22, 1.85) at age 42. This association remained after consideration of potential socioeconomic, psychosocial and relational mediators. Relational (parent-child relationship quality, parental involvement and adult partnership status) and socioeconomic factors (overcrowding, financial hardship, housing tenure, household amenities, free school meal receipt and educational attainment) appeared to be the most important of the groups of mediators investigated. No differences by gender or the timing of parental separation were observed. Parental separation experienced in childhood was associated with increased risk of smoking. Families undergoing separation should be further supported in order to prevent the uptake of smoking and to prevent later health problems. © The Author 2017. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.

Estimating GFR Among Participants in the Chronic Renal Insufficiency Cohort (CRIC) Study

PubMed Central

Anderson, Amanda Hyre; Yang, Wei; Hsu, Chi-yuan; Joffe, Marshall M.; Leonard, Mary B.; Xie, Dawei; Chen, Jing; Greene, Tom; Jaar, Bernard G.; Kao, Patricia; Kusek, John W.; Landis, J. Richard; Lash, James P.; Townsend, Raymond R.; Weir, Matthew R.; Feldman, Harold I.

2012-01-01

Background Glomerular filtration rate (GFR) is considered the best measure of kidney function, but repeated assessment is not feasible in most research studies. Study Design Cross-sectional study of 1,433 participants from the Chronic Renal Insufficiency Cohort (CRIC) Study (i.e., the GFR subcohort) to derive an internal GFR estimating equation using a split sample approach. Setting & Participants Adults from 7 US metropolitan areas with mild to moderate chronic kidney disease; 48% had diabetes and 37% were black. Index Test CRIC GFR estimating equation Reference Test or Outcome Urinary 125I-iothalamate clearance testing (measured GFR) Other Measurements Laboratory measures including serum creatinine and cystatin C, and anthropometrics Results In the validation dataset, the model that included serum creatinine, serum cystatin C, age, gender, and race was the most parsimonious and similarly predictive of mGFR compared to a model additionally including bioelectrical impedance analysis phase angle, CRIC clinical center, and 24-hour urinary creatinine excretion. Specifically, the root mean square errors for the separate model were 0.207 vs. 0.202, respectively. The performance of the CRIC GFR estimating equation was most accurate among the subgroups of younger participants, men, non-blacks, non-Hispanics, those without diabetes, those with body mass index <30 kg/m2, those with higher 24-hour urine creatinine excretion, those with lower levels of high-sensitivity C-reactive protein, and those with higher mGFR. Limitations Urinary clearance of 125I-iothalamate is an imperfect measure of true GFR; cystatin C is not standardized to certified reference material; lack of external validation; small sample sizes limit analyses of subgroup-specific predictors. Conclusions The CRIC GFR estimating equation predicts measured GFR accurately in the CRIC cohort using serum creatinine and cystatin C, age, gender, and race. Its performance was best among younger and healthier participants. PMID:22658574

Chromatin organisation and cancer prognosis: a pan-cancer study.

PubMed

Kleppe, Andreas; Albregtsen, Fritz; Vlatkovic, Ljiljana; Pradhan, Manohar; Nielsen, Birgitte; Hveem, Tarjei S; Askautrud, Hanne A; Kristensen, Gunnar B; Nesbakken, Arild; Trovik, Jone; Wæhre, Håkon; Tomlinson, Ian; Shepherd, Neil A; Novelli, Marco; Kerr, David J; Danielsen, Håvard E

2018-03-01

Chromatin organisation affects gene expression and regional mutation frequencies and contributes to carcinogenesis. Aberrant organisation of DNA has been correlated with cancer prognosis in analyses of the chromatin component of tumour cell nuclei using image texture analysis. As yet, the methodology has not been sufficiently validated to permit its clinical application. We aimed to define and validate a novel prognostic biomarker for the automatic detection of heterogeneous chromatin organisation. Machine learning algorithms analysed the chromatin organisation in 461 000 images of tumour cell nuclei stained for DNA from 390 patients (discovery cohort) treated for stage I or II colorectal cancer at the Aker University Hospital (Oslo, Norway). The resulting marker of chromatin heterogeneity, termed Nucleotyping, was subsequently independently validated in six patient cohorts: 442 patients with stage I or II colorectal cancer in the Gloucester Colorectal Cancer Study (UK); 391 patients with stage II colorectal cancer in the QUASAR 2 trial; 246 patients with stage I ovarian carcinoma; 354 patients with uterine sarcoma; 307 patients with prostate carcinoma; and 791 patients with endometrial carcinoma. The primary outcome was cancer-specific survival. In all patient cohorts, patients with chromatin heterogeneous tumours had worse cancer-specific survival than patients with chromatin homogeneous tumours (univariable analysis hazard ratio [HR] 1·7, 95% CI 1·2-2·5, in the discovery cohort; 1·8, 1·0-3·0, in the Gloucester validation cohort; 2·2, 1·1-4·5, in the QUASAR 2 validation cohort; 3·1, 1·9-5·0, in the ovarian carcinoma cohort; 2·5, 1·8-3·4, in the uterine sarcoma cohort; 2·3, 1·2-4·6, in the prostate carcinoma cohort; and 4·3, 2·8-6·8, in the endometrial carcinoma cohort). After adjusting for established prognostic patient characteristics in multivariable analyses, Nucleotyping was prognostic in all cohorts except for the prostate carcinoma cohort (HR 1·7, 95% CI 1·1-2·5, in the discovery cohort; 1·9, 1·1-3·2, in the Gloucester validation cohort; 2·6, 1·2-5·6, in the QUASAR 2 cohort; 1·8, 1·1-3·0, for ovarian carcinoma; 1·6, 1·0-2·4, for uterine sarcoma; 1·43, 0·68-2·99, for prostate carcinoma; and 1·9, 1·1-3·1, for endometrial carcinoma). Chromatin heterogeneity was a significant predictor of cancer-specific survival in microsatellite unstable (HR 2·9, 95% CI 1·0-8·4) and microsatellite stable (1·8, 1·2-2·7) stage II colorectal cancer, but microsatellite instability was not a significant predictor of outcome in chromatin homogeneous (1·3, 0·7-2·4) or chromatin heterogeneous (0·8, 0·3-2·0) stage II colorectal cancer. The consistent prognostic prediction of Nucleotyping in different biological and technical circumstances suggests that the marker of chromatin heterogeneity can be reliably assessed in routine clinical practice and could be used to objectively assist decision making in a range of clinical settings. An immediate application would be to identify high-risk patients with stage II colorectal cancer who might have greater absolute benefit from adjuvant chemotherapy. Clinical trials are warranted to evaluate the survival benefit and cost-effectiveness of using Nucleotyping to guide treatment decisions in multiple clinical settings. The Research Council of Norway, the South-Eastern Norway Regional Health Authority, the National Institute for Health Research, and the Wellcome Trust. Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC-BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Pediatric Heart Donor Assessment Tool (PH-DAT): A novel donor risk scoring system to predict 1-year mortality in pediatric heart transplantation.

PubMed

Zafar, Farhan; Jaquiss, Robert D; Almond, Christopher S; Lorts, Angela; Chin, Clifford; Rizwan, Raheel; Bryant, Roosevelt; Tweddell, James S; Morales, David L S

2018-03-01

In this study we sought to quantify hazards associated with various donor factors into a cumulative risk scoring system (the Pediatric Heart Donor Assessment Tool, or PH-DAT) to predict 1-year mortality after pediatric heart transplantation (PHT). PHT data with complete donor information (5,732) were randomly divided into a derivation cohort and a validation cohort (3:1). From the derivation cohort, donor-specific variables associated with 1-year mortality (exploratory p-value < 0.2) were incorporated into a multivariate logistic regression model. Scores were assigned to independent predictors (p < 0.05) based on relative odds ratios (ORs). The final model had an acceptable predictive value (c-statistic = 0.62). The significant 5 variables (ischemic time, stroke as the cause of death, donor-to-recipient height ratio, donor left ventricular ejection fraction, glomerular filtration rate) were used for the scoring system. The validation cohort demonstrated a strong correlation between the observed and expected rates of 1-year mortality (r = 0.87). The risk of 1-year mortality increases by 11% (OR 1.11 [1.08 to 1.14]; p < 0.001) in the derivation cohort and 9% (OR 1.09 [1.04 to 1.14]; p = 0.001) in the validation cohort with an increase of 1-point in score. Mortality risk increased 5 times from the lowest to the highest donor score in this cohort. Based on this model, a donor score range of 10 to 28 predicted 1-year recipient mortality of 11% to 31%. This novel pediatric-specific, donor risk scoring system appears capable of predicting post-transplant mortality. Although the PH-DAT may benefit organ allocation and assessment of recipient risk while controlling for donor risk, prospective validation of this model is warranted. Copyright © 2018 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Logistic regression model for diagnosis of transition zone prostate cancer on multi-parametric MRI.

PubMed

Dikaios, Nikolaos; Alkalbani, Jokha; Sidhu, Harbir Singh; Fujiwara, Taiki; Abd-Alazeez, Mohamed; Kirkham, Alex; Allen, Clare; Ahmed, Hashim; Emberton, Mark; Freeman, Alex; Halligan, Steve; Taylor, Stuart; Atkinson, David; Punwani, Shonit

2015-02-01

We aimed to develop logistic regression (LR) models for classifying prostate cancer within the transition zone on multi-parametric magnetic resonance imaging (mp-MRI). One hundred and fifty-five patients (training cohort, 70 patients; temporal validation cohort, 85 patients) underwent mp-MRI and transperineal-template-prostate-mapping (TPM) biopsy. Positive cores were classified by cancer definitions: (1) any-cancer; (2) definition-1 [≥Gleason 4 + 3 or ≥ 6 mm cancer core length (CCL)] [high risk significant]; and (3) definition-2 (≥Gleason 3 + 4 or ≥ 4 mm CCL) cancer [intermediate-high risk significant]. For each, logistic-regression mp-MRI models were derived from the training cohort and validated internally and with the temporal cohort. Sensitivity/specificity and the area under the receiver operating characteristic (ROC-AUC) curve were calculated. LR model performance was compared to radiologists' performance. Twenty-eight of 70 patients from the training cohort, and 25/85 patients from the temporal validation cohort had significant cancer on TPM. The ROC-AUC of the LR model for classification of cancer was 0.73/0.67 at internal/temporal validation. The radiologist A/B ROC-AUC was 0.65/0.74 (temporal cohort). For patients scored by radiologists as Prostate Imaging Reporting and Data System (Pi-RADS) score 3, sensitivity/specificity of radiologist A 'best guess' and LR model was 0.14/0.54 and 0.71/0.61, respectively; and radiologist B 'best guess' and LR model was 0.40/0.34 and 0.50/0.76, respectively. LR models can improve classification of Pi-RADS score 3 lesions similar to experienced radiologists. • MRI helps find prostate cancer in the anterior of the gland • Logistic regression models based on mp-MRI can classify prostate cancer • Computers can help confirm cancer in areas doctors are uncertain about.

External validation of blood eosinophils, FE(NO) and serum periostin as surrogates for sputum eosinophils in asthma.

PubMed

Wagener, A H; de Nijs, S B; Lutter, R; Sousa, A R; Weersink, E J M; Bel, E H; Sterk, P J

2015-02-01

Monitoring sputum eosinophils in asthma predicts exacerbations and improves management of asthma. Thus far, blood eosinophils and FE(NO) show contradictory results in predicting eosinophilic airway inflammation. More recently, serum periostin was proposed as a novel biomarker for eosinophilic inflammation. Quantifying the mutual relationships of blood eosinophils, FE(NO), and serum periostin with sputum eosinophils by external validation in two independent cohorts across various severities of asthma. The first cohort consisted of 110 patients with mild to moderate asthma (external validation cohort). The replication cohort consisted of 37 patients with moderate to severe asthma. Both cohorts were evaluated cross-sectionally. Sputum was induced for the assessment of eosinophils. In parallel, blood eosinophil counts, serum periostin concentrations and FENO were assessed. The diagnostic accuracy of these markers to identify eosinophilic asthma (sputum eosinophils ≥3%) was calculated using receiver operating characteristics area under the curve (ROC AUC). In the external validation cohort, ROC AUC for blood eosinophils was 89% (p<0.001) and for FE(NO) level 78% (p<0.001) to detect sputum eosinophilia ≥3%. Serum periostin was not able to distinguish eosinophilic from non-eosinophilic airway inflammation (ROC AUC=55%, p=0.44). When combining these three variables, no improvement was seen. The diagnostic value of blood eosinophils was confirmed in the replication cohort (ROC AUC 85%, p<0.001). In patients with mild to moderate asthma, as well as patients with more severe asthma, blood eosinophils had the highest accuracy in the identification of sputum eosinophilia in asthma. The use of blood eosinophils can facilitate individualised treatment and management of asthma. NTR1846 and NTR2364. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

CpG Methylation Signature Predicts Recurrence in Early-Stage Hepatocellular Carcinoma: Results From a Multicenter Study.

PubMed

Qiu, Jiliang; Peng, Baogang; Tang, Yunqiang; Qian, Yeben; Guo, Pi; Li, Mengfeng; Luo, Junhang; Chen, Bin; Tang, Hui; Lu, Canliang; Cai, Muyan; Ke, Zunfu; He, Wei; Zheng, Yun; Xie, Dan; Li, Binkui; Yuan, Yunfei

2017-03-01

Purpose Early-stage hepatocellular carcinoma (E-HCC) is being diagnosed increasingly, and in one half of diagnosed patients, recurrence will develop. Thus, it is urgent to identify recurrence-related markers. We investigated the effectiveness of CpG methylation in predicting recurrence for patients with E-HCCs. Patients and Methods In total, 576 patients with E-HCC from four independent centers were sorted by three phases. In the discovery phase, 66 tumor samples were analyzed using the Illumina Methylation 450k Beadchip. Two algorithms, Least Absolute Shrinkage and Selector Operation and Support Vector Machine-Recursive Feature Elimination, were used to select significant CpGs. In the training phase, penalized Cox regression was used to further narrow CpGs into 140 samples. In the validation phase, candidate CpGs were validated using an internal cohort (n = 141) and two external cohorts (n = 191 and n =104). Results After combining the 46 CpGs selected by the Least Absolute Shrinkage and Selector Operation and the Support Vector Machine-Recursive Feature Elimination algorithms, three CpGs corresponding to SCAN domain containing 3, Src homology 3-domain growth factor receptor-bound 2-like interacting protein 1, and peptidase inhibitor 3 were highlighted as candidate predictors in the training phase. On the basis of the three CpGs, a methylation signature for E-HCC (MSEH) was developed to classify patients into high- and low-risk recurrence groups in the training cohort ( P < .001). The performance of MSEH was validated in the internal cohort ( P < .001) and in the two external cohorts ( P < .001; P = .002). Furthermore, a nomogram comprising MSEH, tumor differentiation, cirrhosis, hepatitis B virus surface antigen, and antivirus therapy was generated to predict the 5-year recurrence-free survival in the training cohort, and it performed well in the three validation cohorts (concordance index: 0.725, 0.697, and 0.693, respectively). Conclusion MSEH, a three-CpG-based signature, is useful in predicting recurrence for patients with E-HCC.

Derivation and validation of a two-biomarker panel for diagnosis of ARDS in patients with severe traumatic injuries

PubMed Central

Ware, Lorraine B; Zhao, Zhiguo; Koyama, Tatsuki; Brown, Ryan M; Semler, Matthew W; Janz, David R; May, Addison K; Fremont, Richard D; Matthay, Michael A; Cohen, Mitchell J; Calfee, Carolyn S

2017-01-01

Background Acute respiratory distress syndrome (ARDS) is common after severe traumatic injuries but is underdiagnosed and undertreated. We hypothesized that a panel of plasma biomarkers could be used to diagnose ARDS in severe trauma. To test this hypothesis, we derived and validated a biomarker panel in three independent cohorts and compared the diagnostic performance to clinician recognition of ARDS. Methods Eleven plasma biomarkers of inflammation, lung epithelial and endothelial injury were measured in a derivation cohort of 439 severe trauma patients. ARDS status was analyzed by two-investigator consensus, and cases were required to meet Berlin criteria on intensive care unit (ICU) day 1. Controls were subjects without ARDS during the first 4 days of study enrollment. A multivariable logistic regression model was used to generate probabilities for ARDS. A reduced model with the top two performing markers was then tested in two independent validation cohorts. To assess clinical diagnosis of ARDS, medical records in the derivation cohort were systematically searched for documentation of ARDS diagnosis made by a clinical provider. Results Among 11 biomarkers, the combination of the endothelial injury marker angiopoietin-2 (Ang-2) and the lung epithelial injury marker receptor for advanced glycation endproducts (RAGE) provided good discrimination for ARDS in the derivation cohort (area under the curve (AUC)=0.74 (95% CI 0.67 to 0.80). In the validation cohorts, the AUCs for this model were 0.70 (0.61 to 0.77) and 0.78 (0.71 to 0.84). In contrast, provider assessment demonstrated poor diagnostic accuracy for ARDS, with AUC of 0.55 (0.51 to 0.60). Discussion A two-biomarker panel consisting of Ang-2 and RAGE performed well across multiple patient cohorts and outperformed clinical providers for diagnosing ARDS in severe trauma. Clinical application of this model could improve both diagnosis and treatment of ARDS in patients with severe trauma. Level of evidence Diagnostic study, level II. PMID:29766112

Derivation and validation of a two-biomarker panel for diagnosis of ARDS in patients with severe traumatic injuries.

PubMed

Ware, Lorraine B; Zhao, Zhiguo; Koyama, Tatsuki; Brown, Ryan M; Semler, Matthew W; Janz, David R; May, Addison K; Fremont, Richard D; Matthay, Michael A; Cohen, Mitchell J; Calfee, Carolyn S

2017-01-01

Acute respiratory distress syndrome (ARDS) is common after severe traumatic injuries but is underdiagnosed and undertreated. We hypothesized that a panel of plasma biomarkers could be used to diagnose ARDS in severe trauma. To test this hypothesis, we derived and validated a biomarker panel in three independent cohorts and compared the diagnostic performance to clinician recognition of ARDS. Eleven plasma biomarkers of inflammation, lung epithelial and endothelial injury were measured in a derivation cohort of 439 severe trauma patients. ARDS status was analyzed by two-investigator consensus, and cases were required to meet Berlin criteria on intensive care unit (ICU) day 1. Controls were subjects without ARDS during the first 4 days of study enrollment. A multivariable logistic regression model was used to generate probabilities for ARDS. A reduced model with the top two performing markers was then tested in two independent validation cohorts. To assess clinical diagnosis of ARDS, medical records in the derivation cohort were systematically searched for documentation of ARDS diagnosis made by a clinical provider. Among 11 biomarkers, the combination of the endothelial injury marker angiopoietin-2 (Ang-2) and the lung epithelial injury marker receptor for advanced glycation endproducts (RAGE) provided good discrimination for ARDS in the derivation cohort (area under the curve (AUC)=0.74 (95% CI 0.67 to 0.80). In the validation cohorts, the AUCs for this model were 0.70 (0.61 to 0.77) and 0.78 (0.71 to 0.84). In contrast, provider assessment demonstrated poor diagnostic accuracy for ARDS, with AUC of 0.55 (0.51 to 0.60). A two-biomarker panel consisting of Ang-2 and RAGE performed well across multiple patient cohorts and outperformed clinical providers for diagnosing ARDS in severe trauma. Clinical application of this model could improve both diagnosis and treatment of ARDS in patients with severe trauma. Diagnostic study, level II.

Parental separation and pediatric cancer: a Danish cohort study.

PubMed

Grant, Sally; Carlsen, Kathrine; Bidstrup, Pernille Envold; Bastian, Gro Samsø; Lund, Lasse Wegener; Dalton, Susanne Oksbjerg; Johansen, Christoffer

2012-05-01

The purpose of this study was to determine the risk for separation (ending cohabitation) of the parents of a child with a diagnosis of cancer. In a nationwide cohort, we compared the risk for ending cohabitation of the parents of 2450 children (aged 0-20 years) given a diagnosis of cancer with the risk of parents of 44 853 randomly selected, gender- and age-matched cancer-free children. We adjusted for socioeconomic position and demographic factors. Rate ratios and 95% confidence intervals for separation were estimated in a Cox proportional hazards model. The parents of children with cancer did not have a higher risk for separation than the general population (rate ratio: 1.00 [95% confidence interval: 0.91-1.10]). Separate analyses according to type of cancer and survival of the child similarly yielded null results. Experiencing cancer in a child does not seem to be a risk factor for separation. Our study will allow clinicians to reassure parents and to support them in facing the trauma of cancer in their child.

Validation of the pooled cohort risk score in an Asian population - a retrospective cohort study.

PubMed

Chia, Yook Chin; Lim, Hooi Min; Ching, Siew Mooi

2014-11-20

The Pooled Cohort Risk Equation was introduced by the American College of Cardiology (ACC) and American Heart Association (AHA) 2013 in their Blood Cholesterol Guideline to estimate the 10-year atherosclerotic cardiovascular disease (ASCVD) risk. However, absence of Asian ethnicity in the contemporary cohorts and limited studies to examine the use of the risk score limit the applicability of the equation in an Asian population. This study examines the validity of the pooled cohort risk score in a primary care setting and compares the cardiovascular risk using both the pooled cohort risk score and the Framingham General Cardiovascular Disease (CVD) risk score. This is a 10-year retrospective cohort study of randomly selected patients aged 40-79 years. Baseline demographic data, co-morbidities and cardiovascular (CV) risk parameters were captured from patient records in 1998. Pooled cohort risk score and Framingham General CVD risk score for each patient were computed. All ASCVD events (nonfatal myocardial infarction, coronary heart disease (CHD) death, fatal and nonfatal stroke) occurring from 1998-2007 were recorded. A total of 922 patients were studied. In 1998, mean age was 57.5 ± 8.8 years with 66.7% female. There were 47% diabetic patients and 59.9% patients receiving anti-hypertensive treatment. More than 98% of patients with pooled cohort risk score ≥7.5% had FRS >10%. A total of 45 CVD events occurred, 22 (7.2%) in males and 23 (3.7%) in females. The median pooled cohort risk score for the population was 10.1 (IQR 4.7-20.6) while the actual ASCVD events that occurred was 4.9% (45/922). Our study showed moderate discrimination with AUC of 0.63. There was good calibration with Hosmer-Lemeshow test χ2 = 12.6, P = 0.12. The pooled cohort risk score appears to overestimate CV risk but this apparent over-prediction could be a result of treatment. In the absence of a validated score in an untreated population, the pooled cohort risk score appears to be appropriate for use in a primary care setting.

Does my patient have chronic Chagas disease? Development and temporal validation of a diagnostic risk score.

PubMed

Brasil, Pedro Emmanuel Alvarenga Americano do; Xavier, Sergio Salles; Holanda, Marcelo Teixeira; Hasslocher-Moreno, Alejandro Marcel; Braga, José Ueleres

2016-01-01

With the globalization of Chagas disease, unexperienced health care providers may have difficulties in identifying which patients should be examined for this condition. This study aimed to develop and validate a diagnostic clinical prediction model for chronic Chagas disease. This diagnostic cohort study included consecutive volunteers suspected to have chronic Chagas disease. The clinical information was blindly compared to serological tests results, and a logistic regression model was fit and validated. The development cohort included 602 patients, and the validation cohort included 138 patients. The Chagas disease prevalence was 19.9%. Sex, age, referral from blood bank, history of living in a rural area, recognizing the kissing bug, systemic hypertension, number of siblings with Chagas disease, number of relatives with a history of stroke, ECG with low voltage, anterosuperior divisional block, pathologic Q wave, right bundle branch block, and any kind of extrasystole were included in the final model. Calibration and discrimination in the development and validation cohorts (ROC AUC 0.904 and 0.912, respectively) were good. Sensitivity and specificity analyses showed that specificity reaches at least 95% above the predicted 43% risk, while sensitivity is at least 95% below the predicted 7% risk. Net benefit decision curves favor the model across all thresholds. A nomogram and an online calculator (available at http://shiny.ipec.fiocruz.br:3838/pedrobrasil/chronic_chagas_disease_prediction/) were developed to aid in individual risk estimation.

40 CFR 1065.550 - Gas analyzer range validation and drift validation.

Code of Federal Regulations, 2012 CFR

2012-07-01

... a dry sample measured with a CLD and the removed water is corrected based on measured CO2, CO, THC... may not validate the concentration subcomponents (e.g., THC and CH4 for NMHC) separately. For example, for NMHC measurements, perform drift validation on NMHC; do not validate THC and CH4 separately. (2...

40 CFR 1065.550 - Gas analyzer range validation and drift validation.

Code of Federal Regulations, 2013 CFR

2013-07-01

... a dry sample measured with a CLD and the removed water is corrected based on measured CO2, CO, THC... may not validate the concentration subcomponents (e.g., THC and CH4 for NMHC) separately. For example, for NMHC measurements, perform drift validation on NMHC; do not validate THC and CH4 separately. (2...

PCA as a practical indicator of OPLS-DA model reliability.

PubMed

Worley, Bradley; Powers, Robert

Principal Component Analysis (PCA) and Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) are powerful statistical modeling tools that provide insights into separations between experimental groups based on high-dimensional spectral measurements from NMR, MS or other analytical instrumentation. However, when used without validation, these tools may lead investigators to statistically unreliable conclusions. This danger is especially real for Partial Least Squares (PLS) and OPLS, which aggressively force separations between experimental groups. As a result, OPLS-DA is often used as an alternative method when PCA fails to expose group separation, but this practice is highly dangerous. Without rigorous validation, OPLS-DA can easily yield statistically unreliable group separation. A Monte Carlo analysis of PCA group separations and OPLS-DA cross-validation metrics was performed on NMR datasets with statistically significant separations in scores-space. A linearly increasing amount of Gaussian noise was added to each data matrix followed by the construction and validation of PCA and OPLS-DA models. With increasing added noise, the PCA scores-space distance between groups rapidly decreased and the OPLS-DA cross-validation statistics simultaneously deteriorated. A decrease in correlation between the estimated loadings (added noise) and the true (original) loadings was also observed. While the validity of the OPLS-DA model diminished with increasing added noise, the group separation in scores-space remained basically unaffected. Supported by the results of Monte Carlo analyses of PCA group separations and OPLS-DA cross-validation metrics, we provide practical guidelines and cross-validatory recommendations for reliable inference from PCA and OPLS-DA models.

Postpartum maternal separation anxiety, overprotective parenting, and children's social-emotional well-being: longitudinal evidence from an Australian cohort.

PubMed

Cooklin, Amanda R; Giallo, Rebecca; D'Esposito, Fabrizio; Crawford, Sharinne; Nicholson, Jan M

2013-08-01

Postpartum maternal separation anxiety refers to a mothers' experience of worry and concern about leaving her child for short-term separations. The long-term effects of high maternal separation anxiety on maternal parenting behaviors and child outcomes have been not been established empirically. The aim of this study was to ascertain the prospective relationships between maternal separation anxiety during the child's first year of life, and overprotective parenting and children's social and emotional functioning at age 2-3 years. Structural equation modeling with a large representative cohort of Australian mother-child dyads (N = 3,103) indicated that high maternal separation anxiety was associated with more overprotective parenting behaviors and poorer child socioemotional functioning at age 2-3 years. Findings suggest women with high postpartum maternal separation anxiety may sustain this vigilance across the first years following birth, promoting overprotective behaviors, and resulting in increased behavior problems in their children. Support for women around negotiating separation from their children early in parenthood may prevent the establishment of a repertoire of parenting behaviors that includes unnecessarily high vigilance, monitoring, and anxiety about separation. © 2013 American Psychological Association

Time-saving impact of an algorithm to identify potential surgical site infections.

PubMed

Knepper, B C; Young, H; Jenkins, T C; Price, C S

2013-10-01

To develop and validate a partially automated algorithm to identify surgical site infections (SSIs) using commonly available electronic data to reduce manual chart review. Retrospective cohort study of patients undergoing specific surgical procedures over a 4-year period from 2007 through 2010 (algorithm development cohort) or over a 3-month period from January 2011 through March 2011 (algorithm validation cohort). A single academic safety-net hospital in a major metropolitan area. Patients undergoing at least 1 included surgical procedure during the study period. Procedures were identified in the National Healthcare Safety Network; SSIs were identified by manual chart review. Commonly available electronic data, including microbiologic, laboratory, and administrative data, were identified via a clinical data warehouse. Algorithms using combinations of these electronic variables were constructed and assessed for their ability to identify SSIs and reduce chart review. The most efficient algorithm identified in the development cohort combined microbiologic data with postoperative procedure and diagnosis codes. This algorithm resulted in 100% sensitivity and 85% specificity. Time savings from the algorithm was almost 600 person-hours of chart review. The algorithm demonstrated similar sensitivity on application to the validation cohort. A partially automated algorithm to identify potential SSIs was highly sensitive and dramatically reduced the amount of manual chart review required of infection control personnel during SSI surveillance.

Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study.

PubMed

Scicluna, Brendon P; van Vught, Lonneke A; Zwinderman, Aeilko H; Wiewel, Maryse A; Davenport, Emma E; Burnham, Katie L; Nürnberg, Peter; Schultz, Marcus J; Horn, Janneke; Cremer, Olaf L; Bonten, Marc J; Hinds, Charles J; Wong, Hector R; Knight, Julian C; van der Poll, Tom

2017-10-01

Host responses during sepsis are highly heterogeneous, which hampers the identification of patients at high risk of mortality and their selection for targeted therapies. In this study, we aimed to identify biologically relevant molecular endotypes in patients with sepsis. This was a prospective observational cohort study that included consecutive patients admitted for sepsis to two intensive care units (ICUs) in the Netherlands between Jan 1, 2011, and July 20, 2012 (discovery and first validation cohorts) and patients admitted with sepsis due to community-acquired pneumonia to 29 ICUs in the UK (second validation cohort). We generated genome-wide blood gene expression profiles from admission samples and analysed them by unsupervised consensus clustering and machine learning. The primary objective of this study was to establish endotypes for patients with sepsis, and assess the association of these endotypes with clinical traits and survival outcomes. We also established candidate biomarkers for the endotypes to allow identification of patient endotypes in clinical practice. The discovery cohort had 306 patients, the first validation cohort had 216, and the second validation cohort had 265 patients. Four molecular endotypes for sepsis, designated Mars1-4, were identified in the discovery cohort, and were associated with 28-day mortality (log-rank p=0·022). In the discovery cohort, the worst outcome was found for patients classified as having a Mars1 endotype, and at 28 days, 35 (39%) of 90 people with a Mars1 endotype had died (hazard ratio [HR] vs all other endotypes 1·86 [95% CI 1·21-2·86]; p=0·0045), compared with 23 (22%) of 105 people with a Mars2 endotype (HR 0·64 [0·40-1·04]; p=0·061), 16 (23%) of 71 people with a Mars3 endotype (HR 0·71 [0·41-1·22]; p=0·19), and 13 (33%) of 40 patients with a Mars4 endotype (HR 1·13 [0·63-2·04]; p=0·69). Analysis of the net reclassification improvement using a combined clinical and endotype model significantly improved risk prediction to 0·33 (0·09-0·58; p=0·008). A 140-gene expression signature reliably stratified patients with sepsis to the four endotypes in both the first and second validation cohorts. Only Mars1 was consistently significantly associated with 28-day mortality across the cohorts. To facilitate possible clinical use, a biomarker was derived for each endotype; BPGM and TAP2 reliably identified patients with a Mars1 endotype. This study provides a method for the molecular classification of patients with sepsis to four different endotypes upon ICU admission. Detection of sepsis endotypes might assist in providing personalised patient management and in selection for trials. Center for Translational Molecular Medicine, Netherlands. Copyright © 2017 Elsevier Ltd. All rights reserved.

Optimization of ultra-high pressure liquid chromatography - tandem mass spectrometry determination in plasma and red blood cells of four sphingolipids and their evaluation as biomarker candidates of Gaucher's disease.

PubMed

Chipeaux, Caroline; de Person, Marine; Burguet, Nathalie; Billette de Villemeur, Thierry; Rose, Christian; Belmatoug, Nadia; Héron, Sylvie; Le Van Kim, Caroline; Franco, Mélanie; Moussa, Fathi

2017-11-24

While important advances have been recently achieved in the optimization of lipid classes' separation, information on the specific determination of medium polarity lipids such as sphingolipids (SLs) in highly complex matrices remains fragmentary. In human, disorders of SL metabolism known as sphingolipidoses are a heterogeneous group of inherited disorders affecting primarily the central nervous. Early diagnosis of these conditions is of importance notably when a corrective therapy is available. The diagnosis is generally based on the determination of specific SLs in plasma and red blood cells (RBCs). For instance, glucosylceramide (GL1), glucosylsphingosine (Lyso-GL1), sphingosine (Sph), and sphingosine-1-phosphate (S1P) are proposed as relevant biomarkers for Gaucher disease (GD). Our main objective was to evaluate these biomarker candidates in a cohort of GD patients. However, most of current methods of GL1, Lyso-GL1, Sph, and S1P determination in plasma of GD patients require at least two liquid chromatographic runs. On the other hand, except for GL1 nothing is known concerning the RBC sphingolipid content. Yet, several reversed phase LC-MS methods of SLs separation and/or determination in various media with different sample preparation approaches have been proposed since 2010. Here we focused on stationary phase selection and mobile phase composition as well as on the sample preparation step to optimize and validate an UHPLC-MS/MS method for the simultaneous quantification of the four sphingolipids in both plasma and RBCs. A comparison between seven stationary phases including two RP18, two polar embedded RP18, and three HILIC phases shows that under our conditions polar embedded RP18 phases are the most appropriate for the separation of the four SLs, in terms of efficiency, peak symmetry, and separation time. In the same way, a comparison between a single step extraction with methanol and a liquid-liquid extraction with a mixture of methanol/methyl tert-butyl ether, shows that the latter mixture is the most appropriate for the extraction of SLs in terms of recovery and absence of matrix effect. After validation, this method was applied to the evaluation of the targeted SLs in a cohort of 15 known GD patients. The obtained results show that Lyso-GL1 is the only relevant biomarker in both plasma and RBCs for GD diagnosis. As the proposed method is applicable to the determination in such a highly complex matrices of four SLs with a large difference in polarity, and as the sample preparation procedure is freedom of matrix effects, this method can be easily adapted to a large diversity of samples. Copyright © 2017 Elsevier B.V. All rights reserved.

Using the Bergman-Paris Question to screen seniors in the emergency department.

PubMed

Lague, Antoine; Voyer, Philippe; Ouellet, Marie-Christine; Boucher, Vale Rie; Giroux, Marianne; Pelletier, Mathieu; Gouin, E Milie; Daoust, Raoul; Berthelot, Simon; Morin, Miche le; Minh Vu, Thien Tuong; Lee, Jacques; Brousseau, Audrey-Anne; Sirois, Marie-Jose E; E Mond, Marcel

2017-10-16

In the fast pace of the Emergency Department (ED), clinicians are in need of tailored screening tools to detect seniors who are at risk of adverse outcomes. We aimed to explore the usefulness of the Bergman-Paris Question (BPQ) to expose potential undetected geriatric syndromes in community-living seniors presenting to the ED. This is a planned sub-study of the INDEED multicentre prospective cohort study, including independent or semi-independent seniors (≥65 years old) admitted to hospital after an ED stay ≥8 hours and who were not delirious. Patients were assessed using validated screening tests for 3 geriatric syndromes: cognitive and functional impairment, and frailty. The BPQ was asked upon availability of a relative at enrolment. BPQ's sensitivity and specificity analyses were used to ascertain outcomes. A response to the BPQ was available for 171 patients (47% of the main study's cohort). Of this number, 75.4% were positive (suggesting impairment), and 24.6% were negative. To detect one of the three geriatric syndromes, the BPQ had a sensitivity of 85.4% (95% CI [76.3, 92.0]) and a specificity of 35.4% (95% CI [25.1, 46.7]). Similar results were obtained for each separate outcome. Odds ratio demonstrated a higher risk of presence of geriatric syndromes. The Bergman-Paris Question could be an ED screening tool for possible geriatric syndrome. A positive BPQ should prompt the need of further investigations and a negative BPQ possibly warrants no further action. More research is needed to validate the usefulness of the BPQ for day-to-day geriatric screening by ED professionals or geriatricians.

A Model to Predict the Risk of Keratinocyte Carcinomas.

PubMed

Whiteman, David C; Thompson, Bridie S; Thrift, Aaron P; Hughes, Maria-Celia; Muranushi, Chiho; Neale, Rachel E; Green, Adele C; Olsen, Catherine M

2016-06-01

Basal cell and squamous cell carcinomas of the skin are the commonest cancers in humans, yet no validated tools exist to estimate future risks of developing keratinocyte carcinomas. To develop a prediction tool, we used baseline data from a prospective cohort study (n = 38,726) in Queensland, Australia, and used data linkage to capture all surgically excised keratinocyte carcinomas arising within the cohort. Predictive factors were identified through stepwise logistic regression models. In secondary analyses, we derived separate models within strata of prior skin cancer history, age, and sex. The primary model included terms for 10 items. Factors with the strongest effects were >20 prior skin cancers excised (odds ratio 8.57, 95% confidence interval [95% CI] 6.73-10.91), >50 skin lesions destroyed (odds ratio 3.37, 95% CI 2.85-3.99), age ≥ 70 years (odds ratio 3.47, 95% CI 2.53-4.77), and fair skin color (odds ratio 1.75, 95% CI 1.42-2.15). Discrimination in the validation dataset was high (area under the receiver operator characteristic curve 0.80, 95% CI 0.79-0.81) and the model appeared well calibrated. Among those reporting no prior history of skin cancer, a similar model with 10 factors predicted keratinocyte carcinoma events with reasonable discrimination (area under the receiver operator characteristic curve 0.72, 95% CI 0.70-0.75). Algorithms using self-reported patient data have high accuracy for predicting risks of keratinocyte carcinomas. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Pair Housing of Vervets/African Green Monkeys for Biomedical Research

PubMed Central

Jorgensen, Matthew J.; Lambert, Kelsey R.; Breaux, Sarah D.; Baker, Kate C.; Snively, Beverly M.; Weed, James L.

2016-01-01

Vervets, also known as African green monkeys, are a nonhuman primate species widely used in biomedical research. However, there are currently few references available describing techniques and rates of success for pair-housing this species. We present data from four cohorts of vervets from three different facilities: (i) the Wake Forest Vervet Research Colony (VRC; n = 72 female pairs, n = 52 male pairs), (ii) the University of Louisiana at Lafayette—New Iberia Research Center (UL-NIRC; n = 57 female pairs, n = 54 male pairs), (iii) the Tulane National Primate Research Center (TNRPC; n = 18 male pairs), and (iv) a cohort of imported males (n = 18 pairs) at Wake Forest. Compatibility was measured at 14, 30, and 60 days following introduction. Success rates for pair-housing at14 days ranged from 96% to 98% for females and 96% to 100% for males at the VRC and UL-NIRC but were lower in the smaller imported male cohorts (TNPRC: 50%; WF: 28%). Among the UL-NIRC cohort and VRC male cohort, most of the pair separations after 14 days were due to reasons unrelated to social incompatibility. In contrast, a large proportion of TNPRC and imported male pairs successful at 14 days required separation within 60 days due to incompatibility. Multiple logistic regressions were performed using cohort, mean age of pair and weight difference between pair-mates as potential predictors of compatibility at 14 days. All three predicted the 14-day outcome in males but not females. A separate analysis in the VRC cohort found no evidence that prior familiarity in a group setting influenced outcomes. Variations in success rates across cohorts may have been influenced by introduction methodology. Behavioral differences between vervets and macaques, coupled with our findings, lead us to theorize that the gradual introduction techniques commonly implemented to pair house macaques may not be beneficial or suitable for this species. PMID:26539878

The Amsterdam wrist rules: the multicenter prospective derivation and external validation of a clinical decision rule for the use of radiography in acute wrist trauma.

PubMed

Walenkamp, Monique M J; Bentohami, Abdelali; Slaar, Annelie; Beerekamp, M Suzan H; Maas, Mario; Jager, L Cara; Sosef, Nico L; van Velde, Romuald; Ultee, Jan M; Steyerberg, Ewout W; Goslings, J Carel; Schep, Niels W L

2015-12-18

Although only 39 % of patients with wrist trauma have sustained a fracture, the majority of patients is routinely referred for radiography. The purpose of this study was to derive and externally validate a clinical decision rule that selects patients with acute wrist trauma in the Emergency Department (ED) for radiography. This multicenter prospective study consisted of three components: (1) derivation of a clinical prediction model for detecting wrist fractures in patients following wrist trauma; (2) external validation of this model; and (3) design of a clinical decision rule. The study was conducted in the EDs of five Dutch hospitals: one academic hospital (derivation cohort) and four regional hospitals (external validation cohort). We included all adult patients with acute wrist trauma. The main outcome was fracture of the wrist (distal radius, distal ulna or carpal bones) diagnosed on conventional X-rays. A total of 882 patients were analyzed; 487 in the derivation cohort and 395 in the validation cohort. We derived a clinical prediction model with eight variables: age; sex, swelling of the wrist; swelling of the anatomical snuffbox, visible deformation; distal radius tender to palpation; pain on radial deviation and painful axial compression of the thumb. The Area Under the Curve at external validation of this model was 0.81 (95 % CI: 0.77-0.85). The sensitivity and specificity of the Amsterdam Wrist Rules (AWR) in the external validation cohort were 98 % (95 % CI: 95-99 %) and 21 % (95 % CI: 15 %-28). The negative predictive value was 90 % (95 % CI: 81-99 %). The Amsterdam Wrist Rules is a clinical prediction rule with a high sensitivity and negative predictive value for fractures of the wrist. Although external validation showed low specificity and 100 % sensitivity could not be achieved, the Amsterdam Wrist Rules can provide physicians in the Emergency Department with a useful screening tool to select patients with acute wrist trauma for radiography. The upcoming implementation study will further reveal the impact of the Amsterdam Wrist Rules on the anticipated reduction of X-rays requested, missed fractures, Emergency Department waiting times and health care costs. This study was registered in the Dutch Trial Registry, reference number NTR2544 on October 1(st), 2010.

Primary central nervous system lymphoma and glioblastoma differentiation based on conventional magnetic resonance imaging by high-throughput SIFT features.

PubMed

Chen, Yinsheng; Li, Zeju; Wu, Guoqing; Yu, Jinhua; Wang, Yuanyuan; Lv, Xiaofei; Ju, Xue; Chen, Zhongping

2018-07-01

Due to the totally different therapeutic regimens needed for primary central nervous system lymphoma (PCNSL) and glioblastoma (GBM), accurate differentiation of the two diseases by noninvasive imaging techniques is important for clinical decision-making. Thirty cases of PCNSL and 66 cases of GBM with conventional T1-contrast magnetic resonance imaging (MRI) were analyzed in this study. Convolutional neural networks was used to segment tumor automatically. A modified scale invariant feature transform (SIFT) method was utilized to extract three-dimensional local voxel arrangement information from segmented tumors. Fisher vector was proposed to normalize the dimension of SIFT features. An improved genetic algorithm (GA) was used to extract SIFT features with PCNSL and GBM discrimination ability. The data-set was divided into a cross-validation cohort and an independent validation cohort by the ratio of 2:1. Support vector machine with the leave-one-out cross-validation based on 20 cases of PCNSL and 44 cases of GBM was employed to build and validate the differentiation model. Among 16,384 high-throughput features, 1356 features show significant differences between PCNSL and GBM with p < 0.05 and 420 features with p < 0.001. A total of 496 features were finally chosen by improved GA algorithm. The proposed method produces PCNSL vs. GBM differentiation with an area under the curve (AUC) curve of 99.1% (98.2%), accuracy 95.3% (90.6%), sensitivity 85.0% (80.0%) and specificity 100% (95.5%) on the cross-validation cohort (and independent validation cohort). Since the local voxel arrangement characterization provided by SIFT features, proposed method produced more competitive PCNSL and GBM differentiation performance by using conventional MRI than methods based on advanced MRI.

Development and validation of immune dysfunction score to predict 28-day mortality of sepsis patients

PubMed Central

Fang, Wen-Feng; Douglas, Ivor S.; Chen, Yu-Mu; Lin, Chiung-Yu; Kao, Hsu-Ching; Fang, Ying-Tang; Huang, Chi-Han; Chang, Ya-Ting; Huang, Kuo-Tung; Wang, Yi-His; Wang, Chin-Chou

2017-01-01

Background Sepsis-induced immune dysfunction ranging from cytokines storm to immunoparalysis impacts outcomes. Monitoring immune dysfunction enables better risk stratification and mortality prediction and is mandatory before widely application of immunoadjuvant therapies. We aimed to develop and validate a scoring system according to patients’ immune dysfunction status for 28-day mortality prediction. Methods A prospective observational study from a cohort of adult sepsis patients admitted to ICU between August 2013 and June 2016 at Kaohsiung Chang Gung Memorial Hospital in Taiwan. We evaluated immune dysfunction status through measurement of baseline plasma Cytokine levels, Monocyte human leukocyte-DR expression by flow cytometry, and stimulated immune response using post LPS stimulated cytokine elevation ratio. An immune dysfunction score was created for 28-day mortality prediction and was validated. Results A total of 151 patients were enrolled. Data of the first consecutive 106 septic patients comprised the training cohort, and of other 45 patients comprised the validation cohort. Among the 106 patients, 21 died and 85 were still alive on day 28 after ICU admission. (mortality rate, 19.8%). Independent predictive factors revealed via multivariate logistic regression analysis included segmented neutrophil-to-monocyte ratio, granulocyte-colony stimulating factor, interleukin-10, and monocyte human leukocyte antigen-antigen D–related levels, all of which were selected to construct the score, which predicted 28-day mortality with area under the curve of 0.853 and 0.789 in the training and validation cohorts, respectively. Conclusions The immune dysfunction scoring system developed here included plasma granulocyte-colony stimulating factor level, interleukin-10 level, serum segmented neutrophil-to-monocyte ratio, and monocyte human leukocyte antigen-antigen D–related expression appears valid and reproducible for predicting 28-day mortality. PMID:29073262

Associations of prodynorphin sequence variation with alcohol dependence and related traits are phenotype-specific and sex-dependent

PubMed Central

Winham, Stacey J.; Preuss, Ulrich W.; Geske, Jennifer R.; Zill, Peter; Heit, John A.; Bakalkin, Georgy; Biernacka, Joanna M.; Karpyak, Victor M.

2015-01-01

We previously demonstrated that prodynorphin (PDYN) haplotypes and single nucleotide polymorphism (SNP) rs2281285 are associated with alcohol dependence and the propensity to drink in negative emotional states, and recent studies suggest that PDYN gene effects on substance dependence risk may be sex-related. We examined sex-dependent associations of PDYN variation with alcohol dependence and related phenotypes, including negative craving, time until relapse after treatment and the length of sobriety episodes before seeking treatment, in discovery and validation cohorts of European ancestry. We found a significant haplotype-by-sex interaction (p  =  0.03), suggesting association with alcohol dependence in males (p = 1E-4) but not females. The rs2281285 G allele increased risk for alcohol dependence in males in the discovery cohort (OR = 1.49, p = 0.002), with a similar trend in the validation cohort (OR = 1.35, p = 0.086). However, rs2281285 showed a trend towards association with increased negative craving in females in both the discovery (beta = 10.16, p = 0.045) and validation samples (OR = 7.11, p = 0.066). In the discovery cohort, rs2281285 was associated with time until relapse after treatment in females (HR = 1.72, p = 0.037); in the validation cohort, it was associated with increased length of sobriety episodes before treatment in males (beta = 13.49, p = 0.001). Our findings suggest that sex-dependent effects of PDYN variants in alcohol dependence are phenotype-specific. PMID:26502829

Associations of prodynorphin sequence variation with alcohol dependence and related traits are phenotype-specific and sex-dependent.

PubMed

Winham, Stacey J; Preuss, Ulrich W; Geske, Jennifer R; Zill, Peter; Heit, John A; Bakalkin, Georgy; Biernacka, Joanna M; Karpyak, Victor M

2015-10-27

We previously demonstrated that prodynorphin (PDYN) haplotypes and single nucleotide polymorphism (SNP) rs2281285 are associated with alcohol dependence and the propensity to drink in negative emotional states, and recent studies suggest that PDYN gene effects on substance dependence risk may be sex-related. We examined sex-dependent associations of PDYN variation with alcohol dependence and related phenotypes, including negative craving, time until relapse after treatment and the length of sobriety episodes before seeking treatment, in discovery and validation cohorts of European ancestry. We found a significant haplotype-by-sex interaction (p  =  0.03), suggesting association with alcohol dependence in males (p = 1E-4) but not females. The rs2281285 G allele increased risk for alcohol dependence in males in the discovery cohort (OR = 1.49, p = 0.002), with a similar trend in the validation cohort (OR = 1.35, p = 0.086). However, rs2281285 showed a trend towards association with increased negative craving in females in both the discovery (beta = 10.16, p = 0.045) and validation samples (OR = 7.11, p = 0.066). In the discovery cohort, rs2281285 was associated with time until relapse after treatment in females (HR = 1.72, p = 0.037); in the validation cohort, it was associated with increased length of sobriety episodes before treatment in males (beta = 13.49, p = 0.001). Our findings suggest that sex-dependent effects of PDYN variants in alcohol dependence are phenotype-specific.

Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype

PubMed Central

Wei, Caimiao; Gould, Rebekah; Yu, Xian; Zhang, Ya; Liu, Mei; Walls, Andrew; Bousamra, Alex; Ramineni, Maheshwari; Sinn, Bruno; Hunt, Kelly; Buchholz, Thomas A.; Valero, Vicente; Buzdar, Aman U.; Yang, Wei; Brewster, Abenaa M.; Moulder, Stacy; Pusztai, Lajos; Hatzis, Christos; Hortobagyi, Gabriel N.

2017-01-01

Purpose To determine the long-term prognosis in each phenotypic subset of breast cancer related to residual cancer burden (RCB) after neoadjuvant chemotherapy alone, or with concurrent human epidermal growth factor receptor 2 (HER2)–targeted treatment. Methods We conducted a pathologic review to measure the continuous RCB index (wherein pathologic complete response has RCB = 0; residual disease is categorized into three predefined classes of RCB index [RCB-I, RCB-II, and RCB-III]), and yp-stage of residual disease. Patients were prospectively observed for survival. Three patient cohorts received paclitaxel (T) followed by fluorouracil, doxorubicin, and cyclophosphamide (T/FAC): original development cohort (T/FAC-1), validation cohort (T/FAC-2), and independent validation cohort (T/FAC-3). Another validation cohort received FAC chemotherapy only, and a fifth cohort received concurrent trastuzumab (H) with sequential paclitaxel and fluorouracil, epirubicin, and cyclophosphamide (FEC; H+T/FEC). Phenotypic subsets were defined by hormone receptor (HR) and HER2 status at diagnosis, classified as HR-positive/HER2-negative, HER2-positive (HR-negative/HER2-positive or HR-positive/HER2-positive), or triple receptor–negative. Relapse-free survival estimates were determined from Kaplan-Meier analysis and compared using the log-rank test. Results Five cohorts (T/FAC-1 [n = 219], T/FAC-2 [n = 262], T/FAC-3 [n = 342], FAC [n = 132], and H+T/FEC [n = 203]) had median event-free follow-up of 13.5, 9.1, 6.8, 16.4, and 7.1 years, respectively. Continuous RCB index was prognostic within each phenotypic subset, independent of other clinical-pathologic variables. RCB classes stratified prognostic risk overall, within each phenotypic subset, and within yp-stage categories. Estimates of 10-year relapse-free survival rates in the four RCB classes (pathologic complete response, RCB-I, RCB-II, and RCB-III) were 86%, 81%, 55%, and 23% for triple receptor–negative; 83%, 97%, 74%, and 52% for HR-positive/HER2-negative in the combined T/FAC cohorts; and 95%, 77%, 47%, and 21% in the H+T/FEC cohort. Conclusion RCB was prognostic for long-term survival after neoadjuvant chemotherapy in all three phenotypic subsets of breast cancer. Our institutional findings should be externally validated. PMID:28135148

Susceptibility to corticosteroid-induced adrenal suppression: a genome-wide association study.

PubMed

Hawcutt, Daniel B; Francis, Ben; Carr, Daniel F; Jorgensen, Andrea L; Yin, Peng; Wallin, Naomi; O'Hara, Natalie; Zhang, Eunice J; Bloch, Katarzyna M; Ganguli, Amitava; Thompson, Ben; McEvoy, Laurence; Peak, Matthew; Crawford, Andrew A; Walker, Brian R; Blair, Joanne C; Couriel, Jonathan; Smyth, Rosalind L; Pirmohamed, Munir

2018-06-01

A serious adverse effect of corticosteroid therapy is adrenal suppression. Our aim was to identify genetic variants affecting susceptibility to corticosteroid-induced adrenal suppression. We enrolled children with asthma who used inhaled corticosteroids as part of their treatment from 25 sites across the UK (discovery cohort), as part of the Pharmacogenetics of Adrenal Suppression with Inhaled Steroids (PASS) study. We included two validation cohorts, one comprising children with asthma (PASS study) and the other consisting of adults with chronic obstructive pulmonary disorder (COPD) who were recruited from two UK centres for the Pharmacogenomics of Adrenal Suppression in COPD (PASIC) study. Participants underwent a low-dose short synacthen test. Adrenal suppression was defined as peak cortisol less than 350 nmol/L (in children) and less than 500 nmol/L (in adults). A case-control genome-wide association study was done with the control subset augmented by Wellcome Trust Case Control Consortium 2 (WTCCC2) participants. Single nucleotide polymorphisms (SNPs) that fulfilled criteria to be advanced to replication were tested by a random-effects inverse variance meta-analysis. This report presents the primary analysis. The PASS study is registered in the European Genome-phenome Archive (EGA). The PASS study is complete whereas the PASIC study is ongoing. Between November, 2008, and September, 2011, 499 children were enrolled to the discovery cohort. Between October, 2011, and December, 2012, 81 children were enrolled to the paediatric validation cohort, and from February, 2010, to June, 2015, 78 adults were enrolled to the adult validation cohort. Adrenal suppression was present in 35 (7%) children in the discovery cohort and six (7%) children and 17 (22%) adults in the validation cohorts. In the discovery cohort, 40 SNPs were found to be associated with adrenal suppression (genome-wide significance p<1 × 10 -6 ), including an intronic SNP within the PDGFD gene locus (rs591118; odds ratio [OR] 7·32, 95% CI 3·15-16·99; p=5·8 × 10 -8 ). This finding for rs591118 was validated successfully in both the paediatric asthma (OR 3·86, 95% CI 1·19-12·50; p=0·02) and adult COPD (2·41, 1·10-5·28; p=0·03) cohorts. The proportions of patients with adrenal suppression by rs591118 genotype were six (3%) of 214 patients with the GG genotype, 15 (6%) of 244 with the AG genotype, and 22 (25%) of 87 with the AA genotype. Meta-analysis of the paediatric cohorts (discovery and validation) and all three cohorts showed genome-wide significance of rs591118 (respectively, OR 5·89, 95% CI 2·97-11·68; p=4·3 × 10 -9 ; and 4·05, 2·00-8·21; p=3·5 × 10 -10 ). Our findings suggest that genetic variation in the PDGFD gene locus increases the risk of adrenal suppression in children and adults who use corticosteroids to treat asthma and COPD, respectively. Department of Health Chair in Pharmacogenetics. Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Exposure to parental separation in childhood and later parenting quality as an adult: evidence from a 30-year longitudinal study.

PubMed

Friesen, Myron D; John Horwood, L; Fergusson, David M; Woodward, Lianne J

2017-01-01

Previous research has documented that exposure to parental separation/divorce during childhood can be associated with long-term consequences into adulthood. This study sought to extend this literature by examining associations between childhood exposure to parental separation/divorce and later parenting behavior as an adult in a New Zealand birth cohort. Data were drawn from the Christchurch Health and Development Study (CHDS), a longitudinal study of a birth cohort of 1,265 children born in 1977 in Christchurch, New Zealand. Information about exposure to parental separation and divorce was gathered annually from birth to 15 years. At the 30-year follow-up, all cohort members who had become parents (biological or nonbiological) were assessed on several parenting dimensions (sensitivity, warmth, overreactivity, inconsistency, quality of child management, and physical punishment). The analyses showed that exposure to more frequent parental separation in childhood and adolescence was associated with lower levels of parental sensitivity and warmth, greater overreactivity, and an increased use of physical punishment as a parent, after controlling for a wide range of family socioeconomic and psychosocial factors, and individual child characteristics. The findings suggest that as exposure to parental separation increases, so does the likelihood of experiencing multiple developmental challenges in childhood and adolescence. As an adult, these life-course experiences can have small but significant associations with the quality of parenting behavior. © 2016 Association for Child and Adolescent Mental Health.

Development and validation of risk prediction algorithms to estimate future risk of common cancers in men and women: prospective cohort study

PubMed Central

Hippisley-Cox, Julia; Coupland, Carol

2015-01-01

Objective To derive and validate a set of clinical risk prediction algorithm to estimate the 10-year risk of 11 common cancers. Design Prospective open cohort study using routinely collected data from 753 QResearch general practices in England. We used 565 practices to develop the scores and 188 for validation. Subjects 4.96 million patients aged 25–84 years in the derivation cohort; 1.64 million in the validation cohort. Patients were free of the relevant cancer at baseline. Methods Cox proportional hazards models in the derivation cohort to derive 10-year risk algorithms. Risk factors considered included age, ethnicity, deprivation, body mass index, smoking, alcohol, previous cancer diagnoses, family history of cancer, relevant comorbidities and medication. Measures of calibration and discrimination in the validation cohort. Outcomes Incident cases of blood, breast, bowel, gastro-oesophageal, lung, oral, ovarian, pancreas, prostate, renal tract and uterine cancers. Cancers were recorded on any one of four linked data sources (general practitioner (GP), mortality, hospital or cancer records). Results We identified 228 241 incident cases during follow-up of the 11 types of cancer. Of these 25 444 were blood; 41 315 breast; 32 626 bowel, 12 808 gastro-oesophageal; 32 187 lung; 4811 oral; 6635 ovarian; 7119 pancreatic; 35 256 prostate; 23 091 renal tract; 6949 uterine cancers. The lung cancer algorithm had the best performance with an R2 of 64.2%; D statistic of 2.74; receiver operating characteristic curve statistic of 0.91 in women. The sensitivity for the top 10% of women at highest risk of lung cancer was 67%. Performance of the algorithms in men was very similar to that for women. Conclusions We have developed and validated a prediction models to quantify absolute risk of 11 common cancers. They can be used to identify patients at high risk of cancers for prevention or further assessment. The algorithms could be integrated into clinical computer systems and used to identify high-risk patients. Web calculator: There is a simple web calculator to implement the Qcancer 10 year risk algorithm together with the open source software for download (available at http://qcancer.org/10yr/). PMID:25783428

Accuracy and generalizability of using automated methods for identifying adverse events from electronic health record data: a validation study protocol.

PubMed

Rochefort, Christian M; Buckeridge, David L; Tanguay, Andréanne; Biron, Alain; D'Aragon, Frédérick; Wang, Shengrui; Gallix, Benoit; Valiquette, Louis; Audet, Li-Anne; Lee, Todd C; Jayaraman, Dev; Petrucci, Bruno; Lefebvre, Patricia

2017-02-16

Adverse events (AEs) in acute care hospitals are frequent and associated with significant morbidity, mortality, and costs. Measuring AEs is necessary for quality improvement and benchmarking purposes, but current detection methods lack in accuracy, efficiency, and generalizability. The growing availability of electronic health records (EHR) and the development of natural language processing techniques for encoding narrative data offer an opportunity to develop potentially better methods. The purpose of this study is to determine the accuracy and generalizability of using automated methods for detecting three high-incidence and high-impact AEs from EHR data: a) hospital-acquired pneumonia, b) ventilator-associated event and, c) central line-associated bloodstream infection. This validation study will be conducted among medical, surgical and ICU patients admitted between 2013 and 2016 to the Centre hospitalier universitaire de Sherbrooke (CHUS) and the McGill University Health Centre (MUHC), which has both French and English sites. A random 60% sample of CHUS patients will be used for model development purposes (cohort 1, development set). Using a random sample of these patients, a reference standard assessment of their medical chart will be performed. Multivariate logistic regression and the area under the curve (AUC) will be employed to iteratively develop and optimize three automated AE detection models (i.e., one per AE of interest) using EHR data from the CHUS. These models will then be validated on a random sample of the remaining 40% of CHUS patients (cohort 1, internal validation set) using chart review to assess accuracy. The most accurate models developed and validated at the CHUS will then be applied to EHR data from a random sample of patients admitted to the MUHC French site (cohort 2) and English site (cohort 3)-a critical requirement given the use of narrative data -, and accuracy will be assessed using chart review. Generalizability will be determined by comparing AUCs from cohorts 2 and 3 to those from cohort 1. This study will likely produce more accurate and efficient measures of AEs. These measures could be used to assess the incidence rates of AEs, evaluate the success of preventive interventions, or benchmark performance across hospitals.

Dietary fat, fat subtypes and hepatocellular carcinoma in a large European cohort.

PubMed

Duarte-Salles, Talita; Fedirko, Veronika; Stepien, Magdalena; Aleksandrova, Krasimira; Bamia, Christina; Lagiou, Pagona; Laursen, Anne Sofie Dam; Hansen, Louise; Overvad, Kim; Tjønneland, Anne; Boutron-Ruault, Marie-Christine; Fagherazzi, Guy; His, Mathilde; Boeing, Heiner; Katzke, Verena; Kühn, Tilman; Trichopoulou, Antonia; Valanou, Elissavet; Kritikou, Maria; Masala, Giovanna; Panico, Salvatore; Sieri, Sabina; Ricceri, Fulvio; Tumino, Rosario; Bueno-de-Mesquita, H B As; Peeters, Petra H; Hjartåker, Anette; Skeie, Guri; Weiderpass, Elisabete; Ardanaz, Eva; Bonet, Catalina; Chirlaque, Maria-Dolores; Dorronsoro, Miren; Quirós, J Ramón; Johansson, Ingegerd; Ohlsson, Bodil; Sjöberg, Klas; Wennberg, Maria; Khaw, Kay-Tee; Travis, Ruth C; Wareham, Nick; Ferrari, Pietro; Freisling, Heinz; Romieu, Isabelle; Cross, Amanda J; Gunter, Marc; Lu, Yunxia; Jenab, Mazda

2015-12-01

The role of amount and type of dietary fat consumption in the etiology of hepatocellular carcinoma (HCC) is poorly understood, despite suggestive biological plausibility. The associations of total fat, fat subtypes and fat sources with HCC incidence were investigated in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, which includes 191 incident HCC cases diagnosed between 1992 and 2010. Diet was assessed by country-specific, validated dietary questionnaires. A single 24-hr diet recall from a cohort subsample was used for measurement error calibration. Hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated from Cox proportional hazard models. Hepatitis B and C viruses (HBV/HCV) status and biomarkers of liver function were assessed separately in a nested case-control subset with available blood samples (HCC = 122). In multivariable calibrated models, there was a statistically significant inverse association between total fat intake and risk of HCC (per 10 g/day, HR = 0.80, 95% CI: 0.65-0.99), which was mainly driven by monounsaturated fats (per 5 g/day, HR = 0.71, 95% CI: 0.55-0.92) rather than polyunsaturated fats (per 5 g/day, HR = 0.92, 95% CI: 0.68-1.25). There was no association between saturated fats (HR = 1.08, 95% CI: 0.88-1.34) and HCC risk. The ratio of polyunsaturated/monounsaturated fats to saturated fats was not significantly associated with HCC risk (per 0.2 point, HR = 0.86, 95% CI: 0.73-1.01). Restriction of analyses to HBV/HCV free participants or adjustment for liver function did not substantially alter the findings. In this large prospective European cohort, higher consumption of monounsaturated fats is associated with lower HCC risk. © 2015 UICC.

Validation of Medicaid claims-based diagnosis of myocardial infarction using an HIV clinical cohort

PubMed Central

Brouwer, Emily S.; Napravnik, Sonia; Eron, Joseph J; Simpson, Ross J; Brookhart, M. Alan; Stalzer, Brant; Vinikoor, Michael; Floris-Moore, Michelle; Stürmer, Til

2014-01-01

Background In non-experimental comparative effectiveness research using healthcare databases, outcome measurements must be validated to evaluate and potentially adjust for misclassification bias. We aimed to validate claims-based myocardial infarction algorithms in a Medicaid population using an HIV clinical cohort as the gold standard. Methods Medicaid administrative data were obtained for the years 2002–2008 and linked to the UNC CFAR HIV Clinical Cohort based on social security number, first name and last name and myocardial infarction were adjudicated. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated. Results There were 1,063 individuals included. Over a median observed time of 2.5 years, 17 had a myocardial infarction. Specificity ranged from 0.979–0.993 with the highest specificity obtained using criteria with the ICD-9 code in the primary and secondary position and a length of stay ≥ 3 days. Sensitivity of myocardial infarction ascertainment varied from 0.588–0.824 depending on algorithm. Conclusion: Specificities of varying claims-based myocardial infarction ascertainment criteria are high but small changes impact positive predictive value in a cohort with low incidence. Sensitivities vary based on ascertainment criteria. Type of algorithm used should be prioritized based on study question and maximization of specific validation parameters that will minimize bias while also considering precision. PMID:23604043

Development, validity and reliability testing of the East Midlands Evaluation Tool (EMET) for measuring impacts on trainees' confidence and competence following end of life care training.

PubMed

Whittaker, B; Parry, R; Bird, L; Watson, S; Faull, C

2017-02-02

To develop, test and validate a versatile questionnaire, the East Midlands Evaluation Tool (EMET), for measuring effects of end of life care training events on trainees' self-reported confidence and competence. A paper-based questionnaire was designed on the basis of the English Department of Health's core competences for end of life care, with sections for completion pretraining, immediately post-training and also for longer term follow-up. Preliminary versions were field tested at 55 training events delivered by 13 organisations to 1793 trainees working in diverse health and social care backgrounds. Iterative rounds of development aimed to maximise relevance to events and trainees. Internal consistency was assessed by calculating interitem correlations on questionnaire responses during field testing. Content validity was assessed via qualitative content analysis of (1) responses to questionnaires completed by field tester trainers and (2) field notes from a workshop with a separate cohort of experienced trainers. Test-retest reliability was assessed via repeat administration to a cohort of student nurses. The EMET comprises 27 items with Likert-scaled responses supplemented with questions seeking free-text responses. It measures changes in self-assessed confidence and competence on 5 subscales: communication skills; assessment and care planning; symptom management; advance care planning; overarching values and knowledge. Test-retest reliability was found to be good, as was internal consistency: the questions successfully assess different aspects of the same underlying concept. The EMET provides a time-efficient, reliable and flexible means of evaluating effects of training on self-reported confidence and competence in the key elements of end of life care. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Validation of a novel multibiomarker test to assess rheumatoid arthritis disease activity.

PubMed

Curtis, Jeffrey R; van der Helm-van Mil, Annette H; Knevel, Rachel; Huizinga, Tom W; Haney, Douglas J; Shen, Yijing; Ramanujan, Saroja; Cavet, Guy; Centola, Michael; Hesterberg, Lyndal K; Chernoff, David; Ford, Kerri; Shadick, Nancy A; Hamburger, Max; Fleischmann, Roy; Keystone, Edward; Weinblatt, Michael E

2012-12-01

Quantitative assessment of disease activity in rheumatoid arthritis (RA) is important for patient management, and additional objective information may aid rheumatologists in clinical decision making. We validated a recently developed multibiomarker disease activity (MBDA) test relative to clinical disease activity in diverse RA cohorts. Serum samples were obtained from the Index for Rheumatoid Arthritis Measurement, Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study, and Leiden Early Arthritis Clinic cohorts. Levels of 12 biomarkers were measured and combined according to a prespecified algorithm to generate the composite MBDA score. The relationship of the MBDA score to clinical disease activity was characterized separately in seropositive and seronegative patients using Pearson's correlations and the area under the receiver operating characteristic curve (AUROC) to discriminate between patients with low and moderate/high disease activity. Associations between changes in MBDA score and clinical responses 6-12 weeks after initiation of anti-tumor necrosis factor or methotrexate treatment were evaluated by the AUROC. The MBDA score was significantly associated with the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) in both seropositive (AUROC 0.77, P < 0.001) and seronegative (AUROC 0.70, P < 0.001) patients. In subgroups based on age, sex, body mass index, and treatment, the MBDA score was associated with the DAS28-CRP (P < 0.05) in all seropositive and most seronegative subgroups. Changes in the MBDA score at 6-12 weeks could discriminate both American College of Rheumatology criteria for 50% improvement responses (P = 0.03) and DAS28-CRP improvement (P = 0.002). Changes in the MBDA score at 2 weeks were also associated with subsequent DAS28-CRP response (P = 0.02). Our findings establish the criterion and discriminant validity of a novel multibiomarker test as an objective measure of RA disease activity to aid in the management of RA in patients with this condition. Copyright © 2012 by the American College of Rheumatology.

Validation of a novel multibiomarker test to assess rheumatoid arthritis disease activity

PubMed Central

Curtis, Jeffrey R; van der Helm-van Mil, Annette H; Knevel, Rachel; Huizinga, Tom W; Haney, Douglas J; Shen, Yijing; Ramanujan, Saroja; Cavet, Guy; Centola, Michael; Hesterberg, Lyndal K; Chernoff, David; Ford, Kerri; Shadick, Nancy A; Hamburger, Max; Fleischmann, Roy; Keystone, Edward; Weinblatt, Michael E

2012-01-01

Objective Quantitative assessment of disease activity in rheumatoid arthritis (RA) is important for patient management, and additional objective information may aid rheumatologists in clinical decision making. We validated a recently developed multibiomarker disease activity (MBDA) test relative to clinical disease activity in diverse RA cohorts. Methods Serum samples were obtained from the Index for Rheumatoid Arthritis Measurement, Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study, and Leiden Early Arthritis Clinic cohorts. Levels of 12 biomarkers were measured and combined according to a prespecified algorithm to generate the composite MBDA score. The relationship of the MBDA score to clinical disease activity was characterized separately in seropositive and seronegative patients using Pearson's correlations and the area under the receiver operating characteristic curve (AUROC) to discriminate between patients with low and moderate/high disease activity. Associations between changes in MBDA score and clinical responses 6–12 weeks after initiation of anti–tumor necrosis factor or methotrexate treatment were evaluated by the AUROC. Results The MBDA score was significantly associated with the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) in both seropositive (AUROC 0.77, P < 0.001) and seronegative (AUROC 0.70, P < 0.001) patients. In subgroups based on age, sex, body mass index, and treatment, the MBDA score was associated with the DAS28-CRP (P < 0.05) in all seropositive and most seronegative subgroups. Changes in the MBDA score at 6–12 weeks could discriminate both American College of Rheumatology criteria for 50% improvement responses (P = 0.03) and DAS28-CRP improvement (P = 0.002). Changes in the MBDA score at 2 weeks were also associated with subsequent DAS28-CRP response (P = 0.02). Conclusion Our findings establish the criterion and discriminant validity of a novel multibiomarker test as an objective measure of RA disease activity to aid in the management of RA in patients with this condition. PMID:22736476

MRI-Based Texture Analysis to Differentiate Sinonasal Squamous Cell Carcinoma from Inverted Papilloma.

PubMed

Ramkumar, S; Ranjbar, S; Ning, S; Lal, D; Zwart, C M; Wood, C P; Weindling, S M; Wu, T; Mitchell, J R; Li, J; Hoxworth, J M

2017-05-01

Because sinonasal inverted papilloma can harbor squamous cell carcinoma, differentiating these tumors is relevant. The objectives of this study were to determine whether MR imaging-based texture analysis can accurately classify cases of noncoexistent squamous cell carcinoma and inverted papilloma and to compare this classification performance with neuroradiologists' review. Adult patients who had inverted papilloma or squamous cell carcinoma resected were eligible (coexistent inverted papilloma and squamous cell carcinoma were excluded). Inclusion required tumor size of >1.5 cm and preoperative MR imaging with axial T1, axial T2, and axial T1 postcontrast sequences. Five well-established texture analysis algorithms were applied to an ROI from the largest tumor cross-section. For a training dataset, machine-learning algorithms were used to identify the most accurate model, and performance was also evaluated in a validation dataset. On the basis of 3 separate blinded reviews of the ROI, isolated tumor, and entire images, 2 neuroradiologists predicted tumor type in consensus. The inverted papilloma ( n = 24) and squamous cell carcinoma ( n = 22) cohorts were matched for age and sex, while squamous cell carcinoma tumor volume was larger ( P = .001). The best classification model achieved similar accuracies for training (17 squamous cell carcinomas, 16 inverted papillomas) and validation (7 squamous cell carcinomas, 6 inverted papillomas) datasets of 90.9% and 84.6%, respectively ( P = .537). For the combined training and validation cohorts, the machine-learning accuracy (89.1%) was better than that of the neuroradiologists' ROI review (56.5%, P = .0004) but not significantly different from the neuroradiologists' review of the tumors (73.9%, P = .060) or entire images (87.0%, P = .748). MR imaging-based texture analysis has the potential to differentiate squamous cell carcinoma from inverted papilloma and may, in the future, provide incremental information to the neuroradiologist. © 2017 by American Journal of Neuroradiology.

Validation of the depression anxiety stress scales (DASS) 21 as a screening instrument for depression and anxiety in a rural community-based cohort of northern Vietnamese women.

PubMed

Tran, Thach Duc; Tran, Tuan; Fisher, Jane

2013-01-12

Depression and anxiety are recognised increasingly as serious public health problems among women in low- and lower-middle income countries. The aim of this study was to validate the 21-item Depression Anxiety and Stress Scale (DASS21) for use in screening for these common mental disorders among rural women with young children in the North of Vietnam. The DASS-21 was translated from English to Vietnamese, culturally verified, back-translated and administered to women who also completed, separately, a psychiatrist-administered Structured Clinical Interview for DSM IV Axis 1 diagnoses of depressive and anxiety disorders. The sample was a community-based representative cohort of adult women with young children living in Ha Nam Province in northern Viet Nam. Cronbach's alpha, Exploratory Factor Analyses (EFA) and Receiver Operating Characteristic (ROC) analyses were performed to identify the psychometric properties of the Depression, Anxiety, and Stress subscales and the overall scale. Complete data were available for 221 women. The internal consistency (Cronbach's alpha) of each sub-scale and the overall scale were high, ranging from 0.70 for the Stress subscale to 0.88 for the overall scale, but EFA indicated that the 21 items all loaded on one factor. Scores on each of the three sub-scales, and the combinations of two or three of them were able to detect the common mental disorders of depression and anxiety in women with a sensitivity of 79.1% and a specificity of 77.0% at the optimal cut off of >33. However, they did not distinguish between those experiencing only depression or only anxiety. The total score of the 21 items of the DASS21-Vietnamese validation appears to be comprehensible and sensitive to detecting common mental disorders in women with young children in primary health care in rural northern Vietnam and therefore might also be useful to screen for these conditions in other resource-constrained settings.

AXIN2 expression predicts prostate cancer recurrence and regulates invasion and tumor growth.

PubMed

Hu, Brian R; Fairey, Adrian S; Madhav, Anisha; Yang, Dongyun; Li, Meng; Groshen, Susan; Stephens, Craig; Kim, Philip H; Virk, Navneet; Wang, Lina; Martin, Sue Ellen; Erho, Nicholas; Davicioni, Elai; Jenkins, Robert B; Den, Robert B; Xu, Tong; Xu, Yucheng; Gill, Inderbir S; Quinn, David I; Goldkorn, Amir

2016-05-01

Treatment of prostate cancer (PCa) may be improved by identifying biological mechanisms of tumor growth that directly impact clinical disease progression. We investigated whether genes associated with a highly tumorigenic, drug resistant, progenitor phenotype impact PCa biology and recurrence. Radical prostatectomy (RP) specimens (±disease recurrence, N = 276) were analyzed by qRT-PCR to quantify expression of genes associated with self-renewal, drug resistance, and tumorigenicity in prior studies. Associations between gene expression and PCa recurrence were confirmed by bootstrap internal validation and by external validation in independent cohorts (total N = 675) and in silico. siRNA knockdown and lentiviral overexpression were used to determine the effect of gene expression on PCa invasion, proliferation, and tumor growth. Four candidate genes were differentially expressed in PCa recurrence. Of these, low AXIN2 expression was internally validated in the discovery cohort. Validation in external cohorts and in silico demonstrated that low AXIN2 was independently associated with more aggressive PCa, biochemical recurrence, and metastasis-free survival after RP. Functionally, siRNA-mediated depletion of AXIN2 significantly increased invasiveness, proliferation, and tumor growth. Conversely, ectopic overexpression of AXIN2 significantly reduced invasiveness, proliferation, and tumor growth. Low AXIN2 expression was associated with PCa recurrence after RP in our test population as well as in external validation cohorts, and its expression levels in PCa cells significantly impacted invasiveness, proliferation, and tumor growth. Given these novel roles, further study of AXIN2 in PCa may yield promising new predictive and therapeutic strategies. © 2016 Wiley Periodicals, Inc.

Proposal and validation of a new model to estimate survival for hepatocellular carcinoma patients.

PubMed

Liu, Po-Hong; Hsu, Chia-Yang; Hsia, Cheng-Yuan; Lee, Yun-Hsuan; Huang, Yi-Hsiang; Su, Chien-Wei; Lee, Fa-Yauh; Lin, Han-Chieh; Huo, Teh-Ia

2016-08-01

The survival of hepatocellular carcinoma (HCC) patients is heterogeneous. We aim to develop and validate a simple prognostic model to estimate survival for HCC patients (MESH score). A total of 3182 patients were randomised into derivation and validation cohort. Multivariate analysis was used to identify independent predictors of survival in the derivation cohort. The validation cohort was employed to examine the prognostic capabilities. The MESH score allocated 1 point for each of the following parameters: large tumour (beyond Milan criteria), presence of vascular invasion or metastasis, Child-Turcotte-Pugh score ≥6, performance status ≥2, serum alpha-fetoprotein level ≥20 ng/ml, and serum alkaline phosphatase ≥200 IU/L, with a maximal of 6 points. In the validation cohort, significant survival differences were found across all MESH scores from 0 to 6 (all p < 0.01). The MESH system was associated with the highest homogeneity and lowest corrected Akaike information criterion compared with Barcelona Clínic Liver Cancer, Hong Kong Liver Cancer (HKLC), Cancer of the Liver Italian Program, Taipei Integrated Scoring and model to estimate survival in ambulatory HCC Patients systems. The prognostic accuracy of the MESH scores remained constant in patients with hepatitis B- or hepatitis C-related HCC. The MESH score can also discriminate survival for patients from early to advanced stages of HCC. This newly proposed simple and accurate survival model provides enhanced prognostic accuracy for HCC. The MESH system is a useful supplement to the BCLC and HKLC classification schemes in refining treatment strategies. Copyright © 2016 Elsevier Ltd. All rights reserved.

The PEARL score predicts 90-day readmission or death after hospitalisation for acute exacerbation of COPD

PubMed Central

Echevarria, C; Steer, J; Heslop-Marshall, K; Stenton, S C; Hughes, R; Wijesinghe, M; Harrison, R N; Steen, N; Simpson, A J; Gibson, G J; Bourke, S C

2017-01-01

Background One in three patients hospitalised due to acute exacerbation of COPD (AECOPD) is readmitted within 90 days. No tool has been developed specifically in this population to predict readmission or death. Clinicians are unable to identify patients at particular risk, yet resources to prevent readmission are allocated based on clinical judgement. Methods In participating hospitals, consecutive admissions of patients with AECOPD were identified by screening wards and reviewing coding records. A tool to predict 90-day readmission or death without readmission was developed in two hospitals (the derivation cohort) and validated in: (a) the same hospitals at a later timeframe (internal validation cohort) and (b) four further UK hospitals (external validation cohort). Performance was compared with ADO, BODEX, CODEX, DOSE and LACE scores. Results Of 2417 patients, 936 were readmitted or died within 90 days of discharge. The five independent variables in the final model were: Previous admissions, eMRCD score, Age, Right-sided heart failure and Left-sided heart failure (PEARL). The PEARL score was consistently discriminative and accurate with a c-statistic of 0.73, 0.68 and 0.70 in the derivation, internal validation and external validation cohorts. Higher PEARL scores were associated with a shorter time to readmission. Conclusions The PEARL score is a simple tool that can effectively stratify patients' risk of 90-day readmission or death, which could help guide readmission avoidance strategies within the clinical and research setting. It is superior to other scores that have been used in this population. Trial registration number UKCRN ID 14214. PMID:28235886

Preinjury Psychological Status, Injury Severity and Postdeployment Posttraumatic Stress Disorder

DTIC Science & Technology

2011-05-01

Millennium Cohort Study Team. Smallpox vaccination : comparison of self-reported and electronic vaccine records in the Millennium Cohort Study. Hum Vaccin ...Smith B, Leard CA, Smith TC, Reed RJ, Ryan MAK; Millennium Cohort Study Team. Anthrax vaccination in the Millennium Cohort: validation and measures of...in Adults With Autism Spectrum Dis- orders” by Suzuki et al, published in the March 2011 is- sue of the Archives (2011;68(3):306-313), some figure

Emergency Heart Failure Mortality Risk Grade score performance for 7-day mortality prediction in patients with heart failure attended at the emergency department: validation in a Spanish cohort.

PubMed

Gil, Víctor; Miró, Òscar; Schull, Michael J; Llorens, Pere; Herrero-Puente, Pablo; Jacob, Javier; Ríos, José; Lee, Douglas S; Martín-Sánchez, Francisco J

2018-06-01

The Emergency Heart Failure Mortality Risk Grade (EHMRG) scale, derived in 86 Canadian emergency departments (EDs), stratifies patients with acute-decompensated heart failure (ADHF) according to their 7-day mortality risk. We evaluated its external validity in a Spanish cohort. We applied the EHMRG scale to ADHF patients consecutively included in the Epidemiology of Acute Heart Failure in Emergency departments (EAHFE) registry (29 Spanish EDs) and measured its performance. Patients were distributed into quintiles according to the original and their self-defined score cutoffs. The 7-day mortality rates were compared internally among different categories and with categories of Canadian cohorts. The EAHFE group [n: 1553 patients; 80 (10) years; 55.6% women] had a 5.5% 7-day mortality rate and the EHMRG scale c-statistic was 0.741 (95% confidence interval: 0.688-0.793) compared with 0.807 (0.761-0.842) and 0.804 (0.763-0.840) obtained in the Canadian derivation and validation cohorts. The mortality rate of the EAHFE group mortality increased progressively as the quintile categories increased using intervals defined by either the Canadian or the Spanish EHMRG score cutoffs, although with more regular increments with the EAHFE-defined intervals; using the latter, patients at quintiles 2, 3, 4, 5a and 5b had (compared with quintile 1) odds ratios of 1.77, 3.36, 4.44, 9.39 and 16.19, respectively. The EHMRG scale stratified risk in an ADHF cohort that included both palliative and nonpalliative patients in Spanish EDs, showing an extrapolation to a higher mortality risk cohort than the original derivation sample. Stratification improved when the score was recalibrated in the Spanish cohort.

Two risk score models for predicting incident Type 2 diabetes in Japan.

PubMed

Doi, Y; Ninomiya, T; Hata, J; Hirakawa, Y; Mukai, N; Iwase, M; Kiyohara, Y

2012-01-01

Risk scoring methods are effective for identifying persons at high risk of Type 2 diabetes mellitus, but such approaches have not yet been established in Japan. A total of 1935 subjects of a derivation cohort were followed up for 14 years from 1988 and 1147 subjects of a validation cohort independent of the derivation cohort were followed up for 5 years from 2002. Risk scores were estimated based on the coefficients (β) of Cox proportional hazards model in the derivation cohort and were verified in the validation cohort. In the derivation cohort, the non-invasive risk model was established using significant risk factors; namely, age, sex, family history of diabetes, abdominal circumference, body mass index, hypertension, regular exercise and current smoking. We also created another scoring risk model by adding fasting plasma glucose levels to the non-invasive model (plus-fasting plasma glucose model). The area under the curve of the non-invasive model was 0.700 and it increased significantly to 0.772 (P < 0.001) in the plus-fasting plasma glucose model. The ability of the non-invasive model to predict Type 2 diabetes was comparable with that of impaired glucose tolerance, and the plus-fasting plasma glucose model was superior to it. The cumulative incidence of Type 2 diabetes was significantly increased with elevating quintiles of the sum scores of both models in the validation cohort (P for trend < 0.001). We developed two practical risk score models for easily identifying individuals at high risk of incident Type 2 diabetes without an oral glucose tolerance test in the Japanese population. © 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.

A Two-Biomarker Model Predicts Mortality in the Critically Ill with Sepsis.

PubMed

Mikacenic, Carmen; Price, Brenda L; Harju-Baker, Susanna; O'Mahony, D Shane; Robinson-Cohen, Cassianne; Radella, Frank; Hahn, William O; Katz, Ronit; Christiani, David C; Himmelfarb, Jonathan; Liles, W Conrad; Wurfel, Mark M

2017-10-15

Improving the prospective identification of patients with systemic inflammatory response syndrome (SIRS) and sepsis at low risk for organ dysfunction and death is a major clinical challenge. To develop and validate a multibiomarker-based prediction model for 28-day mortality in critically ill patients with SIRS and sepsis. A derivation cohort (n = 888) and internal test cohort (n = 278) were taken from a prospective study of critically ill intensive care unit (ICU) patients meeting two of four SIRS criteria at an academic medical center for whom plasma was obtained within 24 hours. The validation cohort (n = 759) was taken from a prospective cohort enrolled at another academic medical center ICU for whom plasma was obtained within 48 hours. We measured concentrations of angiopoietin-1, angiopoietin-2, IL-6, IL-8, soluble tumor necrosis factor receptor-1, soluble vascular cell adhesion molecule-1, granulocyte colony-stimulating factor, and soluble Fas. We identified a two-biomarker model in the derivation cohort that predicted mortality (area under the receiver operator characteristic curve [AUC], 0.79; 95% confidence interval [CI], 0.74-0.83). It performed well in the internal test cohort (AUC, 0.75; 95% CI, 0.65-0.85) and the external validation cohort (AUC, 0.77; 95% CI, 0.72-0.83). We determined a model score threshold demonstrating high negative predictive value (0.95) for death. In addition to a low risk of death, patients below this threshold had shorter ICU length of stay, lower incidence of acute kidney injury, acute respiratory distress syndrome, and need for vasopressors. We have developed a simple, robust biomarker-based model that identifies patients with SIRS/sepsis at low risk for death and organ dysfunction.

Diagnosing gestational diabetes mellitus in the Danish National Birth Cohort.

PubMed

Olsen, Sjurdur F; Houshmand-Oeregaard, Azedeh; Granström, Charlotta; Langhoff-Roos, Jens; Damm, Peter; Bech, Bodil H; Vaag, Allan A; Zhang, Cuilin

2017-05-01

The Danish National Birth Cohort (DNBC) contains comprehensive information on diet, lifestyle, constitutional and other major characteristics of women during pregnancy. It provides a unique source for studies on health consequences of gestational diabetes mellitus. Our aim was to identify and validate the gestational diabetes mellitus cases in the cohort. We extracted clinical information from hospital records for 1609 pregnancies included in the Danish National Birth Cohort with a diagnosis of diabetes during or before pregnancy registered in the Danish National Patient Register and/or from a Danish National Birth Cohort interview during pregnancy. We further validated the diagnosis of gestational diabetes mellitus in 2126 randomly selected pregnancies from the entire Danish National Birth Cohort. From the individual hospital records, an expert panel evaluated gestational diabetes mellitus status based on results from oral glucose tolerance tests, fasting blood glucose and Hb1c values, as well as diagnoses made by local obstetricians. The audit categorized 783 pregnancies as gestational diabetes mellitus, corresponding to 0.89% of the 87 792 pregnancies for which a pregnancy interview for self-reported diabetes in pregnancy was available. From the randomly selected group the combined information from register and interviews could correctly identify 96% (95% CI 80-99.9%) of all cases in the entire Danish National Birth Cohort population. Positive predictive value, however, was only 59% (56-61%). The combined use of data from register and interview provided a high sensitivity for gestational diabetes mellitus diagnosis. The low positive predictive value, however, suggests that systematic validation by hospital record review is essential not to underestimate the health consequences of gestational diabetes mellitus in future studies. © 2016 Nordic Federation of Societies of Obstetrics and Gynecology.

Predicting Early Mortality After Hip Fracture Surgery: The Hip Fracture Estimator of Mortality Amsterdam.

PubMed

Karres, Julian; Kieviet, Noera; Eerenberg, Jan-Peter; Vrouenraets, Bart C

2018-01-01

Early mortality after hip fracture surgery is high and preoperative risk assessment for the individual patient is challenging. A risk model could identify patients in need of more intensive perioperative care, provide insight in the prognosis, and allow for risk adjustment in audits. This study aimed to develop and validate a risk prediction model for 30-day mortality after hip fracture surgery: the Hip fracture Estimator of Mortality Amsterdam (HEMA). Data on 1050 consecutive patients undergoing hip fracture surgery between 2004 and 2010 were retrospectively collected and randomly split into a development cohort (746 patients) and validation cohort (304 patients). Logistic regression analysis was performed in the development cohort to determine risk factors for the HEMA. Discrimination and calibration were assessed in both cohorts using the area under the receiver operating characteristic curve (AUC), the Hosmer-Lemeshow goodness-of-fit test, and by stratification into low-, medium- and high-risk groups. Nine predictors for 30-day mortality were identified and used in the final model: age ≥85 years, in-hospital fracture, signs of malnutrition, myocardial infarction, congestive heart failure, current pneumonia, renal failure, malignancy, and serum urea >9 mmol/L. The HEMA showed good discrimination in the development cohort (AUC = 0.81) and the validation cohort (AUC = 0.79). The Hosmer-Lemeshow test indicated no lack of fit in either cohort (P > 0.05). The HEMA is based on preoperative variables and can be used to predict the risk of 30-day mortality after hip fracture surgery for the individual patient. Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Replication of Rubella Vaccine Population Genetic Studies: Validation of HLA Genotype and Humoral Response Associations

PubMed Central

Ovsyannikova, Inna G.; Jacobson, Robert M.; Vierkant, Robert A.; O’Byrne, Megan M.; Poland, Gregory A.

2009-01-01

Purported genetic associations found in population studies require validation for confirmation. We previously reported rubella vaccine-induced immune responses and HLA associations in 346 adolescents, age 12–18 years (1st cohort), following two doses of a rubella-containing vaccine. We sought to replicate the associations discovered in that work by verifying these associations in a new cohort of 396 subjects, age 11–19 years (2nd cohort), all having had two doses of a rubella-containing vaccine. We found that B*2705 (median 1st cohort 20.9 IU/ml, p=0.028; 2nd cohort 20.5 IU/ml, p=0.001) and DPA1*0201 (median 1st cohort 32.5 IU/ml, p=0.048; 2nd cohort 25.8 IU/ml, p=0.025) alleles were consistently associated with lower rubella-induced antibodies. Further, DPB1*0401 (median 1st cohort 43.5 IU/ml, p=0.021; 2nd cohort 36.2 IU/ml, p=0.002) alleles were associated with higher antibody levels in both populations. The association of DRB1*04-DQB1*03-DPB1*03 (mean 1st cohort 25.2 IU/ml, p=0.011; 2nd cohort 21.4 IU/ml, p=0.032) and DRB1*15/16-DQB1*06-DPB1*03 (1st cohort 16.3 IU/ml, p=0.043; 2nd cohort 19.1 IU/ml, p=0.023) haplotypes with lower rubella-specific antibodies were observed in both studies. This study provides confirmatory evidence for an association between specific class I and II HLA markers and haplotypes with rubella vaccine-induced humoral responses and lends further weight to their influence on rubella immune responses. PMID:19761839

Dietary patterns and changes in body composition in children between 9 and 11 years

PubMed Central

Smith, Andrew D. A. C.; Emmett, Pauline M.; Newby, P. K.; Northstone, Kate

2014-01-01

Objective Childhood obesity is rising and dietary intake is a potentially modifiable factor that plays an important role in its development. We aim to investigate the association between dietary patterns, obtained through principal components analysis and gains in fat and lean mass in childhood. Design Diet diaries at 10 years of age collected from children taking part in the Avon Longitudinal Study of Parents and Children. Body composition was assessed using dual-energy X-ray absorptiometry at 9 and 11. Setting Longitudinal birth cohort. Subjects 3911 children with complete data. Results There was an association between the Health Aware (positive loadings on high-fiber bread, and fruits and vegetables; negative loadings on chips, crisps, processed meat, and soft drinks) pattern score and decreased fat mass gain in girls. After adjusting for confounders, an increase of 1 standard deviation (sd) in this score led to an estimated 1.2% decrease in fat mass gain in valid-reporters and 2.1% in under-reporters. A similar decrease was found only in under-reporting boys. There was also an association between the Packed Lunch (high consumption of white bread, sandwich fillings, and snacks) pattern score and decreased fat mass gain (1.1% per sd) in valid-reporting but not under-reporting girls. The main association with lean mass gain was an increase with Packed Lunch pattern score in valid-reporting boys only. Conclusions There is a small association between dietary patterns and change in fat mass in mid-childhood. Differences between under- and valid-reporters emphasize the need to consider valid-reporters separately in such studies. PMID:25018688

Development and validation of a pre-hospital "Red Flag" alert for activation of intra-hospital haemorrhage control response in blunt trauma.

PubMed

Hamada, Sophie Rym; Rosa, Anne; Gauss, Tobias; Desclefs, Jean-Philippe; Raux, Mathieu; Harrois, Anatole; Follin, Arnaud; Cook, Fabrice; Boutonnet, Mathieu; Attias, Arie; Ausset, Sylvain; Boutonnet, Mathieu; Dhonneur, Gilles; Duranteau, Jacques; Langeron, Olivier; Paugam-Burtz, Catherine; Pirracchio, Romain; de St Maurice, Guillaume; Vigué, Bernard; Rouquette, Alexandra; Duranteau, Jacques

2018-05-05

Haemorrhagic shock is the leading cause of early preventable death in severe trauma. Delayed treatment is a recognized prognostic factor that can be prevented by efficient organization of care. This study aimed to develop and validate Red Flag, a binary alert identifying blunt trauma patients with high risk of severe haemorrhage (SH), to be used by the pre-hospital trauma team in order to trigger an adequate intra-hospital standardized haemorrhage control response: massive transfusion protocol and/or immediate haemostatic procedures. A multicentre retrospective study of prospectively collected data from a trauma registry (Traumabase®) was performed. SH was defined as: packed red blood cell (RBC) transfusion in the trauma room, or transfusion ≥ 4 RBC in the first 6 h, or lactate ≥ 5 mmol/L, or immediate haemostatic surgery, or interventional radiology and/or death of haemorrhagic shock. Pre-hospital characteristics were selected using a multiple logistic regression model in a derivation cohort to develop a Red Flag binary alert whose performances were confirmed in a validation cohort. Among the 3675 patients of the derivation cohort, 672 (18%) had SH. The final prediction model included five pre-hospital variables: Shock Index ≥ 1, mean arterial blood pressure ≤ 70 mmHg, point of care haemoglobin ≤ 13 g/dl, unstable pelvis and pre-hospital intubation. The Red Flag alert was triggered by the presence of any combination of at least two criteria. Its predictive performances were sensitivity 75% (72-79%), specificity 79% (77-80%) and area under the receiver operating characteristic curve 0.83 (0.81-0.84) in the derivation cohort, and were not significantly different in the independent validation cohort of 2999 patients. The Red Flag alert developed and validated in this study has high performance to accurately predict or exclude SH.

An Interpretable Machine Learning Model for Accurate Prediction of Sepsis in the ICU.

PubMed

Nemati, Shamim; Holder, Andre; Razmi, Fereshteh; Stanley, Matthew D; Clifford, Gari D; Buchman, Timothy G

2018-04-01

Sepsis is among the leading causes of morbidity, mortality, and cost overruns in critically ill patients. Early intervention with antibiotics improves survival in septic patients. However, no clinically validated system exists for real-time prediction of sepsis onset. We aimed to develop and validate an Artificial Intelligence Sepsis Expert algorithm for early prediction of sepsis. Observational cohort study. Academic medical center from January 2013 to December 2015. Over 31,000 admissions to the ICUs at two Emory University hospitals (development cohort), in addition to over 52,000 ICU patients from the publicly available Medical Information Mart for Intensive Care-III ICU database (validation cohort). Patients who met the Third International Consensus Definitions for Sepsis (Sepsis-3) prior to or within 4 hours of their ICU admission were excluded, resulting in roughly 27,000 and 42,000 patients within our development and validation cohorts, respectively. None. High-resolution vital signs time series and electronic medical record data were extracted. A set of 65 features (variables) were calculated on hourly basis and passed to the Artificial Intelligence Sepsis Expert algorithm to predict onset of sepsis in the proceeding T hours (where T = 12, 8, 6, or 4). Artificial Intelligence Sepsis Expert was used to predict onset of sepsis in the proceeding T hours and to produce a list of the most significant contributing factors. For the 12-, 8-, 6-, and 4-hour ahead prediction of sepsis, Artificial Intelligence Sepsis Expert achieved area under the receiver operating characteristic in the range of 0.83-0.85. Performance of the Artificial Intelligence Sepsis Expert on the development and validation cohorts was indistinguishable. Using data available in the ICU in real-time, Artificial Intelligence Sepsis Expert can accurately predict the onset of sepsis in an ICU patient 4-12 hours prior to clinical recognition. A prospective study is necessary to determine the clinical utility of the proposed sepsis prediction model.

The PLAN score: a bedside prediction rule for death and severe disability following acute ischemic stroke.

PubMed

O'Donnell, Martin J; Fang, Jiming; D'Uva, Cami; Saposnik, Gustavo; Gould, Linda; McGrath, Emer; Kapral, Moira K

2012-11-12

We sought to develop and validate a simple clinical prediction rule for death and severe disability after acute ischemic stroke that can be used by general clinicians at the time of hospital admission. We analyzed data from a registry of 9847 patients (4943 in the derivation cohort and 4904 in the validation cohort) hospitalized with acute ischemic stroke and included in the Registry of the Canadian Stroke Network (July 1, 2003, to March 31, 2008; 11 regional stroke centers in Ontario, Canada). Outcome measures were 30-day and 1-year mortality and a modified Rankin score of 5 to 6 at discharge. Overall 30-day mortality was 11.5% (derivation cohort) and 13.5% (validation cohort). In the final multivariate model, we included 9 clinical variables that could be categorized as preadmission comorbidities (5 points for preadmission dependence [1.5], cancer [1.5], congestive heart failure [1.0], and atrial fibrillation [1.0]), level of consciousness (5 points for reduced level of consciousness), age (10 points, 1 point/decade), and neurologic focal deficit (5 points for significant/total weakness of the leg [2], weakness of the arm [2], and aphasia or neglect [1]). Maximum score is 25. In the validation cohort, the PLAN score (derived from preadmission comorbidities, level of consciousness, age, and neurologic deficit) predicted 30-day mortality (C statistic, 0.87), death or severe dependence at discharge (0.88), and 1-year mortality (0.84). The PLAN score also predicted favorable outcome (modified Rankin score, 0-2) at discharge (C statistic, 0.80). The PLAN clinical prediction rule identifies patients who will have a poor outcome after hospitalization for acute ischemic stroke. The score comprises clinical data available at the time of admission and may be determined by nonspecialist clinicians. Additional studies to independently validate the PLAN rule in different populations and settings are required.

Pharmacokinetic modeling of gentamicin in treatment of infective endocarditis: Model development and validation of existing models.

PubMed

Gomes, Anna; van der Wijk, Lars; Proost, Johannes H; Sinha, Bhanu; Touw, Daan J

2017-01-01

Gentamicin shows large variations in half-life and volume of distribution (Vd) within and between individuals. Thus, monitoring and accurately predicting serum levels are required to optimize effectiveness and minimize toxicity. Currently, two population pharmacokinetic models are applied for predicting gentamicin doses in adults. For endocarditis patients the optimal model is unknown. We aimed at: 1) creating an optimal model for endocarditis patients; and 2) assessing whether the endocarditis and existing models can accurately predict serum levels. We performed a retrospective observational two-cohort study: one cohort to parameterize the endocarditis model by iterative two-stage Bayesian analysis, and a second cohort to validate and compare all three models. The Akaike Information Criterion and the weighted sum of squares of the residuals divided by the degrees of freedom were used to select the endocarditis model. Median Prediction Error (MDPE) and Median Absolute Prediction Error (MDAPE) were used to test all models with the validation dataset. We built the endocarditis model based on data from the modeling cohort (65 patients) with a fixed 0.277 L/h/70kg metabolic clearance, 0.698 (±0.358) renal clearance as fraction of creatinine clearance, and Vd 0.312 (±0.076) L/kg corrected lean body mass. External validation with data from 14 validation cohort patients showed a similar predictive power of the endocarditis model (MDPE -1.77%, MDAPE 4.68%) as compared to the intensive-care (MDPE -1.33%, MDAPE 4.37%) and standard (MDPE -0.90%, MDAPE 4.82%) models. All models acceptably predicted pharmacokinetic parameters for gentamicin in endocarditis patients. However, these patients appear to have an increased Vd, similar to intensive care patients. Vd mainly determines the height of peak serum levels, which in turn correlate with bactericidal activity. In order to maintain simplicity, we advise to use the existing intensive-care model in clinical practice to avoid potential underdosing of gentamicin in endocarditis patients.

Pharmacokinetic modeling of gentamicin in treatment of infective endocarditis: Model development and validation of existing models

PubMed Central

van der Wijk, Lars; Proost, Johannes H.; Sinha, Bhanu; Touw, Daan J.

2017-01-01

Gentamicin shows large variations in half-life and volume of distribution (Vd) within and between individuals. Thus, monitoring and accurately predicting serum levels are required to optimize effectiveness and minimize toxicity. Currently, two population pharmacokinetic models are applied for predicting gentamicin doses in adults. For endocarditis patients the optimal model is unknown. We aimed at: 1) creating an optimal model for endocarditis patients; and 2) assessing whether the endocarditis and existing models can accurately predict serum levels. We performed a retrospective observational two-cohort study: one cohort to parameterize the endocarditis model by iterative two-stage Bayesian analysis, and a second cohort to validate and compare all three models. The Akaike Information Criterion and the weighted sum of squares of the residuals divided by the degrees of freedom were used to select the endocarditis model. Median Prediction Error (MDPE) and Median Absolute Prediction Error (MDAPE) were used to test all models with the validation dataset. We built the endocarditis model based on data from the modeling cohort (65 patients) with a fixed 0.277 L/h/70kg metabolic clearance, 0.698 (±0.358) renal clearance as fraction of creatinine clearance, and Vd 0.312 (±0.076) L/kg corrected lean body mass. External validation with data from 14 validation cohort patients showed a similar predictive power of the endocarditis model (MDPE -1.77%, MDAPE 4.68%) as compared to the intensive-care (MDPE -1.33%, MDAPE 4.37%) and standard (MDPE -0.90%, MDAPE 4.82%) models. All models acceptably predicted pharmacokinetic parameters for gentamicin in endocarditis patients. However, these patients appear to have an increased Vd, similar to intensive care patients. Vd mainly determines the height of peak serum levels, which in turn correlate with bactericidal activity. In order to maintain simplicity, we advise to use the existing intensive-care model in clinical practice to avoid potential underdosing of gentamicin in endocarditis patients. PMID:28475651

Ruling out coronary artery disease in primary care: development and validation of a simple prediction rule.

PubMed

Bösner, Stefan; Haasenritter, Jörg; Becker, Annette; Karatolios, Konstantinos; Vaucher, Paul; Gencer, Baris; Herzig, Lilli; Heinzel-Gutenbrunner, Monika; Schaefer, Juergen R; Abu Hani, Maren; Keller, Heidi; Sönnichsen, Andreas C; Baum, Erika; Donner-Banzhoff, Norbert

2010-09-07

Chest pain can be caused by various conditions, with life-threatening cardiac disease being of greatest concern. Prediction scores to rule out coronary artery disease have been developed for use in emergency settings. We developed and validated a simple prediction rule for use in primary care. We conducted a cross-sectional diagnostic study in 74 primary care practices in Germany. Primary care physicians recruited all consecutive patients who presented with chest pain (n = 1249) and recorded symptoms and findings for each patient (derivation cohort). An independent expert panel reviewed follow-up data obtained at six weeks and six months on symptoms, investigations, hospital admissions and medications to determine the presence or absence of coronary artery disease. Adjusted odds ratios of relevant variables were used to develop a prediction rule. We calculated measures of diagnostic accuracy for different cut-off values for the prediction scores using data derived from another prospective primary care study (validation cohort). The prediction rule contained five determinants (age/sex, known vascular disease, patient assumes pain is of cardiac origin, pain is worse during exercise, and pain is not reproducible by palpation), with the score ranging from 0 to 5 points. The area under the curve (receiver operating characteristic curve) was 0.87 (95% confidence interval [CI] 0.83-0.91) for the derivation cohort and 0.90 (95% CI 0.87-0.93) for the validation cohort. The best overall discrimination was with a cut-off value of 3 (positive result 3-5 points; negative result

External validation of prognostic models to predict risk of gestational diabetes mellitus in one Dutch cohort: prospective multicentre cohort study.

PubMed

Lamain-de Ruiter, Marije; Kwee, Anneke; Naaktgeboren, Christiana A; de Groot, Inge; Evers, Inge M; Groenendaal, Floris; Hering, Yolanda R; Huisjes, Anjoke J M; Kirpestein, Cornel; Monincx, Wilma M; Siljee, Jacqueline E; Van 't Zelfde, Annewil; van Oirschot, Charlotte M; Vankan-Buitelaar, Simone A; Vonk, Mariska A A W; Wiegers, Therese A; Zwart, Joost J; Franx, Arie; Moons, Karel G M; Koster, Maria P H

2016-08-30

 To perform an external validation and direct comparison of published prognostic models for early prediction of the risk of gestational diabetes mellitus, including predictors applicable in the first trimester of pregnancy.  External validation of all published prognostic models in large scale, prospective, multicentre cohort study.  31 independent midwifery practices and six hospitals in the Netherlands.  Women recruited in their first trimester (<14 weeks) of pregnancy between December 2012 and January 2014, at their initial prenatal visit. Women with pre-existing diabetes mellitus of any type were excluded.  Discrimination of the prognostic models was assessed by the C statistic, and calibration assessed by calibration plots.  3723 women were included for analysis, of whom 181 (4.9%) developed gestational diabetes mellitus in pregnancy. 12 prognostic models for the disorder could be validated in the cohort. C statistics ranged from 0.67 to 0.78. Calibration plots showed that eight of the 12 models were well calibrated. The four models with the highest C statistics included almost all of the following predictors: maternal age, maternal body mass index, history of gestational diabetes mellitus, ethnicity, and family history of diabetes. Prognostic models had a similar performance in a subgroup of nulliparous women only. Decision curve analysis showed that the use of these four models always had a positive net benefit.  In this external validation study, most of the published prognostic models for gestational diabetes mellitus show acceptable discrimination and calibration. The four models with the highest discriminative abilities in this study cohort, which also perform well in a subgroup of nulliparous women, are easy models to apply in clinical practice and therefore deserve further evaluation regarding their clinical impact. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Testing multiple statistical hypotheses resulted in spurious associations: a study of astrological signs and health.

PubMed

Austin, Peter C; Mamdani, Muhammad M; Juurlink, David N; Hux, Janet E

2006-09-01

To illustrate how multiple hypotheses testing can produce associations with no clinical plausibility. We conducted a study of all 10,674,945 residents of Ontario aged between 18 and 100 years in 2000. Residents were randomly assigned to equally sized derivation and validation cohorts and classified according to their astrological sign. Using the derivation cohort, we searched through 223 of the most common diagnoses for hospitalization until we identified two for which subjects born under one astrological sign had a significantly higher probability of hospitalization compared to subjects born under the remaining signs combined (P<0.05). We tested these 24 associations in the independent validation cohort. Residents born under Leo had a higher probability of gastrointestinal hemorrhage (P=0.0447), while Sagittarians had a higher probability of humerus fracture (P=0.0123) compared to all other signs combined. After adjusting the significance level to account for multiple comparisons, none of the identified associations remained significant in either the derivation or validation cohort. Our analyses illustrate how the testing of multiple, non-prespecified hypotheses increases the likelihood of detecting implausible associations. Our findings have important implications for the analysis and interpretation of clinical studies.

Interrogation of the platelet-derived growth factor receptor alpha locus and corneal astigmatism in Australians of Northern European ancestry: results of a genome-wide association study.

PubMed

Yazar, Seyhan; Mishra, Aniket; Ang, Wei; Kearns, Lisa S; Mountain, Jenny A; Pennell, Craig; Montgomery, Grant W; Young, Terri L; Hammond, Christopher J; Macgregor, Stuart; Mackey, David A; Hewitt, Alex W

2013-01-01

Corneal astigmatism is a common eye disorder characterized by irregularities in corneal curvature. Recently, the rs7677751 single nucleotide polymorphism (SNP) at the platelet-derived growth factor receptor alpha (PDGFRA) locus was found to be associated with corneal astigmatism in people of Asian ancestry. In the present study, we sought to replicate this finding and identify other genetic markers of corneal astigmatism in an Australian population of Northern European ancestry. Data from two cohorts were included in this study. The first cohort consisted of 1,013 individuals who were part of the Western Australian Pregnancy Cohort (Raine) Study: 20-year follow-up Eye Study. The second cohort comprised 1,788 individuals of 857 twin families who were recruited through the Twins Eye Study in Tasmania and the Brisbane Adolescent Twin Study. Corneal astigmatism was calculated as the absolute difference between the keratometry readings in two meridians, and genotype data were extracted from genome-wide arrays. Initially, each cohort was analyzed separately, before being combined for meta- and subsequent genome-wide pathway analysis. Following meta-analysis, SNP rs7677751 at the PDGFRA locus had a combined p=0.32. No variant was found to be statistically significantly associated with corneal astigmatism at the genome-wide level (p<5.0×10(-8)). The SNP with strongest association was rs1164064 (p=1.86×10(-6)) on chromosome 3q13. Gene-based pathway analysis identified a significant association between the Gene Ontology "segmentation" (GO:0035282) pathway, corrected p=0.009. Our data suggest that the PDGFRA locus does not transfer a major risk of corneal astigmatism in people of Northern European ancestry. Better-powered studies are required to validate the novel putative findings of our study.

Derivation and validation of a novel risk score for safe discharge after acute lower gastrointestinal bleeding: a modelling study.

PubMed

Oakland, Kathryn; Jairath, Vipul; Uberoi, Raman; Guy, Richard; Ayaru, Lakshmana; Mortensen, Neil; Murphy, Mike F; Collins, Gary S

2017-09-01

Acute lower gastrointestinal bleeding is a common reason for emergency hospital admission, and identification of patients at low risk of harm, who are therefore suitable for outpatient investigation, is a clinical and research priority. We aimed to develop and externally validate a simple risk score to identify patients with lower gastrointestinal bleeding who could safely avoid hospital admission. We undertook model development with data from the National Comparative Audit of Lower Gastrointestinal Bleeding from 143 hospitals in the UK in 2015. Multivariable logistic regression modelling was used to identify predictors of safe discharge, defined as the absence of rebleeding, blood transfusion, therapeutic intervention, 28 day readmission, or death. The model was converted into a simplified risk scoring system and was externally validated in 288 patients admitted with lower gastrointestinal bleeding (184 safely discharged) from two UK hospitals (Charing Cross Hospital, London, and Hammersmith Hospital, London) that had not contributed data to the development cohort. We calculated C statistics for the new model and did a comparative assessment with six previously developed risk scores. Of 2336 prospectively identified admissions in the development cohort, 1599 (68%) were safely discharged. Age, sex, previous admission for lower gastrointestinal bleeding, rectal examination findings, heart rate, systolic blood pressure, and haemoglobin concentration strongly discriminated safe discharge in the development cohort (C statistic 0·84, 95% CI 0·82-0·86) and in the validation cohort (0·79, 0·73-0·84). Calibration plots showed the new risk score to have good calibration in the validation cohort. The score was better than the Rockall, Blatchford, Strate, BLEED, AIMS65, and NOBLADS scores in predicting safe discharge. A score of 8 or less predicts a 95% probability of safe discharge. We developed and validated a novel clinical prediction model with good discriminative performance to identify patients with lower gastrointestinal bleeding who are suitable for safe outpatient management, which has important economic and resource implications. Bowel Disease Research Foundation and National Health Service Blood and Transplant. Copyright © 2017 Elsevier Ltd. All rights reserved.

Residual standard deviation: Validation of a new measure of dual-task cost in below-knee prosthesis users.

PubMed

Howard, Charla L; Wallace, Chris; Abbas, James; Stokic, Dobrivoje S

2017-01-01

We developed and evaluated properties of a new measure of variability in stride length and cadence, termed residual standard deviation (RSD). To calculate RSD, stride length and cadence are regressed against velocity to derive the best fit line from which the variability (SD) of the distance between the actual and predicted data points is calculated. We examined construct, concurrent, and discriminative validity of RSD using dual-task paradigm in 14 below-knee prosthesis users and 13 age- and education-matched controls. Subjects walked first over an electronic walkway while performing separately a serial subtraction and backwards spelling task, and then at self-selected slow, normal, and fast speeds used to derive the best fit line for stride length and cadence against velocity. Construct validity was demonstrated by significantly greater increase in RSD during dual-task gait in prosthesis users than controls (group-by-condition interaction, stride length p=0.0006, cadence p=0.009). Concurrent validity was established against coefficient of variation (CV) by moderate-to-high correlations (r=0.50-0.87) between dual-task cost RSD and dual-task cost CV for both stride length and cadence in prosthesis users and controls. Discriminative validity was documented by the ability of dual-task cost calculated from RSD to effectively differentiate prosthesis users from controls (area under the receiver operating characteristic curve, stride length 0.863, p=0.001, cadence 0.808, p=0.007), which was better than the ability of dual-task cost CV (0.692, 0.648, respectively, not significant). These results validate RSD as a new measure of variability in below-knee prosthesis users. Future studies should include larger cohorts and other populations to ascertain its generalizability. Copyright © 2016 Elsevier B.V. All rights reserved.

Is self-reporting workplace activity worthwhile? Validity and reliability of occupational sitting and physical activity questionnaire in desk-based workers.

PubMed

Pedersen, Scott J; Kitic, Cecilia M; Bird, Marie-Louise; Mainsbridge, Casey P; Cooley, P Dean

2016-08-19

With the advent of workplace health and wellbeing programs designed to address prolonged occupational sitting, tools to measure behaviour change within this environment should derive from empirical evidence. In this study we measured aspects of validity and reliability for the Occupational Sitting and Physical Activity Questionnaire that asks employees to recount the percentage of work time they spend in the seated, standing, and walking postures during a typical workday. Three separate cohort samples (N = 236) were drawn from a population of government desk-based employees across several departmental agencies. These volunteers were part of a larger state-wide intervention study. Workplace sitting and physical activity behaviour was measured both subjectively against the International Physical Activity Questionnaire, and objectively against ActivPal accelerometers before the intervention began. Criterion validity and concurrent validity for each of the three posture categories were assessed using Spearman's rank correlation coefficients, and a bias comparison with 95 % limits of agreement. Test-retest reliability of the survey was reported with intraclass correlation coefficients. Criterion validity for this survey was strong for sitting and standing estimates, but weak for walking. Participants significantly overestimated the amount of walking they did at work. Concurrent validity was moderate for sitting and standing, but low for walking. Test-retest reliability of this survey proved to be questionable for our sample. Based on our findings we must caution occupational health and safety professionals about the use of employee self-report data to estimate workplace physical activity. While the survey produced accurate measurements for time spent sitting at work it was more difficult for employees to estimate their workplace physical activity.

Creation of a pediatric mature B-cell non-Hodgkin lymphoma cohort within the Pediatric Health Information System Database.

PubMed

Citrin, Rebecca; Horowitz, Joseph P; Reilly, Anne F; Li, Yimei; Huang, Yuan-Shung; Getz, Kelly D; Seif, Alix E; Fisher, Brian T; Aplenc, Richard

2017-01-01

Mature B-cell non-Hodgkin lymphoma (B-NHL) constitutes a collection of relatively rare pediatric malignancies. In order to utilize administrative data to perform large-scale epidemiologic studies within this population, a two-step process was used to assemble a 12-year cohort of B-NHL patients treated between 2004 and 2015 within the Pediatric Health Information System database. Patients were identified by ICD-9 codes, and their chemotherapy data were then manually reviewed against standard B-NHL treatment regimens. A total of 1,409 patients were eligible for cohort inclusion. This process was validated at a single center, utilizing both an institutional tumor registry and medical record review as the gold standards. The validation demonstrated appropriate sensitivity (91.5%) and positive predictive value (95.1%) to allow for the future use of this cohort for epidemiologic and comparative effectiveness research.

Validation of Computerized Automatic Calculation of the Sequential Organ Failure Assessment Score

PubMed Central

Harrison, Andrew M.; Pickering, Brian W.; Herasevich, Vitaly

2013-01-01

Purpose. To validate the use of a computer program for the automatic calculation of the sequential organ failure assessment (SOFA) score, as compared to the gold standard of manual chart review. Materials and Methods. Adult admissions (age > 18 years) to the medical ICU with a length of stay greater than 24 hours were studied in the setting of an academic tertiary referral center. A retrospective cross-sectional analysis was performed using a derivation cohort to compare automatic calculation of the SOFA score to the gold standard of manual chart review. After critical appraisal of sources of disagreement, another analysis was performed using an independent validation cohort. Then, a prospective observational analysis was performed using an implementation of this computer program in AWARE Dashboard, which is an existing real-time patient EMR system for use in the ICU. Results. Good agreement between the manual and automatic SOFA calculations was observed for both the derivation (N=94) and validation (N=268) cohorts: 0.02 ± 2.33 and 0.29 ± 1.75 points, respectively. These results were validated in AWARE (N=60). Conclusion. This EMR-based automatic tool accurately calculates SOFA scores and can facilitate ICU decisions without the need for manual data collection. This tool can also be employed in a real-time electronic environment. PMID:23936639

Refining Low Physical Activity Measurement Improves Frailty Assessment in Advanced Lung Disease and Survivors of Critical Illness.

PubMed

Baldwin, Matthew R; Singer, Jonathan P; Huang, Debbie; Sell, Jessica; Gonzalez, Wendy C; Pollack, Lauren R; Maurer, Mathew S; D'Ovidio, Frank F; Bacchetta, Matthew; Sonett, Joshua R; Arcasoy, Selim M; Shah, Lori; Robbins, Hilary; Hays, Steven R; Kukreja, Jasleen; Greenland, John R; Shah, Rupal J; Leard, Lorriana; Morrell, Matthew; Gries, Cynthia; Katz, Patricia P; Christie, Jason D; Diamond, Joshua M; Lederer, David J

2017-08-01

The frail phenotype has gained popularity as a clinically relevant measure in adults with advanced lung disease and in critical illness survivors. Because respiratory disease and chronic illness can greatly limit physical activity, the measurement of participation in traditional leisure time activities as a frailty component may lead to substantial misclassification of frailty in pulmonary and critical care patients. To test and validate substituting the Duke Activity Status Index (DASI), a simple 12-item questionnaire, for the Minnesota Leisure Time Physical Activity (MLTA) questionnaire, a detailed questionnaire covering 18 leisure time activities, as the measure of low activity in the Fried frailty phenotype (FFP) instrument. In separate multicenter prospective cohort studies of adults with advanced lung disease who were candidates for lung transplant and older survivors of acute respiratory failure, we assessed the FFP using either the MLTA or the DASI. For both the DASI and MLTA, we evaluated content validity by testing floor effects and construct validity through comparisons with conceptually related factors. We tested the predictive validity of substituting the DASI for the MLTA in the FFP assessment using Cox models to estimate associations between the FFP and delisting/death before transplant in those with advanced lung disease and 6-month mortality in older intensive care unit (ICU) survivors. Among 618 adults with advanced lung disease and 130 older ICU survivors, the MLTA had a substantially greater floor effect than the DASI (42% vs. 1%, and 49% vs. 12%, respectively). The DASI correlated more strongly with strength and function measures than did the MLTA in both cohorts. In models adjusting for age, sex, comorbidities, and illness severity, substitution of the DASI for the MLTA led to stronger associations of the FFP with delisting/death in lung transplant candidates (FFP-MLTA hazard ratio [HR], 1.42; 95% confidence interval [CI], 0.55-3.65; FFP-DASI HR, 2.99; 95% CI, 1.03-8.65) and with mortality in older ICU survivors (FFP-MLTA HR, 2.68; 95% CI, 0.62-11.6; FFP-DASI HR, 5.71; 95% CI, 1.34-24.3). The DASI improves the construct and predictive validity of frailty assessment in adults with advanced lung disease or recent critical illness. This simple questionnaire should replace the more complex MLTA in assessing the frailty phenotype in these populations.

SPINK1 Overexpression in Localized Prostate Cancer: a Rare Event Inversely Associated with ERG Expression and Exclusive of Homozygous PTEN Deletion.

PubMed

Huang, Kuo-Cheng; Evans, Andrew; Donnelly, Bryan; Bismar, Tarek A

2017-04-01

SPINK1 is proposed as potential prognostic marker in prostate cancer (PCA). However, its relation to PTEN and ERG in localized PCA remains unclear. The study population consisted of two independent cohorts of men treated by radical prostatectomy for localized PCA (discovery n = 218 and validation n = 129). Patterns of association between SPINK1 and each of ERG and PTEN were evaluated by immunohistochemistry and fluorescence in situ hybridization. Associations between SPINK1 expression and various pathologic parameters and clinical outcome were also investigated. SPINK1 was expressed in 15.3 % and 10.9 % of cases in the discovery and validation cohort, respectively. SPINK expression was observed in 5.56 % of high-grade prostatic intraepithelial neoplasia and 1.1 % of adjacent morphologically benign prostatic glands. SPINK1 and ERG expression were almost exclusive, with only 1.0 % of the cases co-expressing both in the same core sample. SPINK1 interfocal and within-core heterogeneity was noted in 29.2 % and 64.6 % of cases, respectively. SPINK1 expression was not significantly associated with PTEN deletion in the two cohorts (p = 0.871 for discovery cohort and p = 0.293 for validation cohort). While SPINK1 expression did occur with hemizygous PTEN deletion, there was a complete absence of SPINK1 expression in PCA showing homozygous PTEN deletion, which was confirmed in the validation cohort (p = 0.02). Despite SPINK1's association with higher Gleason score (>7) (p = 0.02), it was not associated with other pathological parameters or biochemical recurrence post-radical prostatectomy. We documented absolute exclusivity between SPINK1 overexpression and homozygous PTEN deletion in localized PCA. SPINK1 and ERG expressions are exclusive events in PCA. SPINK1 is not of added prognostic value in localized PCA.

The Basilar Artery on Computed Tomography Angiography Prognostic Score for Basilar Artery Occlusion.

PubMed

Alemseged, Fana; Shah, Darshan G; Diomedi, Marina; Sallustio, Fabrizio; Bivard, Andrew; Sharma, Gagan; Mitchell, Peter J; Dowling, Richard J; Bush, Steven; Yan, Bernard; Caltagirone, Carlo; Floris, Roberto; Parsons, Mark W; Levi, Christopher R; Davis, Stephen M; Campbell, Bruce C V

2017-03-01

Basilar artery occlusion is associated with high risk of disability and mortality. This study aimed to assess the prognostic value of a new radiological score: the Basilar Artery on Computed Tomography Angiography (BATMAN) score. A retrospective analysis of consecutive stroke patients with basilar artery occlusion diagnosed on computed tomographic angiography was performed. BATMAN score is a 10-point computed tomographic angiography-based grading system which incorporates thrombus burden and the presence of collaterals. Reliability was assessed with intraclass coefficient correlation. Good outcome was defined as modified Rankin Scale score of ≤3 at 3 months and successful reperfusion as thrombolysis in cerebral infarction 2b-3. BATMAN score was externally validated and compared with the Posterior Circulation Collateral score. The derivation cohort included 83 patients with 41 in the validation cohort. In receiver operating characteristic (ROC) analysis, BATMAN score had an area under receiver operating characteristic curve of 0.81 (95% confidence interval [CI], 0.7-0.9) in derivation cohort and an area under receiver operating characteristic curve of 0.74 (95% CI, 0.6-0.9) in validation cohort. In logistic regression adjusted for age and clinical severity, BATMAN score of <7 was associated with poor outcome in derivation cohort (odds ratio, 5.5; 95% CI, 1.4-21; P =0.01), in validation cohort (odds ratio, 6.9; 95% CI, 1.4-33; P =0.01), and in endovascular patients, after adjustment for recanalization and time to treatment (odds ratio, 4.8; 95% CI, 1.2-18; P =0.01). BATMAN score of <7 was not associated with recanalization. Interrater agreement was substantial (intraclass coefficient correlation, 0.85; 95% CI, 0.8-0.9). BATMAN score had greater accuracy compared with Posterior Circulation Collateral score ( P =0.04). The addition of collateral quality to clot burden in BATMAN score seems to improve prognostic accuracy in basilar artery occlusion patients. © 2017 American Heart Association, Inc.

Validation of administrative data used for the diagnosis of upper gastrointestinal events following nonsteroidal anti-inflammatory drug prescription.

PubMed

Abraham, N S; Cohen, D C; Rivers, B; Richardson, P

2006-07-15

To validate veterans affairs (VA) administrative data for the diagnosis of nonsteroidal anti-inflammatory drug (NSAID)-related upper gastrointestinal events (UGIE) and to develop a diagnostic algorithm. A retrospective study of veterans prescribed an NSAID as identified from the national pharmacy database merged with in-patient and out-patient data, followed by primary chart abstraction. Contingency tables were constructed to allow comparison with a random sample of patients prescribed an NSAID, but without UGIE. Multivariable logistic regression analysis was used to derive a predictive algorithm. Once derived, the algorithm was validated in a separate cohort of veterans. Of 906 patients, 606 had a diagnostic code for UGIE; 300 were a random subsample of 11 744 patients (control). Only 161 had a confirmed UGIE. The positive predictive value (PPV) of diagnostic codes was poor, but improved from 27% to 51% with the addition of endoscopic procedural codes. The strongest predictors of UGIE were an in-patient ICD-9 code for gastric ulcer, duodenal ulcer and haemorrhage combined with upper endoscopy. This algorithm had a PPV of 73% when limited to patients >or=65 years (c-statistic 0.79). Validation of the algorithm revealed a PPV of 80% among patients with an overlapping NSAID prescription. NSAID-related UGIE can be assessed using VA administrative data. The optimal algorithm includes an in-patient ICD-9 code for gastric or duodenal ulcer and gastrointestinal bleeding combined with a procedural code for upper endoscopy.

CT colonography after incomplete optical colonoscopy

PubMed Central

Theis, Jake; Kim, David H.; Lubner, Meghan G.; del Rio, Alejandro Muñoz; Pickhardt, Perry J.

2017-01-01

Purpose To objectively compare the volume, density, and distribution of luminal fluid for same-day oral-contrast-enhanced CTC following incomplete optical colonoscopy (OC) versus deferred CTC on a separate day utilizing a dedicated CTC bowel preparation. Methods HIPAA-compliant, IRB-approved retrospective study compared 103 same-day CTC studies after incomplete OC (utilizing 30 ml oral diatrizoate) against 151 CTC examinations performed on a separate day after failed OC using a dedicated CTC bowel preparation (oral magnesium citrate/dilute barium/diatrizoate the evening before). A subgroup of 15 patients who had both same-day CTC and separate-day routine CTC was also identified and underwent separate analysis. CTC exams were analyzed for opacified fluid distribution within the GI tract, as well as density and volume. Data was analyzed utilizing Kruskal-Wallis and Wilcoxon Signed Rank tests. Results Opacified luminal fluid extended to the rectum in 56% (58/103) of same-day CTC versus 100% (151/151) of deferred separate-day CTC (p<0.0001). For same-day CTC, contrast failed to reach the colon in 11% (11/103) and failed to reach the left colon in 26% (27/103). Volumetric colonic fluid segmentation for fluid analysis (successful in 80 same-day and 147 separate-day cases) showed significantly more fluid in the same-day cohort (mean, 227 ml vs. 166 ml; p<0.0001); the actual difference is underestimated due to excluded cases. Mean colonic fluid attenuation was significantly lower in the same-day cohort (545 HU vs. 735 HU; p<0.0001). Similar findings were identified in the smaller cohort with direct intra-patient CTC comparison. Conclusions Dedicated CTC bowel preparation on a separate day following incomplete OC results in a much higher quality examination compared with same-day CTC. PMID:26830606

Development of a Middle-Age and Geriatric Trauma Mortality Risk Score A Tool to Guide Palliative Care Consultations.

PubMed

Konda, Sanjit R; Seymour, Rachel; Manoli, Arthur; Gales, Jordan; Karunakar, Madhav A

2016-11-01

This study aimed to develop a tool to quantify risk of inpatient mortality among geriatric and middleaged trauma patients. This study sought to demonstrate the ability of the novel risk score in the early identification of high risk trauma patients for resource-sparing interventions, including referral to palliative medicine. This retrospective cohort study utilized data from a single level 1 trauma center. Regression analysis was used to create a novel risk of inpatient mortality score. A total of 2,387 low energy and 1,201 high-energy middle-aged (range: 55 to 64 years of age) and geriatric (65 years of age or odler) trauma patients comprised the study cohort. Model validation was performed using 37,474 lowenergy and 97,034 high-energy patients from the National Trauma Databank (NTDB). Potential hospital cost reduction was calculated for early referral of high risk trauma patients to palliative medicine services in comparison to no palliative medicine referral. Factors predictive of inpatient mortality among the study and validation patient cohorts included; age, Glasgow Coma Scale, and Abbreviated Injury Scale for the head and neck and chest. Within the validation cohort, the novel mortality risk score demonstrated greater predictive capacity than existing trauma scores [STTGMALE-AUROC: 0.83 vs. TRISS 0.80, (p < 0.01), STTGMAHE-AUROC: 0.86 vs. TRISS 0.85, (p < 0.01)]. Our model demonstrated early palliative medicine evaluation could produce $1,083,082 in net hospital savings per year. This novel risk score for older trauma patients has shown fidelity in prediction of inpatient mortality; in the study and validation cohorts. This tool may be used for early intervention in the care of patients at high risk of mortality and resource expenditure.

Decision Support Tool for Early Differential Diagnosis of Acute Lung Injury and Cardiogenic Pulmonary Edema in Medical Critically Ill Patients

PubMed Central

Shahjehan, Khurram; Li, Guangxi; Dhokarh, Rajanigandha; Kashyap, Rahul; Janish, Christopher; Alsara, Anas; Jaffe, Allan S.; Hubmayr, Rolf D.; Gajic, Ognjen

2012-01-01

Background: At the onset of acute hypoxic respiratory failure, critically ill patients with acute lung injury (ALI) may be difficult to distinguish from those with cardiogenic pulmonary edema (CPE). No single clinical parameter provides satisfying prediction. We hypothesized that a combination of those will facilitate early differential diagnosis. Methods: In a population-based retrospective development cohort, validated electronic surveillance identified critically ill adult patients with acute pulmonary edema. Recursive partitioning and logistic regression were used to develop a decision support tool based on routine clinical information to differentiate ALI from CPE. Performance of the score was validated in an independent cohort of referral patients. Blinded post hoc expert review served as gold standard. Results: Of 332 patients in a development cohort, expert reviewers (κ, 0.86) classified 156 as having ALI and 176 as having CPE. The validation cohort had 161 patients (ALI = 113, CPE = 48). The score was based on risk factors for ALI and CPE, age, alcohol abuse, chemotherapy, and peripheral oxygen saturation/Fio2 ratio. It demonstrated good discrimination (area under curve [AUC] = 0.81; 95% CI, 0.77-0.86) and calibration (Hosmer-Lemeshow [HL] P = .16). Similar performance was obtained in the validation cohort (AUC = 0.80; 95% CI, 0.72-0.88; HL P = .13). Conclusions: A simple decision support tool accurately classifies acute pulmonary edema, reserving advanced testing for a subset of patients in whom satisfying prediction cannot be made. This novel tool may facilitate early inclusion of patients with ALI and CPE into research studies as well as improve and rationalize clinical management and resource use. PMID:22030803

Posttreatment Variables Improve Outcome Prediction after Intra-Arterial Therapy for Acute Ischemic Stroke

PubMed Central

Prabhakaran, Shyam; Jovin, Tudor G.; Tayal, Ashis H.; Hussain, Muhammad S.; Nguyen, Thanh N.; Sheth, Kevin N.; Terry, John B.; Nogueira, Raul G.; Horev, Anat; Gandhi, Dheeraj; Wisco, Dolora; Glenn, Brenda A.; Ludwig, Bryan; Clemmons, Paul F.; Cronin, Carolyn A.; Tian, Melissa; Liebeskind, David; Zaidat, Osama O.; Castonguay, Alicia C.; Martin, Coleman; Mueller-Kronast, Nils; English, Joey D.; Linfante, Italo; Malisch, Timothy W.; Gupta, Rishi

2014-01-01

Background There are multiple clinical and radiographic factors that influence outcomes after endovascular reperfusion therapy (ERT) in acute ischemic stroke (AIS). We sought to derive and validate an outcome prediction score for AIS patients undergoing ERT based on readily available pretreatment and posttreatment factors. Methods The derivation cohort included 511 patients with anterior circulation AIS treated with ERT at 10 centers between September 2009 and July 2011. The prospective validation cohort included 223 patients with anterior circulation AIS treated in the North American Solitaire Acute Stroke registry. Multivariable logistic regression identified predictors of good outcome (modified Rankin score ≤2 at 3 months) in the derivation cohort; model β coefficients were used to assign points and calculate a risk score. Discrimination was tested using C statistics with 95% confidence intervals (CIs) in the derivation and validation cohorts. Calibration was assessed using the Hosmer-Lemeshow test and plots of observed to expected outcomes. We assessed the net reclassification improvement for the derived score compared to the Totaled Health Risks in Vascular Events (THRIVE) score. Subgroup analysis in patients with pretreatment Alberta Stroke Program Early CT Score (ASPECTS) and posttreatment final infarct volume measurements was also performed to identify whether these radiographic predictors improved the model compared to simpler models. Results Good outcome was noted in 186 (36.4%) and 100 patients (44.8%) in the derivation and validation cohorts, respectively. Combining readily available pretreatment and posttreatment variables, we created a score (acronym: SNARL) based on the following parameters: symptomatic hemorrhage [2 points: none, hemorrhagic infarction (HI)1–2 or parenchymal hematoma (PH) type 1; 0 points: PH2], baseline National Institutes of Health Stroke Scale score (3 points: 0–10; 1 point: 11–20; 0 points: >20), age (2 points: <60 years; 1 point: 60–79 years; 0 points: >79 years), reperfusion (3 points: Thrombolysis In Cerebral Ischemia score 2b or 3) and location of clot (1 point: M2; 0 points: M1 or internal carotid artery). The SNARL score demonstrated good discrimination in the derivation (C statistic 0.79, 95% CI 0.75–0.83) and validation cohorts (C statistic 0.74, 95% CI 0.68–0.81) and was superior to the THRIVE score (derivation cohort: C statistic 0.65, 95% CI 0.60–0.70; validation cohort: C-statistic 0.59, 95% CI 0.52–0.67; p < 0.01 in both cohorts) but was inferior to a score that included age, ASPECTS, reperfusion status and final infarct volume (C statistic 0.86, 95% CI 0.82–0.91; p = 0.04). Compared with the THRIVE score, the SNARL score resulted in a net reclassification improvement of 34.8%. Conclusions Among AIS patients treated with ERT, pretreatment scores such as the THRIVE score provide only fair prognostic information. Inclusion of posttreatment variables such as reperfusion and symptomatic hemorrhage greatly influences outcome and results in improved outcome prediction. PMID:24942008

Validity of the estimates of oral cholera vaccine effectiveness derived from the test-negative design.

PubMed

Ali, Mohammad; You, Young Ae; Sur, Dipika; Kanungo, Suman; Kim, Deok Ryun; Deen, Jacqueline; Lopez, Anna Lena; Wierzba, Thomas F; Bhattacharya, Sujit K; Clemens, John D

2016-01-20

The test-negative design (TND) has emerged as a simple method for evaluating vaccine effectiveness (VE). Its utility for evaluating oral cholera vaccine (OCV) effectiveness is unknown. We examined this method's validity in assessing OCV effectiveness by comparing the results of TND analyses with those of conventional cohort analyses. Randomized controlled trials of OCV were conducted in Matlab (Bangladesh) and Kolkata (India), and an observational cohort design was used in Zanzibar (Tanzania). For all three studies, VE using the TND was estimated from the odds ratio (OR) relating vaccination status to fecal test status (Vibrio cholerae O1 positive or negative) among diarrheal patients enrolled during surveillance (VE= (1-OR)×100%). In cohort analyses of these studies, we employed the Cox proportional hazard model for estimating VE (=1-hazard ratio)×100%). OCV effectiveness estimates obtained using the TND (Matlab: 51%, 95% CI:37-62%; Kolkata: 67%, 95% CI:57-75%) were similar to the cohort analyses of these RCTs (Matlab: 52%, 95% CI:43-60% and Kolkata: 66%, 95% CI:55-74%). The TND VE estimate for the Zanzibar data was 94% (95% CI:84-98%) compared with 82% (95% CI:58-93%) in the cohort analysis. After adjusting for residual confounding in the cohort analysis of the Zanzibar study, using a bias indicator condition, we observed almost no difference in the two estimates. Our findings suggest that the TND is a valid approach for evaluating OCV effectiveness in routine vaccination programs. Copyright © 2015 Elsevier Ltd. All rights reserved.

Predictive Mortality Index for Community-Dwelling Elderly Koreans

PubMed Central

Kim, Nan H.; Cho, Hyun J.; Kim, Soriul; Seo, Ji H.; Lee, Hyun J.; Yu, Ji H.; Chung, Hye S.; Yoo, Hye J.; Seo, Ji A.; Kim, Sin Gon; Baik, Sei Hyun; Choi, Dong Seop; Shin, Chol; Choi, Kyung Mook

2016-01-01

Abstract There are very few predictive indexes for long-term mortality among community-dwelling elderly Asian individuals, despite its importance, given the rapid and continuous increase in this population. We aimed to develop 10-year predictive mortality indexes for community-dwelling elderly Korean men and women based on routinely collected clinical data. We used data from 2244 elderly individuals (older than 60 years of age) from the southwest Seoul Study, a prospective cohort study, for the development of a prognostic index. An independent longitudinal cohort of 679 elderly participants was selected from the Korean Genome Epidemiology Study in Ansan City for validation. During a 10-year follow-up, 393 participants (17.5%) from the development cohort died. Nine risk factors were identified and weighed in the Cox proportional regression model to create a point scoring system: age, male sex, smoking, diabetes, systolic blood pressure, triglyceride, total cholesterol, white blood cell count, and hemoglobin. In the development cohort, the 10-year mortality risk was 6.6%, 14.8%, 18.2%, and 38.4% among subjects with 1 to 4, 5 to 7, 8 to 9, and ≥10 points, respectively. In the validation cohort, the 10-year mortality risk was 5.2%, 12.0%, 16.0%, and 16.0% according to these categories. The C-statistic for the point system was 0.73 and 0.67 in the development and validation cohorts, respectively. The present study provides valuable information for prognosis among elderly Koreans and may guide individualized approaches for appropriate care in a rapidly aging society. PMID:26844511

The Self-Sufficiency Project at 36 Months: Effects on Children of a Program That Increased Parental Employment and Income.

ERIC Educational Resources Information Center

Morris, Pamela; Michalopoulos, Charles

This report examines effects of the Self-Sufficiency Project (SSP) for three age groups of children (younger cohort aged 3-5, middle cohort aged 6-11, and older cohort aged 12-18) at the 36-month interview. A companion report on effects of the SSP on adults is available separately. Chapter 1 describes the SSP incentive, project design, and SSP…

The impact of breast cancer-specific birth cohort effects among younger and older Chinese populations.

PubMed

Sung, Hyuna; Rosenberg, Philip S; Chen, Wan-Qing; Hartman, Mikael; Lim, Wei-Yen; Chia, Kee Seng; Wai-Kong Mang, Oscar; Tse, Lapah; Anderson, William F; Yang, Xiaohong R

2016-08-01

Historically low breast cancer incidence rates among Asian women have risen worldwide; purportedly due to the adoption of a "Western" life style among younger generations (i.e., the more recent birth cohorts). However, no study has simultaneously compared birth cohort effects between both younger and older women in different Asian and Western populations. Using cancer registry data from rural and urban China, Singapore and the United States (1990-2008), we estimated age-standardized incidence rates (ASR), annual percentage change (EAPC) in the ASR, net drifts, birth cohort specific incidence rates and cohort rate ratios (CRR). Younger (30-49 years, 1943-1977 birth cohorts) and older women (50-79 years; 1913-1957 birth cohorts) were assessed separately. CRRs among Chinese populations were estimated using birth cohort specific rates with US non-Hispanic white women (NHW) serving as the reference population with an assigned CRR of 1.0. We observed higher EAPCs and net drifts among those Chinese populations with lower ASRs. Similarly, we observed the most rapidly increasing cohort-specific incidence rates among those Chinese populations with the lowest baseline CRRs. Both trends were more significant among older than younger women. Average CRRs were 0.06-0.44 among older and 0.18-0.81 among younger women. Rapidly rising cohort specific rates have narrowed the historic disparity between Chinese and US NHW breast cancer populations particularly in regions with the lowest baseline rates and among older women. Future analytic studies are needed to investigate risk factors accounting for the rapid increase of breast cancer among older and younger women separately in Asian populations. © 2016 UICC.

Intergrated Systems Biology Approach for Ovarian Cancer Biomarker Discovery — EDRN Public Portal

Cancer.gov

The overall objective is to validate serum protein markers for early diagnosis of ovarian cancer with the ultimate goal being to develop a multiparametric panel consisting of 2-4 novel markers with 10 known markers for phase 3 analysis. In phase 1, we will screen for markers able to pass a threshold of 98% specificity and 30% sensitivity in a cohort of 300 women. Markers that pass phase 1 validation will be investigated in a phase 2 PRoBE cohort with a 98% specificity and 70% sensitivity cut-off. Finally, markers that pass phase 2 validation will be evaluated in EDRN CVC laboratory specimens with a cut-off of > 98% specificity and 90% sensitivity.

Risks for Early Substance Involvement Associated with Parental Alcoholism and Parental Separation in an Adolescent Female Cohort*

PubMed Central

Waldron, Mary; Vaughan, Ellen L.; Bucholz, Kathleen K.; Lynskey, Michael T.; Sartor, Carolyn E.; Duncan, Alexis E.; Madden, Pamela A.F.; Heath, Andrew C.

2014-01-01

Background We examined timing of substance involvement as a joint function of parental history of alcoholism and parental separation during childhood. Method Data were drawn from a large cohort of female like-sex twins [n = 613 African Ancestry (AA), n = 3550 European or other Ancestry (EA)]. Cox proportional hazards regression was conducted predicting age at first use of alcohol, first alcohol intoxication, first use and regular use of cigarettes, and first use of cannabis and other illicit drugs from dummy variables coding for parental alcoholism and parental separation. Propensity score analysis was also conducted comparing intact and separated families by predicted probability of parental separation. Results In EA families, increased risk of substance involvement was found in both alcoholic and separated families, particularly through ages 10 or 14 years, with risk to offspring from alcoholic separated families further increased. In AA families, associations with parental alcoholism and parental separation were weak and with few exceptions statistically nonsignificant. While propensity score findings confirmed unique risks observed in EA families, intact and separated AA families were poorly matched on risk-factors presumed to predate parental separation, especially parental alcoholism, requiring cautious interpretation of AA survival-analytic findings. Conclusion For offspring of European ancestry, parental separation predicts early substance involvement that is not explained by parental alcoholism nor associated family background characteristics. Additional research is needed to better characterize risks associated with parental separation in African American families. PMID:24647368

Risks for early substance involvement associated with parental alcoholism and parental separation in an adolescent female cohort.

PubMed

Waldron, Mary; Vaughan, Ellen L; Bucholz, Kathleen K; Lynskey, Michael T; Sartor, Carolyn E; Duncan, Alexis E; Madden, Pamela A F; Heath, Andrew C

2014-05-01

We examined timing of substance involvement as a joint function of parental history of alcoholism and parental separation during childhood. Data were drawn from a large cohort of female like-sex twins [n=613 African Ancestry (AA), n=3550 European or other ancestry (EA)]. Cox proportional hazards regression was conducted predicting age at first use of alcohol, first alcohol intoxication, first use and regular use of cigarettes, and first use of cannabis and other illicit drugs from dummy variables coding for parental alcoholism and parental separation. Propensity score analysis was also conducted comparing intact and separated families by predicted probability of parental separation. In EA families, increased risk of substance involvement was found in both alcoholic and separated families, particularly through ages 10 or 14 years, with risk to offspring from alcoholic separated families further increased. In AA families, associations with parental alcoholism and parental separation were weak and with few exceptions statistically nonsignificant. While propensity score findings confirmed unique risks observed in EA families, intact and separated AA families were poorly matched on risk-factors presumed to predate parental separation, especially parental alcoholism, requiring cautious interpretation of AA survival-analytic findings. For offspring of European ancestry, parental separation predicts early substance involvement that is not explained by parental alcoholism nor associated family background characteristics. Additional research is needed to better characterize risks associated with parental separation in African American families. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Shared and Distinct Rupture Discriminants of Small and Large Intracranial Aneurysms.

PubMed

Varble, Nicole; Tutino, Vincent M; Yu, Jihnhee; Sonig, Ashish; Siddiqui, Adnan H; Davies, Jason M; Meng, Hui

2018-04-01

Many ruptured intracranial aneurysms (IAs) are small. Clinical presentations suggest that small and large IAs could have different phenotypes. It is unknown if small and large IAs have different characteristics that discriminate rupture. We analyzed morphological, hemodynamic, and clinical parameters of 413 retrospectively collected IAs (training cohort; 102 ruptured IAs). Hierarchal cluster analysis was performed to determine a size cutoff to dichotomize the IA population into small and large IAs. We applied multivariate logistic regression to build rupture discrimination models for small IAs, large IAs, and an aggregation of all IAs. We validated the ability of these 3 models to predict rupture status in a second, independently collected cohort of 129 IAs (testing cohort; 14 ruptured IAs). Hierarchal cluster analysis in the training cohort confirmed that small and large IAs are best separated at 5 mm based on morphological and hemodynamic features (area under the curve=0.81). For small IAs (<5 mm), the resulting rupture discrimination model included undulation index, oscillatory shear index, previous subarachnoid hemorrhage, and absence of multiple IAs (area under the curve=0.84; 95% confidence interval, 0.78-0.88), whereas for large IAs (≥5 mm), the model included undulation index, low wall shear stress, previous subarachnoid hemorrhage, and IA location (area under the curve=0.87; 95% confidence interval, 0.82-0.93). The model for the aggregated training cohort retained all the parameters in the size-dichotomized models. Results in the testing cohort showed that the size-dichotomized rupture discrimination model had higher sensitivity (64% versus 29%) and accuracy (77% versus 74%), marginally higher area under the curve (0.75; 95% confidence interval, 0.61-0.88 versus 0.67; 95% confidence interval, 0.52-0.82), and similar specificity (78% versus 80%) compared with the aggregate-based model. Small (<5 mm) and large (≥5 mm) IAs have different hemodynamic and clinical, but not morphological, rupture discriminants. Size-dichotomized rupture discrimination models performed better than the aggregate model. © 2018 American Heart Association, Inc.

Development and validation of optimal cut-off value in inter-arm systolic blood pressure difference for prediction of cardiovascular events.

PubMed

Hirono, Akira; Kusunose, Kenya; Kageyama, Norihito; Sumitomo, Masayuki; Abe, Masahiro; Fujinaga, Hiroyuki; Sata, Masataka

2018-01-01

An inter-arm systolic blood pressure difference (IAD) is associated with cardiovascular disease. The aim of this study was to develop and validate the optimal cut-off value of IAD as a predictor of major adverse cardiac events in patients with arteriosclerosis risk factors. From 2009 to 2014, 1076 patients who had at least one cardiovascular risk factor were included in the analysis. We defined 700 randomly selected patients as a development cohort to confirm that IAD was the predictor of cardiovascular events and to determine optimal cut-off value of IAD. Next, we validated outcomes in the remaining 376 patients as a validation cohort. The blood pressure (BP) of both arms measurements were done simultaneously using the ankle-brachial blood pressure index (ABI) form of automatic device. The primary endpoint was the cardiovascular event and secondary endpoint was the all-cause mortality. During a median period of 2.8 years, 143 patients reached the primary endpoint in the development cohort. In the multivariate Cox proportional hazards analysis, IAD was the strong predictor of cardiovascular events (hazard ratio: 1.03, 95% confidence interval: 1.01-1.05, p=0.005). The receiver operating characteristic curve revealed that 5mmHg was the optimal cut-off point of IAD to predict cardiovascular events (p<0.001). In the validation cohort, the presence of a large IAD (IAD ≥5mmHg) was significantly associated with the primary endpoint (p=0.021). IAD is significantly associated with future cardiovascular events in patients with arteriosclerosis risk factors. The optimal cut-off value of IAD is 5mmHg. Copyright © 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Sensitivity and specificity of a screening test to document traumatic experiences and to diagnose post-traumatic stress disorder in ARDS patients after intensive care treatment.

PubMed

Stoll, C; Kapfhammer, H P; Rothenhäusler, H B; Haller, M; Briegel, J; Schmidt, M; Krauseneck, T; Durst, K; Schelling, G

1999-07-01

Many survivors of critical illness and intensive care unit (ICU) treatment have traumatic memories such as nightmares, panic or pain which can be associated with the development of posttraumatic stress disorder (PTSD). In order to simplify the rapid and early detection of PTSD in such patients, we modified an existing questionnaire for diagnosis of PTSD and validated the instrument in a cohort of ARDS patients after long-term ICU therapy. Follow-up cohort study. The 20-bed ICU of a university teaching hospital. A cohort of 52 long-term survivors of the acute respiratory distress syndrome (ARDS). The questionnaire was administered to the study cohort at two time points 2 years apart. At the second evaluation, the patients underwent a structured interview with two trained psychiatrists to diagnose PTSD according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria. The reliability and validity of the questionnaire was then estimated and its specificity, sensitivity and optimal decision threshold determined using receiver operating characteristic (ROC) curve analyses. The questionnaire showed a high internal consistency (Crohnbach's alpha = 0.93) and a high test-retest reliability (intraclass correlation coefficient alpha = 0.89). There was evidence of construct validity by a linear relationship between scores and the number of traumatic memories from the ICU the patients described (Spearman's rho = 0.48, p < 0.01). Criterion validity was demonstrated by ROC curve analyses resulting in a sensitivity of 77.0% and a specificity of 97.5% for the diagnosis of PTSD. The questionnaire was found to be a responsive, valid and reliable instrument to screen survivors of intensive care for PTSD.

External validation and clinical utility of a prediction model for 6-month mortality in patients undergoing hemodialysis for end-stage kidney disease.

PubMed

Forzley, Brian; Er, Lee; Chiu, Helen Hl; Djurdjev, Ognjenka; Martinusen, Dan; Carson, Rachel C; Hargrove, Gaylene; Levin, Adeera; Karim, Mohamud

2018-02-01

End-stage kidney disease is associated with poor prognosis. Health care professionals must be prepared to address end-of-life issues and identify those at high risk for dying. A 6-month mortality prediction model for patients on dialysis derived in the United States is used but has not been externally validated. We aimed to assess the external validity and clinical utility in an independent cohort in Canada. We examined the performance of the published 6-month mortality prediction model, using discrimination, calibration, and decision curve analyses. Data were derived from a cohort of 374 prevalent dialysis patients in two regions of British Columbia, Canada, which included serum albumin, age, peripheral vascular disease, dementia, and answers to the "the surprise question" ("Would I be surprised if this patient died within the next year?"). The observed mortality in the validation cohort was 11.5% at 6 months. The prediction model had reasonable discrimination (c-stat = 0.70) but poor calibration (calibration-in-the-large = -0.53 (95% confidence interval: -0.88, -0.18); calibration slope = 0.57 (95% confidence interval: 0.31, 0.83)) in our data. Decision curve analysis showed the model only has added value in guiding clinical decision in a small range of threshold probabilities: 8%-20%. Despite reasonable discrimination, the prediction model has poor calibration in this external study cohort; thus, it may have limited clinical utility in settings outside of where it was derived. Decision curve analysis clarifies limitations in clinical utility not apparent by receiver operating characteristic curve analysis. This study highlights the importance of external validation of prediction models prior to routine use in clinical practice.

The QT Scale: A Weight Scale Measuring the QTc Interval.

PubMed

Couderc, Jean-Philippe; Beshaw, Connor; Niu, Xiaodan; Serrano-Finetti, Ernesto; Casas, Oscar; Pallas-Areny, Ramon; Rosero, Spencer; Zareba, Wojciech

2017-01-01

Despite the strong evidence of the clinical utility of QTc prolongation as a surrogate marker of cardiac risk, QTc measurement is not part of clinical routine either in hospital or in physician offices. We evaluated a novel device ("the QT scale") to measure heart rate (HR) and QTc interval. The QT scale is a weight scale embedding an ECG acquisition system with four limb sensors (feet and hands: lead I, II, and III). We evaluated the reliability of QT scale in healthy subjects (cohort 1) and cardiac patients (cohorts 2 and 3) considering a learning (cohort 2) and two validation cohorts. The QT scale and the standard 12-lead recorder were compared using intraclass correlation coefficient (ICC) in cohorts 2 and 3. Absolute value of heart rate and QTc intervals between manual and automatic measurements using ECGs from the QT scale and a clinical device were compared in cohort 1. We enrolled 16 subjects in cohort 1 (8 w, 8 m; 32 ± 8 vs 34 ± 10 years, P = 0.7), 51 patients in cohort 2 (13 w, 38 m; 61 ± 16 vs 58 ± 18 years, P = 0.6), and 13 AF patients in cohort 3 (4 w, 9 m; 63 ± 10 vs 64 ± 10 years, P = 0.9). Similar automatic heart rate and QTc were delivered by the scale and the clinical device in cohort 1: paired difference in RR and QTc were -7 ± 34 milliseconds (P = 0.37) and 3.4 ± 28.6 milliseconds (P = 0.64), respectively. The measurement of stability was slightly lower in ECG from the QT scale than from the clinical device (ICC: 91% vs 80%) in cohort 3. The "QT scale device" delivers valid heart rate and QTc interval measurements. © 2016 Wiley Periodicals, Inc.

Pair housing of Vervets/African Green Monkeys for biomedical research.

PubMed

Jorgensen, Matthew J; Lambert, Kelsey R; Breaux, Sarah D; Baker, Kate C; Snively, Beverly M; Weed, James L

2017-01-01

Vervets, also known as African green monkeys, are a nonhuman primate species widely used in biomedical research. However, there are currently few references available describing techniques and rates of success for pair-housing this species. We present data from four cohorts of vervets from three different facilities: (i) the Wake Forest Vervet Research Colony (VRC; n = 72 female pairs, n= 52 male pairs), (ii) the University of Louisiana at Lafayette-New Iberia Research Center (UL-NIRC; n = 57 female pairs, n = 54 male pairs), (iii) the Tulane National Primate Research Center (TNRPC; n = 18 male pairs), and (iv) a cohort of imported males (n = 18 pairs) at Wake Forest. Compatibility was measured at 14, 30, and 60 days following introduction. Success rates for pair-housing at 14 days ranged from 96% to 98% for females and 96% to 100% for males at the VRC and UL-NIRC but were lower in the smaller imported male cohorts (TNPRC: 50%; WF: 28%). Among the UL-NIRC cohort and VRC male cohort, most of the pair separations after 14 days were due to reasons unrelated to social incompatibility. In contrast, a large proportion of TNPRC and imported male pairs successful at 14 days required separation within 60 days due to incompatibility. Multiple logistic regressions were performed using cohort, mean age of pair and weight difference between pair-mates as potential predictors of compatibility at 14 days. All three predicted the 14-day outcome in males but not females. A separate analysis in the VRC cohort found no evidence that prior familiarity in a group setting influenced outcomes. Variations in success rates across cohorts may have been influenced by introduction methodology. Behavioral differences between vervets and macaques, coupled with our findings, lead us to theorize that the gradual introduction techniques commonly implemented to pair house macaques may not be beneficial or suitable for this species. Am. J. Primatol. 79:e22501, 2017. © 2015 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Decreased expression of RNA interference machinery, Dicer and Drosha, is associated with poor outcome in ovarian cancer patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Merritt, William M.; Lin, Yvonne G.; Han, Liz Y.

2008-05-06

The clinical and functional significance of RNA interference (RNAi) machinery, Dicer and Drosha, in ovarian cancer is not known and was examined. Dicer and Drosha expression was measured in ovarian cancer cell lines (n=8) and invasive epithelial ovarian cancer specimens (n=111) and correlated with clinical outcome. Validation was performed with previously published cohorts of ovarian, breast, and lung cancer patients. Anti-Galectin-3 siRNA and shRNA transfections were used for in vitro functional studies. Dicer and Drosha mRNA and protein levels were decreased in 37% to 63% of ovarian cancer cell lines and in 60% and 51% of human ovarian cancer specimens,more » respectively. Low Dicer was significantly associated with advanced tumor stage (p=0.007), and low Drosha with suboptimal surgical cytoreduction (p=0.02). Tumors with both high Dicer and Drosha were associated with increased median patient survival (>11 years vs. 2.66 years for other groups; p<0.001). In multivariate analysis, high Dicer (HR=0.48; p=0.02), high-grade histology (HR=2.46; p=0.03), and poor chemoresponse (HR=3.95; p<0.001) were identified as independent predictors of disease-specific survival. Findings of poor clinical outcome with low Dicer expression were validated in separate cohorts of cancer patients. Galectin-3 silencing with siRNA transfection was superior to shRNA in cell lines with low Dicer (78-95% vs. 4-8% compared to non-targeting sequences), and similar in cell lines with high Dicer. Our findings demonstrate the clinical and functional impact of RNAi machinery alterations in ovarian carcinoma and support the use of siRNA constructs that do not require endogenous Dicer and Drosha for therapeutic applications.« less

Rapid differentiation of methicillin-resistant and methicillin-susceptible Staphylococcus aureus by flow cytometry after brief antibiotic exposure.

PubMed

Shrestha, Nabin K; Scalera, Nikole M; Wilson, Deborah A; Procop, Gary W

2011-06-01

We noticed that methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) isolates yielded side-scatter (SSC) and fluorescence intensity (FI) differences on flow cytometry (FCM) following incubation in oxacillin broth. The purpose of this study was to determine whether MRSA and MSSA could be reliably differentiated by FCM. S. aureus isolates were incubated in oxacillin-containing Mueller-Hinton broth, stained using the FASTEST total viable organisms kit, and analyzed by FCM in the MicroPRO instrument. SSC versus FI were examined, and gates 1 and 2 were defined to encompass the majority of MSSA and MRSA signal events, respectively. A count ratio (CR) was defined as the ratio of counts in gate 2 to those in gate 1. Initially, 33 isolates were tested after 4 h of incubation for proof-of-concept. Twenty others were then tested after incubation intervals ranging from 30 min to 4 h to determine the earliest possible time for differentiation. Next, 100 separate isolates were tested to determine the best CR cutoff value. Finally, the CR was validated by using an independent cohort of 121 isolates. We noted that MRSA isolates had higher SSC and FI readings than did MSSA isolates after 2 h of incubation. The receiver-operator characteristics curve showed that a CR cutoff of 0.0445 reliably differentiated MRSA from MSSA. In the validation cohort, this cutoff had a sensitivity of 100% and a specificity of 98.7% for identifying MRSA from among S. aureus isolates, following 2 h of incubation. This study demonstrates that MRSA and MSSA can be accurately differentiated by FCM after 2 h of incubation in an oxacillin-containing liquid culture medium.

Rapid Differentiation of Methicillin-Resistant and Methicillin-Susceptible Staphylococcus aureus by Flow Cytometry after Brief Antibiotic Exposure▿

PubMed Central

Shrestha, Nabin K.; Scalera, Nikole M.; Wilson, Deborah A.; Procop, Gary W.

2011-01-01

We noticed that methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) isolates yielded side-scatter (SSC) and fluorescence intensity (FI) differences on flow cytometry (FCM) following incubation in oxacillin broth. The purpose of this study was to determine whether MRSA and MSSA could be reliably differentiated by FCM. S. aureus isolates were incubated in oxacillin-containing Mueller-Hinton broth, stained using the FASTEST total viable organisms kit, and analyzed by FCM in the MicroPRO instrument. SSC versus FI were examined, and gates 1 and 2 were defined to encompass the majority of MSSA and MRSA signal events, respectively. A count ratio (CR) was defined as the ratio of counts in gate 2 to those in gate 1. Initially, 33 isolates were tested after 4 h of incubation for proof-of-concept. Twenty others were then tested after incubation intervals ranging from 30 min to 4 h to determine the earliest possible time for differentiation. Next, 100 separate isolates were tested to determine the best CR cutoff value. Finally, the CR was validated by using an independent cohort of 121 isolates. We noted that MRSA isolates had higher SSC and FI readings than did MSSA isolates after 2 h of incubation. The receiver-operator characteristics curve showed that a CR cutoff of 0.0445 reliably differentiated MRSA from MSSA. In the validation cohort, this cutoff had a sensitivity of 100% and a specificity of 98.7% for identifying MRSA from among S. aureus isolates, following 2 h of incubation. This study demonstrates that MRSA and MSSA can be accurately differentiated by FCM after 2 h of incubation in an oxacillin-containing liquid culture medium. PMID:21471343

Predictive Validity of Sepsis-3 Definitions and Sepsis Outcomes in Critically Ill Patients: A Cohort Study in 49 ICUs in Argentina.

PubMed

Estenssoro, Elisa; Kanoore Edul, Vanina S; Loudet, Cecilia I; Osatnik, Javier; Ríos, Fernando G; Vázquez, Daniela N; Pozo, Mario O; Lattanzio, Bernardo; Pálizas, Fernando; Klein, Francisco; Piezny, Damián; Rubatto Birri, Paolo N; Tuhay, Graciela; Díaz, Anatilde; Santamaría, Analía; Zakalik, Graciela; Dubin, Arnaldo

2018-05-08

The new Sepsis-3 definitions have been scarcely assessed in low- and middle-income countries; besides, regional information of sepsis outcomes is sparse. Our objective was to evaluate Sepsis-3 definition performance in Argentina. Cohort study of 3-month duration beginning on July 1, 2016. Forty-nine ICUs. Consecutive patients admitted to the ICU with suspected infection that triggered blood cultures and antibiotic administration. None. Patients were classified as having infection, sepsis (infection + change in Sequential Organ Failure Assessment ≥ 2 points), and septic shock (vasopressors + lactate > 2 mmol/L). Patients on vasopressors and lactate less than or equal to 2 mmol/L (cardiovascular dysfunction) were analyzed separately, as those on vasopressors without serum lactate measurement. Systemic inflammatory response syndrome was also recorded. Main outcome was hospital mortality. Of 809 patients, 6% had infection, 29% sepsis, 20% cardiovascular dysfunction, 40% septic shock, and 3% received vasopressors with lactate unmeasured. Hospital mortality was 13%, 20%, 39%, 51%, and 41%, respectively (p = 0.000). Independent predictors of outcome were lactate, Sequential Organ Failure Assessment score, comorbidities, prior duration of symptoms (hr), mechanical ventilation requirement, and infection by highly resistant microorganisms. Area under the receiver operating characteristic curves for mortality for systemic inflammatory response syndrome and Sequential Organ Failure Assessment were 0.53 (0.48-0.55) and 0.74 (0.69-0.77), respectively (p = 0.000). Increasing severity of Sepsis-3 categories adequately tracks mortality; cardiovascular dysfunction subgroup, not included in Sepsis-3, has distinct characteristics. Sequential Organ Failure Assessment score shows adequate prognosis accuracy-contrary to systemic inflammatory response syndrome. This study supports the predictive validity of Sepsis-3 definitions.

Optimal SVM parameter selection for non-separable and unbalanced datasets.

PubMed

Jiang, Peng; Missoum, Samy; Chen, Zhao

2014-10-01

This article presents a study of three validation metrics used for the selection of optimal parameters of a support vector machine (SVM) classifier in the case of non-separable and unbalanced datasets. This situation is often encountered when the data is obtained experimentally or clinically. The three metrics selected in this work are the area under the ROC curve (AUC), accuracy, and balanced accuracy. These validation metrics are tested using computational data only, which enables the creation of fully separable sets of data. This way, non-separable datasets, representative of a real-world problem, can be created by projection onto a lower dimensional sub-space. The knowledge of the separable dataset, unknown in real-world problems, provides a reference to compare the three validation metrics using a quantity referred to as the "weighted likelihood". As an application example, the study investigates a classification model for hip fracture prediction. The data is obtained from a parameterized finite element model of a femur. The performance of the various validation metrics is studied for several levels of separability, ratios of unbalance, and training set sizes.

A longitudinal evaluation of the Center for Epidemiologic Studies-Depression scale (CES-D) in a Rheumatoid Arthritis Population using Rasch Analysis

PubMed Central

Covic, Tanya; Pallant, Julie F; Conaghan, Philip G; Tennant, Alan

2007-01-01

Background The aim of this study was to test the internal validity of the total Center for Epidemiologic Studies-Depression (CES-D) scale using Rasch analysis in a rheumatoid arthritis (RA) population. Methods CES-D was administered to 157 patients with RA over three time points within a 12 month period. Rasch analysis was applied using RUMM2020 software to assess the overall fit of the model, the response scale used, individual item fit, differential item functioning (DIF) and person separation. Results Pooled data across three time points was shown to fit the Rasch model with removal of seven items from the original 20-item CES-D scale. It was necessary to rescore the response format from four to three categories in order to improve the scale's fit. Two items demonstrated some DIF for age and gender but were retained within the 13-item CES-D scale. A new cut point for depression score of 9 was found to correspond to the original cut point score of 16 in the full CES-D scale. Conclusion This Rasch analysis of the CES-D in a longstanding RA cohort resulted in the construction of a modified 13-item scale with good internal validity. Further validation of the modified scale is recommended particularly in relation to the new cut point for depression. PMID:17629902

A comparison of the performances of an artificial neural network and a regression model for GFR estimation.

PubMed

Liu, Xun; Li, Ning-shan; Lv, Lin-sheng; Huang, Jian-hua; Tang, Hua; Chen, Jin-xia; Ma, Hui-juan; Wu, Xiao-ming; Lou, Tan-qi

2013-12-01

Accurate estimation of glomerular filtration rate (GFR) is important in clinical practice. Current models derived from regression are limited by the imprecision of GFR estimates. We hypothesized that an artificial neural network (ANN) might improve the precision of GFR estimates. A study of diagnostic test accuracy. 1,230 patients with chronic kidney disease were enrolled, including the development cohort (n=581), internal validation cohort (n=278), and external validation cohort (n=371). Estimated GFR (eGFR) using a new ANN model and a new regression model using age, sex, and standardized serum creatinine level derived in the development and internal validation cohort, and the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) 2009 creatinine equation. Measured GFR (mGFR). GFR was measured using a diethylenetriaminepentaacetic acid renal dynamic imaging method. Serum creatinine was measured with an enzymatic method traceable to isotope-dilution mass spectrometry. In the external validation cohort, mean mGFR was 49±27 (SD) mL/min/1.73 m2 and biases (median difference between mGFR and eGFR) for the CKD-EPI, new regression, and new ANN models were 0.4, 1.5, and -0.5 mL/min/1.73 m2, respectively (P<0.001 and P=0.02 compared to CKD-EPI and P<0.001 comparing the new regression and ANN models). Precisions (IQRs for the difference) were 22.6, 14.9, and 15.6 mL/min/1.73 m2, respectively (P<0.001 for both compared to CKD-EPI and P<0.001 comparing the new ANN and new regression models). Accuracies (proportions of eGFRs not deviating >30% from mGFR) were 50.9%, 77.4%, and 78.7%, respectively (P<0.001 for both compared to CKD-EPI and P=0.5 comparing the new ANN and new regression models). Different methods for measuring GFR were a source of systematic bias in comparisons of new models to CKD-EPI, and both the derivation and validation cohorts consisted of a group of patients who were referred to the same institution. An ANN model using 3 variables did not perform better than a new regression model. Whether ANN can improve GFR estimation using more variables requires further investigation. Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Determination of hydroxylated polychlorinated biphenyls (OH-PCBs) in human urine in a highly occupationally exposed German cohort: New prospects for urinary biomarkers of PCB exposure.

PubMed

Quinete, Natalia; Esser, André; Kraus, Thomas; Schettgen, Thomas

2016-12-01

The present study evaluates for the first time the determination of 20 hydroxylated polychlorinated biphenyl (OH-PCB) congeners and their glucuronide and sulfate conjugates in urine as a biomarker of exposure to PCBs in humans. Thereby, a fast, sensitive and selective online solid phase extraction (SPE) method coupled to LC-MS/MS was validated for the determination of OH-PCBs in human urine, being previously successfully developed and applied for the separation and quantitation of OH-PCBs in human plasma. The lowest limit of quantification (LLOQ) ranged from 0.01 to 0.19ngmL -1 and average extraction recoveries from 79 to 125% for all hydroxylated congeners. Within-run precision and between-run precision were between 2 and 17%. Extraction recovery tests were also performed in urine with different creatinine contents (0.52-3.92gL -1 ) for an estimation of matrix influences and ranged between 69 and 125%. In order to evaluate the applicability of the method, the study was conducted in three different groups, which were distinctly separated as non-exposed to known sources of PCBs (N=21), low-to-moderate PCB-exposed individuals (N=25) and highly occupationally PCB-exposed individuals (N=25), which included workers of a transformer recycling plant, their relatives and workers of surrounding companies from a German cohort. As part of the biomonitoring program HELPcB (Health Effects in High-Level Exposure to polychlorinated biphenyls), urine and blood samples were collected annually from 2010 to 2014. In this way, OH-PCB elimination profile in urine over time, correlations between OH-PCB levels in human plasma and urine, and associations with their parent compounds in plasma of the studied PCB cohort could be also assessed. Tri-chlorinated OH-PCBs were the predominant congeners in urine with concentrations up to 174ngmL -1 . High chlorinated OH-PCBs (penta- through hepta-chlorinated OH-PCBs) were also frequently detected in urine samples from non-exposed and occupationally exposed individuals, although levels were in general very low or lower than LLOQ. Copyright © 2016 Elsevier Ltd. All rights reserved.

Reproducibility and validity of a semi-quantitative FFQ for trace elements.

PubMed

Lee, Yujin; Park, Kyong

2016-09-01

The aim of this study was to test the reproducibility and validity of a self-administered FFQ for the Trace Element Study of Korean Adults in the Yeungnam area (SELEN). Study subjects were recruited from the SELEN cohort selected from rural and urban areas in Yeungnam, Korea. A semi-quantitative FFQ with 146 items was developed considering the dietary characteristics of cohorts in the study area. In a validation study, seventeen men and forty-eight women aged 38-62 years completed 3-d dietary records (DR) and two FFQ over a 3-month period. The validity was examined with the FFQ and DR, and the reproducibility was estimated using partial correlation coefficients, the Bland-Altman method and cross-classification. There were no significant differences between the mean intakes of selected nutrients as estimated from FFQ1, FFQ2 and DR. The median correlation coefficients for all nutrients were 0·47 and 0·56 in the reproducibility and validity tests, respectively. Bland-Altman's index and cross-classification showed acceptable agreement between FFQ1 and FFQ2 and between FFQ2 and DR. Ultimately, 78 % of the subjects were classified into the same and adjacent quartiles for most nutrients. In addition, the weighted κ value indicated that the two methods agreed fairly. In conclusion, this newly developed FFQ was a suitable dietary assessment method for the SELEN cohort study.

Validation of periodontitis screening model using sociodemographic, systemic, and molecular information in a Korean population.

PubMed

Kim, Hyun-Duck; Sukhbaatar, Munkhzaya; Shin, Myungseop; Ahn, Yoo-Been; Yoo, Wook-Sung

2014-12-01

This study aims to evaluate and validate a periodontitis screening model that includes sociodemographic, metabolic syndrome (MetS), and molecular information, including gingival crevicular fluid (GCF), matrix metalloproteinase (MMP), and blood cytokines. The authors selected 506 participants from the Shiwha-Banwol cohort: 322 participants from the 2005 cohort for deriving the screening model and 184 participants from the 2007 cohort for its validation. Periodontitis was assessed by dentists using the community periodontal index. Interleukin (IL)-6, IL-8, and tumor necrosis factor-α in blood and MMP-8, -9, and -13 in GCF were assayed using enzyme-linked immunosorbent assay. MetS was assessed by physicians using physical examination and blood laboratory data. Information about age, sex, income, smoking, and drinking was obtained by interview. Logistic regression analysis was applied to finalize the best-fitting model and validate the model using sensitivity, specificity, and c-statistics. The derived model for periodontitis screening had a sensitivity of 0.73, specificity of 0.85, and c-statistic of 0.86 (P <0.001); those of the validated model were 0.64, 0.91, and 0.83 (P <0.001), respectively. The model that included age, sex, income, smoking, drinking, and blood and GCF biomarkers could be useful in screening for periodontitis. A future prospective study is indicated for evaluating this model's ability to predict the occurrence of periodontitis.

A nomogram to predict the survival of stage IIIA-N2 non-small cell lung cancer after surgery.

PubMed

Mao, Qixing; Xia, Wenjie; Dong, Gaochao; Chen, Shuqi; Wang, Anpeng; Jin, Guangfu; Jiang, Feng; Xu, Lin

2018-04-01

Postoperative survival of patients with stage IIIA-N2 non-small cell lung cancer (NSCLC) is highly heterogeneous. Here, we aimed to identify variables associated with postoperative survival and develop a tool for survival prediction. A retrospective review was performed in the Surveillance, Epidemiology, and End Results database from January 2004 to December 2009. Significant variables were selected by use of the backward stepwise method. The nomogram was constructed with multivariable Cox regression. The model's performance was evaluated by concordance index and calibration curve. The model was validated via an independent cohort from the Jiangsu Cancer Hospital Lung Cancer Center. A total of 1809 patients with stage IIIA-N2 NSCLC who underwent surgery were included in the training cohort. Age, sex, grade, histology, tumor size, visceral pleural invasion, positive lymph nodes, lymph nodes examined, and surgery type (lobectomy vs pneumonectomy) were identified as significant prognostic variables using backward stepwise method. A nomogram was developed from the training cohort and validated using an independent Chinese cohort. The concordance index of the model was 0.673 (95% confidence interval, 0.654-0.692) in training cohort and 0.664 in validation cohort (95% confidence interval, 0.614-0.714). The calibration plot showed optimal consistency between nomogram predicted survival and observed survival. Survival analyses demonstrated significant differences between different subgroups stratified by prognostic scores. This nomogram provided the individual survival prediction for patients with stage IIIA-N2 NSCLC after surgery, which might benefit survival counseling for patients and clinicians, clinical trial design and follow-up, as well as postoperative strategy-making. Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Predicting the 10-Year Risks of Atherosclerotic Cardiovascular Disease in Chinese Population: The China-PAR Project (Prediction for ASCVD Risk in China).

PubMed

Yang, Xueli; Li, Jianxin; Hu, Dongsheng; Chen, Jichun; Li, Ying; Huang, Jianfeng; Liu, Xiaoqing; Liu, Fangchao; Cao, Jie; Shen, Chong; Yu, Ling; Lu, Fanghong; Wu, Xianping; Zhao, Liancheng; Wu, Xigui; Gu, Dongfeng

2016-11-08

The accurate assessment of individual risk can be of great value to guiding and facilitating the prevention of atherosclerotic cardiovascular disease (ASCVD). However, prediction models in common use were formulated primarily in white populations. The China-PAR project (Prediction for ASCVD Risk in China) is aimed at developing and validating 10-year risk prediction equations for ASCVD from 4 contemporary Chinese cohorts. Two prospective studies followed up together with a unified protocol were used as the derivation cohort to develop 10-year ASCVD risk equations in 21 320 Chinese participants. The external validation was evaluated in 2 independent Chinese cohorts with 14 123 and 70 838 participants. Furthermore, model performance was compared with the Pooled Cohort Equations reported in the American College of Cardiology/American Heart Association guideline. Over 12 years of follow-up in the derivation cohort with 21 320 Chinese participants, 1048 subjects developed a first ASCVD event. Sex-specific equations had C statistics of 0.794 (95% confidence interval, 0.775-0.814) for men and 0.811 (95% confidence interval, 0.787-0.835) for women. The predicted rates were similar to the observed rates, as indicated by a calibration χ 2 of 13.1 for men (P=0.16) and 12.8 for women (P=0.17). Good internal and external validations of our equations were achieved in subsequent analyses. Compared with the Chinese equations, the Pooled Cohort Equations had lower C statistics and much higher calibration χ 2 values in men. Our project developed effective tools with good performance for 10-year ASCVD risk prediction among a Chinese population that will help to improve the primary prevention and management of cardiovascular disease. © 2016 American Heart Association, Inc.

Procalcitonin decrease over 72 hours in US critical care units predicts fatal outcome in sepsis patients

PubMed Central

2013-01-01

Introduction Close monitoring and repeated risk assessment of sepsis patients in the intensive care unit (ICU) is important for decisions regarding care intensification or early discharge to the ward. We studied whether considering plasma kinetics of procalcitonin, a biomarker of systemic bacterial infection, over the first 72 critical care hours improved mortality prognostication of septic patients from two US settings. Methods This retrospective analysis included consecutively treated eligible adults with a diagnosis of sepsis from critical care units in two independent institutions in Clearwater, FL and Chicago, IL. Cohorts were used for derivation or validation to study the association between procalcitonin change over the first 72 critical care hours and mortality. Results ICU/in-hospital mortality rates were 29.2%/31.8% in the derivation cohort (n = 154) and 17.6%/29.4% in the validation cohort (n = 102). In logistic regression analysis of both cohorts, procalcitonin change was strongly associated with ICU and in-hospital mortality independent of clinical risk scores (Acute Physiology, Age and Chronic Health Evaluation IV or Simplified Acute Physiology Score II), with area under the curve (AUC) from 0.67 to 0.71. When procalcitonin decreased by at least 80%, the negative predictive value for ICU/in-hospital mortality was 90%/90% in the derivation cohort, and 91%/79% in the validation cohort. When procalcitonin showed no decrease or increased, the respective positive predictive values were 48%/48% and 36%/52%. Discussion In septic patients, procalcitonin kinetics over the first 72 critical care hours provide prognostic information beyond that available from clinical risk scores. If these observations are confirmed, procalcitonin monitoring may assist physician decision-making regarding care intensification or early transfer from the ICU to the floor. PMID:23787145

Evaluation of the Intermittent Exotropia Questionnaire using Rasch analysis.

PubMed

Leske, David A; Holmes, Jonathan M; Melia, B Michele

2015-04-01

The Intermittent Exotropia Questionnaire (IXTQ) is a patient, proxy, and parental report of quality of life specific to children with intermittent exotropia. We refine the IXTQ using Rasch analysis to improve reliability and validity. Rasch analysis was performed on responses of 575 patients with intermittent exotropia enrolled from May 15, 2008, through July 24, 2013, and their parents from each of the 4 IXTQ health-related quality-of-life questionnaires (child 5 through 7 years of age and child 8 through 17 years of age, proxy, and parent questionnaires). Questionnaire performance and structure were confirmed in a separate cohort of 379 patients with intermittent exotropia. One item was removed from the 12-item child and proxy questionnaires, and response options in the 8- to 17-year-old child IXTQ and proxy IXTQ were combined into 3 response options for both questionnaires. Targeting was relatively poor for the child and proxy questionnaires. For the parent questionnaire, 3 subscales (psychosocial, function, and surgery) were evident. One item was removed from the psychosocial subscale. Resulting subscales had appropriate targeting. The Rasch-revised IXTQ may be a useful instrument for determining how intermittent exotropia affects health-related quality of life of children with intermittent exotropia and their parents, particularly for cohort studies.

External Validation of the Updated Partin Tables in a Cohort of French and Italian Men

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bhojani, Naeem; Department of Urology, University of Montreal, Montreal, PQ; Salomon, Laurent

2009-02-01

Purpose: To test the discrimination and calibration properties of the newly developed 2007 Partin Tables in two European cohorts with localized prostate cancer. Methods: Data on clinical and pathologic characteristics were obtained for 1,064 men treated with radical prostatectomy at the Creteil University Health Center in France (n = 839) and at the Milan University Vita-Salute in Italy (n = 225). Overall discrimination was assessed with receiver operating characteristic curve analysis, which quantified the accuracy of stage predictions for each center. Calibration plots graphically explored the relationship between predicted and observed rates of extracapsular extension (ECE), seminal vesicle invasion (SVI)more » and lymph node invasion (LNI). Results: The rates of ECE, SVI, and LNI were 28%, 14%, and 2% in the Creteil cohort vs. 11%, 5%, and 5% in the Milan cohort. In the Creteil cohort, the accuracy of ECE, SVI, and LNI prediction was 61%, 71%, and 82% vs. 66%, 92% and 75% for the Milan cohort. Important departures were recorded between Partin Tables' predicted and observed rates of ECE, SVI, and LNI within both cohorts. Conclusions: The 2007 Partin Tables demonstrated worse performance in European men than they originally did in North American men. This indicates that predictive models need to be externally validated before their implementation into clinical practice.« less

Predictive test for chemotherapy response in resectable gastric cancer: a multi-cohort, retrospective analysis.

PubMed

Cheong, Jae-Ho; Yang, Han-Kwang; Kim, Hyunki; Kim, Woo Ho; Kim, Young-Woo; Kook, Myeong-Cherl; Park, Young-Kyu; Kim, Hyung-Ho; Lee, Hye Seung; Lee, Kyung Hee; Gu, Mi Jin; Kim, Ha Yan; Lee, Jinae; Choi, Seung Ho; Hong, Soonwon; Kim, Jong Won; Choi, Yoon Young; Hyung, Woo Jin; Jang, Eunji; Kim, Hyeseon; Huh, Yong-Min; Noh, Sung Hoon

2018-05-01

Adjuvant chemotherapy after surgery improves survival of patients with stage II-III, resectable gastric cancer. However, the overall survival benefit observed after adjuvant chemotherapy is moderate, suggesting that not all patients with resectable gastric cancer treated with adjuvant chemotherapy benefit from it. We aimed to develop and validate a predictive test for adjuvant chemotherapy response in patients with resectable, stage II-III gastric cancer. In this multi-cohort, retrospective study, we developed through a multi-step strategy a predictive test consisting of two rule-based classifier algorithms with predictive value for adjuvant chemotherapy response and prognosis. Exploratory bioinformatics analyses identified biologically relevant candidate genes in gastric cancer transcriptome datasets. In the discovery analysis, a four-gene, real-time RT-PCR assay was developed and analytically validated in formalin-fixed, paraffin-embedded (FFPE) tumour tissues from an internal cohort of 307 patients with stage II-III gastric cancer treated at the Yonsei Cancer Center with D2 gastrectomy plus adjuvant fluorouracil-based chemotherapy (n=193) or surgery alone (n=114). The same internal cohort was used to evaluate the prognostic and chemotherapy response predictive value of the single patient classifier genes using associations with 5-year overall survival. The results were validated with a subset (n=625) of FFPE tumour samples from an independent cohort of patients treated in the CLASSIC trial (NCT00411229), who received D2 gastrectomy plus capecitabine and oxaliplatin chemotherapy (n=323) or surgery alone (n=302). The primary endpoint was 5-year overall survival. We identified four classifier genes related to relevant gastric cancer features (GZMB, WARS, SFRP4, and CDX1) that formed the single patient classifier assay. In the validation cohort, the prognostic single patient classifier (based on the expression of GZMB, WARS, and SFRP4) identified 79 (13%) of 625 patients as low risk, 296 (47%) as intermediate risk, and 250 (40%) as high risk, and 5-year overall survival for these groups was 83·2% (95% CI 75·2-92·0), 74·8% (69·9-80·1), and 66·0% (60·1-72·4), respectively (p=0·012). The predictive single patient classifier (based on the expression of GZMB, WARS, and CDX1) assigned 281 (45%) of 625 patients in the validation cohort to the chemotherapy-benefit group and 344 (55%) to the no-benefit group. In the predicted chemotherapy-benefit group, 5-year overall survival was significantly improved in those patients who had received adjuvant chemotherapy after surgery compared with those who received surgery only (80% [95% CI 73·5-87·1] vs 64·5% [56·8-73·3]; univariate hazard ratio 0·47 [95% CI 0·30-0·75], p=0·0015), whereas no such improvement in 5-year overall survival was observed in the no-benefit group (72·9% [66·5-79·9] in patients who received chemotherapy plus surgery vs 72·5% [65·8-79·9] in patients who only had surgery; 0·93 [0·62-1·38], p=0·71). The predictive single patient classifier groups (chemotherapy benefit vs no-benefit) could predict adjuvant chemotherapy benefit in terms of 5-year overall survival in the validation cohort (p interaction =0·036 in univariate analysis). Similar results were obtained in the internal evaluation cohort. The single patient classifiers validated in this study provide clinically important prognostic information independent of standard risk-stratification methods and predicted chemotherapy response after surgery in two independent cohorts of patients with resectable, stage II-III gastric cancer. The single patient classifiers could complement TNM staging to optimise decision making in patients with resectable gastric cancer who are eligible for adjuvant chemotherapy after surgery. Further validation of these results in prospective studies is warranted. Ministry of ICT and Future Planning; Ministry of Trade, Industry, and Energy; and Ministry of Health and Welfare. Copyright © 2018 Elsevier Ltd. All rights reserved.

New graduate separations from New Zealand's nursing workforce in the first 5 years after registration: a retrospective cohort analysis of a national administrative data set 2005-2010.

PubMed

North, Nicola; Leung, William; Lee, Rochelle

2014-08-01

To describe workforce separation rates and its relationship with demographic and work characteristics in the 2005 new graduate cohort's first 5 years as practising RNs in NZ. Retaining new graduate RNs is critical to nursing workforce sustainability; one study showed that if an RN is still employed in a hospital setting 5 years after graduation, he/she tends to remain active in the health industry. Retrospective analysis using the Nursing Council of New Zealand's registration data set for years 2005-2010. All newly registered NZ graduates practising in NZ in 2005 (n = 1236) were tracked for 5 years. Within 5 years of graduation, 26% of the cohort had separated from the NZ nursing workforce, 18% in the first year. The under-25s (n = 517), 42% of the cohort, had the highest loss, 32%, in 5 years. Separations were significantly lower for graduates in their 30s vs. their 20s and for those who gained postgraduate tertiary qualifications post-registration (10%) vs. those who did not (29%). Hospitals were the most frequent employment setting over 5 years, the largest increase being community settings. Five-year retention rates in the four largest practice areas were surgical 26%, medical 16%, mental health 60% and continuing care 10%. After 5 years, 24% of those still practising (n = 920) worked in a different health board region. New graduate RN losses were higher than in previous research, with younger RNs at most risk, threatening future sustainability of the nursing workforce and highlighting the need for evidence-based targeted strategies to retain them. © 2013 John Wiley & Sons Ltd.

Gender and socioeconomic disparities in BMI trajectories in the Seychelles: a cohort analysis based on serial population-based surveys.

PubMed

Rossi, Isabelle A; Rousson, Valentin; Viswanathan, Bharathi; Bovet, Pascal

2011-12-09

The relationship between body mass index (BMI) and socioeconomic status (SES) tends to change over time and across populations. In this study, we examined, separately in men and women, whether the association between BMI and SES changed over successive birth cohorts in the Seychelles (Indian Ocean, African region). We used data from all participants in three surveys conducted in 1989, 1994 and 2004 in independent random samples of the population aged 25-64 years in the Seychelles (N = 3'403). We used linear regression to model mean BMI according to age, cohort, SES and smoking status, allowing for a quadratic term for age to account for a curvilinear relation between BMI and age and interactions between SES and age and between SES and cohorts to test whether the relation between SES and BMI changed across subsequent cohorts. All analyses were performed separately in men and women. BMI increased with age in all birth cohorts. BMI was lower in men of low SES than high SES but was higher in women of low SES than high SES. In all SES categories, BMI increased over successive cohorts (1.24 kg/m2 in men and 1.51 kg/m2 for a 10-year increase in birth cohorts, p < 0.001). The difference in BMI between men or women of high vs. low SES did not change significantly across successive cohorts (the interaction between SES and year of birth of cohort was statistically not significant). Smoking was associated with lower BMI in men and women (respectively -1.55 kg/m2 and 2.46 kg/m2, p < 0.001). Although large differences exist between men and women, social patterning of BMI did not change significantly over successive cohorts in this population of a middle-income country in the African region.

Translation, Cross-Cultural Adaptation, and Validation of the Activity Rating Scale for Disorders of the Knee.

PubMed

Flosadottir, Vala; Roos, Ewa M; Ageberg, Eva

2017-09-01

The Activity Rating Scale (ARS) for disorders of the knee evaluates the level of activity by the frequency of participation in 4 separate activities with high demands on knee function, with a score ranging from 0 (none) to 16 (pivoting activities 4 times/wk). To translate and cross-culturally adapt the ARS into Swedish and to assess measurement properties of the Swedish version of the ARS. Cohort study (diagnosis); Level of evidence, 2. The COSMIN guidelines were followed. Participants (N = 100 [55 women]; mean age, 27 years) who were undergoing rehabilitation for a knee injury completed the ARS twice for test-retest reliability. The Knee injury and Osteoarthritis Outcome Score (KOOS), Tegner Activity Scale (TAS), and modernized Saltin-Grimby Physical Activity Level Scale (SGPALS) were administered at baseline to validate the ARS. Construct validity and responsiveness of the ARS were evaluated by testing predefined hypotheses regarding correlations between the ARS, KOOS, TAS, and SGPALS. The Cronbach alpha, intraclass correlation coefficients, absolute reliability, standard error of measurement, smallest detectable change, and Spearman rank-order correlation coefficients were calculated. The ARS showed good internal consistency (α ≈ 0.96), good test-retest reliability (intraclass correlation coefficient >0.9), and no systematic bias between measurements. The standard error of measurement was less than 2 points, and the smallest detectable change was less than 1 point at the group level and less than 5 points at the individual level. More than 75% of the hypotheses were confirmed, indicating good construct validity and good responsiveness of the ARS. The Swedish version of the ARS is valid, reliable, and responsive for evaluating the level of activity based on the frequency of participation in high-demand knee sports activities in young adults with a knee injury.

Ageing, social class and common mental disorders: longitudinal evidence from three cohorts in the West of Scotland.

PubMed

Green, M J; Benzeval, M

2011-03-01

Understanding how common mental disorders such as anxiety and depression vary with socio-economic circumstances as people age can help to identify key intervention points. However, much research treats these conditions as a single disorder when they differ significantly in terms of their disease burden. This paper examines the socio-economic pattern of anxiety and depression separately and longitudinally to develop a better understanding of their disease burden for key social groups at different ages. The Twenty-07 Study has followed 4510 respondents from three cohorts in the West of Scotland for 20 years and 3846 respondents had valid data for these analyses. Hierarchical repeated-measures models were used to investigate the relationship between age, social class and the prevalence of anxiety and depression over time measured as scores of 8 or more out of 21 on the relevant subscale of the Hospital Anxiety and Depression Scale (HADS). Social class differences in anxiety and depression widened with age. For anxiety there was a nonlinear decrease in prevalence with age, decreasing more slowly for those from manual classes compared to non-manual, whereas for depression there was a non-linear increase in prevalence with age, increasing more quickly for those from manual classes compared to non-manual. This relationship is robust to cohort, period and attrition effects. The more burdensome disorder of depression occurs more frequently at ages where socio-economic inequalities in mental health are greatest, representing a 'double jeopardy' for older people from a manual class.

Dynamic Measurement of Disease Activity in Acute Pancreatitis: The Pancreatitis Activity Scoring System

PubMed Central

Wu, Bechien U.; Batech, Michael; Quezada, Michael; Lew, Daniel; Fujikawa, Kelly; Kung, Jonathan; Jamil, Laith H.; Chen, Wansu; Afghani, Elham; Reicher, Sonya; Buxbaum, James; Pandol, Stephen J.

2017-01-01

OBJECTIVES Acute pancreatitis has a highly variable course. Currently there is no widely accepted method to measure disease activity in patients hospitalized for acute pancreatitis. We aimed to develop a clinical activity index that incorporates routine clinical parameters to assist in the measurement, study, and management of acute pancreatitis. METHODS We used the UCLA/RAND appropriateness method to identify items for inclusion in the disease activity instrument. We conducted a systematic literature review followed by two sets of iterative modified Delphi meetings including a panel of international experts between November 2014 and November 2015. The final instrument was then applied to patient data obtained from five separate study cohorts across Southern California to assess profiles of disease activity. RESULTS From a list of 35 items comprising 6 domains, we identified 5 parameters for inclusion in the final weighted clinical activity scoring system: organ failure, systemic inflammatory response syndrome, abdominal pain, requirement for opiates and ability to tolerate oral intake. We applied the weighted scoring system across the 5 study cohorts comprising 3,123 patients. We identified several distinct patterns of disease activity: (i) overall there was an elevated score at baseline relative to discharge across all study cohorts, (ii) there were distinct patterns of disease activity related to duration of illness as well as (iii) early and persistent elevation of disease activity among patients with severe acute pancreatitis defined as persistent organ failure. CONCLUSIONS We present the development and initial validation of a clinical activity score for real-time assessment of disease activity in patients with acute pancreatitis. PMID:28462914

Dynamic Measurement of Disease Activity in Acute Pancreatitis: The Pancreatitis Activity Scoring System.

PubMed

Wu, Bechien U; Batech, Michael; Quezada, Michael; Lew, Daniel; Fujikawa, Kelly; Kung, Jonathan; Jamil, Laith H; Chen, Wansu; Afghani, Elham; Reicher, Sonya; Buxbaum, James; Pandol, Stephen J

2017-07-01

Acute pancreatitis has a highly variable course. Currently there is no widely accepted method to measure disease activity in patients hospitalized for acute pancreatitis. We aimed to develop a clinical activity index that incorporates routine clinical parameters to assist in the measurement, study, and management of acute pancreatitis. We used the UCLA/RAND appropriateness method to identify items for inclusion in the disease activity instrument. We conducted a systematic literature review followed by two sets of iterative modified Delphi meetings including a panel of international experts between November 2014 and November 2015. The final instrument was then applied to patient data obtained from five separate study cohorts across Southern California to assess profiles of disease activity. From a list of 35 items comprising 6 domains, we identified 5 parameters for inclusion in the final weighted clinical activity scoring system: organ failure, systemic inflammatory response syndrome, abdominal pain, requirement for opiates and ability to tolerate oral intake. We applied the weighted scoring system across the 5 study cohorts comprising 3,123 patients. We identified several distinct patterns of disease activity: (i) overall there was an elevated score at baseline relative to discharge across all study cohorts, (ii) there were distinct patterns of disease activity related to duration of illness as well as (iii) early and persistent elevation of disease activity among patients with severe acute pancreatitis defined as persistent organ failure. We present the development and initial validation of a clinical activity score for real-time assessment of disease activity in patients with acute pancreatitis.

Multinational assessment of accuracy of equations for predicting risk of kidney failure: a meta-analysis

PubMed Central

Tangri, Navdeep; Grams, Morgan E.; Levey, Andrew S.; Coresh, Josef; Appel, Lawrence; Astor, Brad C.; Chodick, Gabriel; Collins, Allan J.; Djurdjev, Ognjenka; Elley, C. Raina; Evans, Marie; Garg, Amit X.; Hallan, Stein I.; Inker, Lesley; Ito, Sadayoshi; Jee, Sun Ha; Kovesdy, Csaba P.; Kronenberg, Florian; Lambers Heerspink, Hiddo J.; Marks, Angharad; Nadkarni, Girish N.; Navaneethan, Sankar D.; Nelson, Robert G.; Titze, Stephanie; Sarnak, Mark J.; Stengel, Benedicte; Woodward, Mark; Iseki, Kunitoshi

2016-01-01

Importance Identifying patients at risk of chronic kidney disease (CKD) progression may facilitate more optimal nephrology care. Kidney failure risk equations (KFREs) were previously developed and validated in two Canadian cohorts. Validation in other regions and in CKD populations not under the care of a nephrologist is needed. Objective To evaluate the accuracy of the KFREs across different geographic regions and patient populations through individual-participant data meta-analysis. Data Sources Thirty-one cohorts, including 721,357 participants with CKD Stages 3–5 in over 30 countries spanning 4 continents, were studied. These cohorts collected data from 1982 through 2014. Study Selection Cohorts participating in the CKD Prognosis Consortium with data on end-stage renal disease. Data Extraction and Synthesis Data were obtained and statistical analyses were performed between July 2012 and June 2015. Using the risk factors from the original KFREs, cohort-specific hazard ratios were estimated, and combined in meta-analysis to form new “pooled” KFREs. Original and pooled equation performance was compared, and the need for regional calibration factors was assessed. Main Outcome and Measure Kidney failure (treatment by dialysis or kidney transplantation). Results During a median follow-up of 4 years, 23,829 cases of kidney failure were observed. The original KFREs achieved excellent discrimination (ability to differentiate those who developed kidney failure from those who did not) across all cohorts (overall C statistic, 0.90 (95% CI 0.89–0.92) at 2 years and 0.88 (95% CI 0.86–0.90) at 5 years); discrimination in subgroups by age, race, and diabetes status was similar. There was no improvement with the pooled equations. Calibration (the difference between observed and predicted risk) was adequate in North American cohorts, but the original KFREs overestimated risk in some non-North American cohorts. Addition of a calibration factor that lowered the baseline risk by 32.9% at 2 years and 16.5% at 5 years improved the calibration in 12/15 and 10/13 non-North American cohorts at 2 and 5 years, respectively (p=0.04 and p=0.02). Conclusions and Relevance KFREs developed in a Canadian population showed high discrimination and adequate calibration when validated in 31 multinational cohorts. However, in some regions the addition of a calibration factor may be necessary. PMID:26757465

Development and validation of a prognostic index for 4-year mortality in older adults.

PubMed

Lee, Sei J; Lindquist, Karla; Segal, Mark R; Covinsky, Kenneth E

2006-02-15

Both comorbid conditions and functional measures predict mortality in older adults, but few prognostic indexes combine both classes of predictors. Combining easily obtained measures into an accurate predictive model could be useful to clinicians advising patients, as well as policy makers and epidemiologists interested in risk adjustment. To develop and validate a prognostic index for 4-year mortality using information that can be obtained from patient report. Using the 1998 wave of the Health and Retirement Study (HRS), a population-based study of community-dwelling US adults older than 50 years, we developed the prognostic index from 11,701 individuals and validated the index with 8009. Individuals were asked about their demographic characteristics, whether they had specific diseases, and whether they had difficulty with a series of functional measures. We identified variables independently associated with mortality and weighted the variables to create a risk index. Death by December 31, 2002. The overall response rate was 81%. During the 4-year follow-up, there were 1361 deaths (12%) in the development cohort and 1072 deaths (13%) in the validation cohort. Twelve independent predictors of mortality were identified: 2 demographic variables (age: 60-64 years, 1 point; 65-69 years, 2 points; 70-74 years, 3 points; 75-79 years, 4 points; 80-84 years, 5 points, >85 years, 7 points and male sex, 2 points), 6 comorbid conditions (diabetes, 1 point; cancer, 2 points; lung disease, 2 points; heart failure, 2 points; current tobacco use, 2 points; and body mass index <25, 1 point), and difficulty with 4 functional variables (bathing, 2 points; walking several blocks, 2 points; managing money, 2 points, and pushing large objects, 1 point. Scores on the risk index were strongly associated with 4-year mortality in the validation cohort, with 0 to 5 points predicting a less than 4% risk, 6 to 9 points predicting a 15% risk, 10 to 13 points predicting a 42% risk, and 14 or more points predicting a 64% risk. The risk index showed excellent discrimination with a cstatistic of 0.84 in the development cohort and 0.82 in the validation cohort. This prognostic index, incorporating age, sex, self-reported comorbid conditions, and functional measures, accurately stratifies community-dwelling older adults into groups at varying risk of mortality.

Gene Polymorphisms in the CCL5/CCR5 Pathway as a Genetic Biomarker for Outcome and Hand-Foot Skin Reaction in Metastatic Colorectal Cancer Patients Treated With Regorafenib.

PubMed

Suenaga, Mitsukuni; Schirripa, Marta; Cao, Shu; Zhang, Wu; Yang, Dongyun; Ning, Yan; Cremolini, Chiara; Antoniotti, Carlotta; Borelli, Beatrice; Mashima, Tetsuo; Okazaki, Satoshi; Berger, Martin D; Miyamoto, Yuji; Gopez, Roel; Barzi, Afsaneh; Lonardi, Sara; Yamaguchi, Toshiharu; Falcone, Alfredo; Loupakis, Fotios; Lenz, Heinz-Josef

2018-06-01

The C-C motif chemokine ligand 5/C-C motif chemokine receptor 5 (CCL5/CCR5) pathway has been shown to induce endothelial progenitor cell migration, resulting in increased vascular endothelial growth factor A expression. We hypothesized that genetic polymorphisms in the CCL5/CCR5 pathway predict efficacy and toxicity in patients with metastatic colorectal cancer (mCRC) treated with regorafenib. We analyzed genomic DNA extracted from 229 tumor samples from 2 different cohorts of patients who received regorafenib: an evaluation cohort of 79 Japanese patients and a validation cohort of 150 Italian patients. Single nucleotide polymorphisms of CCL5/CCR5 pathway-related genes were analyzed by PCR-based direct sequencing. CCL4 rs1634517 and CCL3 rs1130371 were associated with progression-free survival in the evaluation cohort (hazard ratio [HR] 1.54, P = .043; HR 1.48, P = .064), and progression-free survival (HR 1.74, P < .001; HR 1.66, P = .002) and overall survival (HR 1.65, P = .004; HR 1.65, P = .004) in the validation cohort. The allelic frequencies of CCL5 single nucleotide polymorphisms varied between the evaluation and validation cohorts (G/G variant in rs2280789, 21.5% vs. 1.3%, P < .001; T/T variant in rs3817655, 22.8% vs. 2.7%, P < .001). In the evaluation cohort, patients with the G/G variant in rs2280789 had a higher incidence of grade 3+ hand-foot skin reaction compared to any A allele (53% vs. 27%, P = .078), and similarly to the T/T variant in rs3817655 compared to any A allele (56% vs. 26%, P = .026). Genetic variants in the CCL5/CCR5 pathway may serve as prognostic markers and may predict severe hand-foot skin reaction in mCRC patients receiving regorafenib therapy. Copyright © 2018 Elsevier Inc. All rights reserved.

PRImary care Streptococcal Management (PRISM) study: identifying clinical variables associated with Lancefield group A β-haemolytic streptococci and Lancefield non-Group A streptococcal throat infections from two cohorts of patients presenting with an acute sore throat

PubMed Central

Little, Paul; Moore, Michael; Hobbs, F D R; Mant, David; McNulty, Cliodna; Williamson, Ian; Cheng, Edith; Stuart, Beth; Kelly, Joanne; Barnett, Jane; Mullee, Mark

2013-01-01

Objective To assess the association between features of acute sore throat and the growth of streptococci from culturing a throat swab. Design Diagnostic cohort. Setting UK general practices. Participants Patients aged 5 or over presenting with an acute sore throat. Patients were recruited for a second cohort (cohort 2, n=517) consecutively after the first (cohort 1, n=606) from similar practices. Main outcome Predictors of the presence of Lancefield A/C/G streptococci. Results The clinical score developed from cohort 1 had poor discrimination in cohort 2 (bootstrapped estimate of area under the receiver operator characteristic (ROC) curve (0.65), due to the poor validity of the individual items in the second data set. Variables significant in multivariate analysis in both cohorts were rapid attendance (prior duration 3 days or less; multivariate adjusted OR 1.92 cohort, 1.67 cohort 2); fever in the last 24 h (1.69, 2.40); and doctor assessment of severity (severely inflamed pharynx/tonsils (2.28, 2.29)). The absence of coryza or cough and purulent tonsils were significant in univariate analysis in both cohorts and in multivariate analysis in one cohort. A five-item score based on Fever, Purulence, Attend rapidly (3 days or less), severely Inflamed tonsils and No cough or coryza (FeverPAIN) had moderate predictive value (bootstrapped area under the ROC curve 0.73 cohort 1, 0.71 cohort 2) and identified a substantial number of participants at low risk of streptococcal infection (38% in cohort 1, 36% in cohort 2 scored ≤1, associated with a streptococcal percentage of 13% and 18%, respectively). A Centor score of ≤1 identified 23% and 26% of participants with streptococcal percentages of 10% and 28%, respectively. Conclusions Items widely used to help identify streptococcal sore throat may not be the most consistent. A modified clinical scoring system (FeverPAIN) which requires further validation may be clinically helpful in identifying individuals who are unlikely to have major pathogenic streptococci. PMID:24163209

PRImary care Streptococcal Management (PRISM) study: identifying clinical variables associated with Lancefield group A β-haemolytic streptococci and Lancefield non-Group A streptococcal throat infections from two cohorts of patients presenting with an acute sore throat.

PubMed

Little, Paul; Moore, Michael; Hobbs, F D R; Mant, David; McNulty, Cliodna; Williamson, Ian; Cheng, Edith; Stuart, Beth; Kelly, Joanne; Barnett, Jane; Mullee, Mark

2013-10-25

To assess the association between features of acute sore throat and the growth of streptococci from culturing a throat swab. Diagnostic cohort. UK general practices. Patients aged 5 or over presenting with an acute sore throat. Patients were recruited for a second cohort (cohort 2, n=517) consecutively after the first (cohort 1, n=606) from similar practices. Predictors of the presence of Lancefield A/C/G streptococci. The clinical score developed from cohort 1 had poor discrimination in cohort 2 (bootstrapped estimate of area under the receiver operator characteristic (ROC) curve (0.65), due to the poor validity of the individual items in the second data set. Variables significant in multivariate analysis in both cohorts were rapid attendance (prior duration 3 days or less; multivariate adjusted OR 1.92 cohort, 1.67 cohort 2); fever in the last 24 h (1.69, 2.40); and doctor assessment of severity (severely inflamed pharynx/tonsils (2.28, 2.29)). The absence of coryza or cough and purulent tonsils were significant in univariate analysis in both cohorts and in multivariate analysis in one cohort. A five-item score based on Fever, Purulence, Attend rapidly (3 days or less), severely Inflamed tonsils and No cough or coryza (FeverPAIN) had moderate predictive value (bootstrapped area under the ROC curve 0.73 cohort 1, 0.71 cohort 2) and identified a substantial number of participants at low risk of streptococcal infection (38% in cohort 1, 36% in cohort 2 scored ≤1, associated with a streptococcal percentage of 13% and 18%, respectively). A Centor score of ≤1 identified 23% and 26% of participants with streptococcal percentages of 10% and 28%, respectively. Items widely used to help identify streptococcal sore throat may not be the most consistent. A modified clinical scoring system (FeverPAIN) which requires further validation may be clinically helpful in identifying individuals who are unlikely to have major pathogenic streptococci.

Improving the Validity of Activity of Daily Living Dependency Risk Assessment

PubMed Central

Clark, Daniel O.; Stump, Timothy E.; Tu, Wanzhu; Miller, Douglas K.

2015-01-01

Objectives Efforts to prevent activity of daily living (ADL) dependency may be improved through models that assess older adults’ dependency risk. We evaluated whether cognition and gait speed measures improve the predictive validity of interview-based models. Method Participants were 8,095 self-respondents in the 2006 Health and Retirement Survey who were aged 65 years or over and independent in five ADLs. Incident ADL dependency was determined from the 2008 interview. Models were developed using random 2/3rd cohorts and validated in the remaining 1/3rd. Results Compared to a c-statistic of 0.79 in the best interview model, the model including cognitive measures had c-statistics of 0.82 and 0.80 while the best fitting gait speed model had c-statistics of 0.83 and 0.79 in the development and validation cohorts, respectively. Conclusion Two relatively brief models, one that requires an in-person assessment and one that does not, had excellent validity for predicting incident ADL dependency but did not significantly improve the predictive validity of the best fitting interview-based models. PMID:24652867

Quarantine, isolation, and cohorting: from cholera to Klebsiella.

PubMed

Rosenberger, Laura H; Riccio, Lin M; Campbell, Kristin Turza; Politano, Amani D; Sawyer, Robert G

2012-04-01

Isolation is defined as the separation of persons with communicable diseases from those who are healthy. This public health practice, along with quarantine, is used to limit the transmission of infectious diseases and provides the foundation of current-day cohorting. Review of the pertinent English-language literature. Mass isolation developed during the medieval Black Death outbreaks in order to protect ports from the transmission of epidemics. In the mid-1800s, infectious disease hospitals were opened. It now is clear that isolation and cohorting of patients and staff interrupts the transmission of disease. Over the next century, with the discovery of penicillin and vaccines against many infectious agents, the contagious disease hospitals began to close. Today, we find smaller outbreaks of microorganisms that have acquired substantial resistance to antimicrobial agents. In the resource-limited hospital, a dedicated area or region of a unit may suffice to separate affected from unaffected patients. Quarantine, or cohorting when patients are infected with the same pathogen, interrupts the spread of infections, just as the contagious disease hospitals did during the epidemics of the 18th and 19th centuries.

Development of metabolic and inflammatory mediator biomarker phenotyping for early diagnosis and triage of pediatric sepsis.

PubMed

Mickiewicz, Beata; Thompson, Graham C; Blackwood, Jaime; Jenne, Craig N; Winston, Brent W; Vogel, Hans J; Joffe, Ari R

2015-09-09

The first steps in goal-directed therapy for sepsis are early diagnosis followed by appropriate triage. These steps are usually left to the physician's judgment, as there is no accepted biomarker available. We aimed to determine biomarker phenotypes that differentiate children with sepsis who require intensive care from those who do not. We conducted a prospective, observational nested cohort study at two pediatric intensive care units (PICUs) and one pediatric emergency department (ED). Children ages 2-17 years presenting to the PICU or ED with sepsis or presenting for procedural sedation to the ED were enrolled. We used the judgment of regional pediatric ED and PICU attending physicians as the standard to determine triage location (PICU or ED). We performed metabolic and inflammatory protein mediator profiling with serum and plasma samples, respectively, collected upon presentation, followed by multivariate statistical analysis. Ninety-four PICU sepsis, 81 ED sepsis, and 63 ED control patients were included. Metabolomic profiling revealed clear separation of groups, differentiating PICU sepsis from ED sepsis with accuracy of 0.89, area under the receiver operating characteristic curve (AUROC) of 0.96 (standard deviation [SD] 0.01), and predictive ability (Q(2)) of 0.60. Protein mediator profiling also showed clear separation of the groups, differentiating PICU sepsis from ED sepsis with accuracy of 0.78 and AUROC of 0.88 (SD 0.03). Combining metabolomic and protein mediator profiling improved the model (Q(2) =0.62), differentiating PICU sepsis from ED sepsis with accuracy of 0.87 and AUROC of 0.95 (SD 0.01). Separation of PICU sepsis or ED sepsis from ED controls was even more accurate. Prespecified age subgroups (2-5 years old and 6-17 years old) improved model accuracy minimally. Seventeen metabolites or protein mediators accounted for separation of PICU sepsis and ED sepsis with 95% confidence. In children ages 2-17 years, combining metabolomic and inflammatory protein mediator profiling early after presentation may differentiate children with sepsis requiring care in a PICU from children with or without sepsis safely cared for outside a PICU. This may aid in making triage decisions, particularly in an ED without pediatric expertise. This finding requires validation in an independent cohort.

Validity of the SAT® for Predicting First-Year Grades: 2010 SAT Validity Sample. Statistical Report 2013-2

ERIC Educational Resources Information Center

Patterson, Brian F.; Mattern, Krista D.

2013-01-01

The continued accumulation of validity evidence for the core uses of educational assessments is critical to ensure that proper inferences will be made for those core purposes. To that end, the College Board has continued to follow previous cohorts of college students and this report provides updated validity evidence for using the SAT to predict…

Validation and Adjustment of the Leipzig-Halifax Acute Aortic Dissection Type A Scorecard.

PubMed

Mejàre-Berggren, Hanna; Olsson, Christian

2017-11-01

The novel Leipzig-Halifax (LH) scorecard for acute aortic dissection type A (AADA) stratifies risk of in-hospital death based on age, malperfusion syndromes, critical preoperative state, and coronary disease. The study aim was to externally validate the LH scorecard performance and, if adequate, propose adjustments. All consecutive AADA patients operated on from 1996 to 2016 (n = 509) were included to generate an external validation cohort. Variables related to in-hospital death were analyzed using univariable and multivariable analysis. The LH scorecard was applied to the validation cohort, compared with the original study, and variable selection was adjusted using validation measures for discrimination and calibration. In-hospital mortality rate was 17.7% (LH cohort 18.7%). Critical preoperative state and Penn class non-Aa were independent predictors (odds ratio [OR] 2.42 and 2.45, respectively) of in-hospital death. The LH scorecard was adjusted to include Penn class non-Aa, critical preoperative state, and coronary disease. Assessing discrimination, area under receiver operator characteristic curve for the LH scorecard was 0.61 versus 0.66 for the new scorecard (p = 0.086). In-hospital mortality rates in low-, medium-, and high-risk groups were 14%, 15%, and 48%, respectively (LH scorecard) versus 11%, 23%, and 43%, respectively (new scorecard), and goodness-of-fit p value was 0.01 versus 0.86, indicating better calibration by the new scorecard. A lower Akaike information criterion value, 464 versus 448, favored the new scorecard. Through adjustment of the LH scorecard after external validation, prognostic performance improved. Further validated, the LH scorecard could be a valuable risk prediction tool. Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Development and Validation of a New Scoring System to Predict Survival in Patients With Myotonic Dystrophy Type 1.

PubMed

Wahbi, Karim; Porcher, Raphaël; Laforêt, Pascal; Fayssoil, Abdallah; Bécane, Henri Marc; Lazarus, Arnaud; Sochala, Maximilien; Stojkovic, Tanya; Béhin, Anthony; Leonard-Louis, Sarah; Arnaud, Pauline; Furling, Denis; Probst, Vincent; Babuty, Dominique; Pellieux, Sybille; Clementy, Nicolas; Bassez, Guillaume; Péréon, Yann; Eymard, Bruno; Duboc, Denis

2018-05-01

Life expectancy is greatly shortened in patients presenting with myotonic dystrophy type 1 (DM1), the most common neuromuscular disease. A reliable prediction of survival in patients with DM1 is critically important to plan personalized health supervision. To develop and validate a prognostic score to predict 10-year survival in patients with DM1. In this longitudinal cohort study, between January 2000 and November 2014, we enrolled 1296 adults referred to 4 tertiary neuromuscular centers in France for management of genetically proven DM1, including 1066 patients in the derivation cohort and 230 in the validation cohort. Data were analyzed from December 2016 to March 2017. Factors associated with survival by multiple variable Cox modeling, including 95% confidence intervals, and development of a predictive score validated internally and externally. Mean values are reported with their standard deviations. Of the 1296 included patients, 670 (51.7%) were women, and the mean (SD) age was 39.8 (13.7) years. Among the 1066 patients (82.3%) in the derivation cohort, 241 (22.6%) died over a median (interquartile range) follow-up of 11.7 (7.7-14.3) years. Age, diabetes, need for support when walking, heart rate, systolic blood pressure, first-degree atrioventricular block, bundle-branch block, and lung vital capacity were associated with death. Simplified score points were attributed to each predictor, and adding these points yielded scores between 0 and 20, with 0 indicating the lowest and 20 the highest risk of death. The 10-year survival rate was 96.6% (95% CI, 94.4-98.9) in the group with 0 to 4 points, 92.2% (95% CI, 88.8-95.6) in the group with 5 to 7 points, 80.7% (95% CI, 75.4-86.1) in the group with 8 to 10 points, 57.9% (95% CI, 49.2-66.6) in the group with 11 to 13 points, and 19.4% (95% CI, 8.6-30.1) in the group with 14 points or more. In 230 patients (17.7%) included in the validation cohort, the 10-year survival rates for the groups with 0 to 4, 5 to 7, 8 to 10, 11 to 13, and 14 points or more were 99.3% (95% CI, 95.0-100), 80.6% (95% CI, 67.1-96.7), 79.3% (95% CI, 66.2-95.1), 43.2% (95% CI, 28.2-66.1), and 21.6% (95% CI, 10.0-46.8), respectively. The calibration curves did not deviate from the reference line. The C index was 0.753 (95% CI, 0.722-0.785) in the derivation cohort and 0.806 (95% CI, 0.758-0.855) in the validation cohort. The DM1 prognostic score is associated with long-term survival.

C-GRApH: A Validated Scoring System for Early Stratification of Neurologic Outcome After Out-of-Hospital Cardiac Arrest Treated With Targeted Temperature Management.

PubMed

Kiehl, Erich L; Parker, Alex M; Matar, Ralph M; Gottbrecht, Matthew F; Johansen, Michelle C; Adams, Mark P; Griffiths, Lori A; Dunn, Steven P; Bidwell, Katherine L; Menon, Venu; Enfield, Kyle B; Gimple, Lawrence W

2017-05-20

Out-of-hospital cardiac arrest (OHCA) results in significant morbidity and mortality, primarily from neurologic injury. Predicting neurologic outcome early post-OHCA remains difficult in patients receiving targeted temperature management. Retrospective analysis was performed on consecutive OHCA patients receiving targeted temperature management (32-34°C) for 24 hours at a tertiary-care center from 2008 to 2012 (development cohort, n=122). The primary outcome was favorable neurologic outcome at hospital discharge, defined as cerebral performance category 1 to 2 (poor 3-5). Patient demographics, pre-OHCA diagnoses, and initial laboratory studies post-resuscitation were compared between favorable and poor neurologic outcomes with multivariable logistic regression used to develop a simple scoring system ( C-GRApH ). The C-GRApH score ranges 0 to 5 using equally weighted variables: ( C ): coronary artery disease, known pre-OHCA; ( G ): glucose ≥200 mg/dL; ( R ): rhythm of arrest not ventricular tachycardia/fibrillation; ( A ): age >45; ( pH ): arterial pH ≤7.0. A validation cohort (n=344) included subsequent patients from the initial site (n=72) and an external quaternary-care health system (n=272) from 2012 to 2014. The c-statistic for predicting neurologic outcome was 0.82 (0.74-0.90, P <0.001) in the development cohort and 0.81 (0.76-0.87, P <0.001) in the validation cohort. When subdivided by C-GRApH score, similar rates of favorable neurologic outcome were seen in both cohorts, 70% each for low (0-1, n=60), 22% versus 19% for medium (2-3, n=307), and 0% versus 2% for high (4-5, n=99) C-GRApH scores in the development and validation cohorts, respectively. C-GRApH stratifies neurologic outcomes following OHCA in patients receiving targeted temperature management (32-34°C) using objective data available at hospital presentation, identifying patient subsets with disproportionally favorable ( C-GRApH ≤1) and poor ( C-GRApH ≥4) prognoses. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Novel equations to estimate lean body mass in maintenance hemodialysis patients.

PubMed

Noori, Nazanin; Kovesdy, Csaba P; Bross, Rachelle; Lee, Martin; Oreopoulos, Antigone; Benner, Deborah; Mehrotra, Rajnish; Kopple, Joel D; Kalantar-Zadeh, Kamyar

2011-01-01

Lean body mass (LBM) is an important nutritional measure representing muscle mass and somatic protein in hemodialysis patients, for whom we developed and tested equations to estimate LBM. A study of diagnostic test accuracy. The development cohort included 118 hemodialysis patients with LBM measured using dual-energy x-ray absorptiometry (DEXA) and near-infrared (NIR) interactance. The validation cohort included 612 additional hemodialysis patients with LBM measured using a portable NIR interactance technique during hemodialysis. 3-month averaged serum concentrations of creatinine, albumin, and prealbumin; normalized protein nitrogen appearance; midarm muscle circumference (MAMC); handgrip strength; and subjective global assessment of nutrition. LBM measured using DEXA in the development cohort and NIR interactance in validation cohorts. In the development cohort, DEXA and NIR interactance correlated strongly (r = 0.94, P < 0.001). DEXA-measured LBM correlated with serum creatinine level, MAMC, and handgrip strength, but not with other nutritional markers. Three regression equations to estimate DEXA-measured LBM were developed based on each of these 3 surrogates and sex, height, weight, and age (and urea reduction ratio for the serum creatinine regression). In the validation cohort, the validity of the equations was tested against the NIR interactance-measured LBM. The equation estimates correlated well with NIR interactance-measured LBM (R² ≥ 0.88), although in higher LBM ranges, they tended to underestimate it. Median (95% confidence interval) differences and interquartile range for differences between equation estimates and NIR interactance-measured LBM were 3.4 (-3.2 to 12.0) and 3.0 (1.1-5.1) kg for serum creatinine and 4.0 (-2.6 to 13.6) and 3.7 (1.3-6.0) kg for MAMC, respectively. DEXA measurements were obtained on a nondialysis day, whereas NIR interactance was performed during hemodialysis treatment, with the likelihood of confounding by volume status variations. Compared with reference measures of LBM, equations using serum creatinine level, MAMC, or handgrip strength and demographic variables can estimate LBM accurately in long-term hemodialysis patients. Copyright © 2010 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Novel Equations to Estimate Lean Body Mass in Maintenance Hemodialysis Patients

PubMed Central

Noori, Nazanin; Kovesdy, Csaba P; Bross, Rachelle; Lee, Martin; Oreopoulos, Antigone; Benner, Deborah; Mehrotra, Rajnish; Kopple, Joel D; Kalantar-Zadeh, Kamyar

2010-01-01

Background Lean body mass (LBM) is an important nutritional measure representing muscle mass and somatic protein in hemodialysis patients, in whom we developed and tested equations to estimate LBM. Study Design A study of diagnostic test accuracy. Setting and Participants The development cohort included 118 hemodialysis patients, with LBM measured using dual-energy -X-ray absorptiometry (DEXA) and near-infrared (NIR) interactance. The validation cohort included 612 additional hemodialysis patients with LBM measured using portable NIR interactance technique during hemodialysis. Index Tests 3-month averaged serum concentrations of creatinine, albumin and prealbumin, normalized protein-nitrogen-appearance, mid-arm muscle circumference (MAMC), handgrip strength, and subjective global assessment of nutrition. Reference Test LBM measured via DEXA in the development cohort and via NIR interactance in validation cohorts. Results In the development cohort, DEXA and NIR interactance were strongly correlated (r=0.94, p<0.001). DEXA-measured LBM correlated with serum creatinine, MAMC, handgrip strength but not with other nutritional markers. Three regression equations to estimate DEXA-measured LBM were developed based on each of these three surrogates and gender, height, weight, and age (and urea reduction ratio for the serum creatinine regression). In the validation cohort, the validity of the equations were tested against the NIR interactance measured LBM. The equation estimates correlated well with NIR interactance measured LBM (R221 ≥0.88), although in higher LBM ranges they tended to underestimate it. Median differences between equation estimates and NIR interactance-measured LBM were 3.4 (25th–75th percentile, −3.2 to 12.0) and 3.0 (25th–75th percentile, 1.1–5.1) kg for serum creatinine and 4.0 (25th–75th percentile, −2.6 to 13.6) and 3.7 (25th–75th percentile, 1.3–6.0) kg for MAMC. Limitations DEXA measurements were performed on a non-dialysis day whereas NIR interactance was obtained during the hemodialysis treatment, with likelihood of confounding by volume status variations. Conclusions Comparing to reference measures of LBM, equations using serum creatinine, MAMC, or handgrip strength and demographic variables can accurately estimate LBM in long-term hemodialysis patients. PMID:21184920

Development and validation of a prognostic scoring system for patients with chronic myelomonocytic leukemia.

PubMed

Such, Esperanza; Germing, Ulrich; Malcovati, Luca; Cervera, José; Kuendgen, Andrea; Della Porta, Matteo G; Nomdedeu, Benet; Arenillas, Leonor; Luño, Elisa; Xicoy, Blanca; Amigo, Mari L; Valcarcel, David; Nachtkamp, Kathrin; Ambaglio, Ilaria; Hildebrandt, Barbara; Lorenzo, Ignacio; Cazzola, Mario; Sanz, Guillermo

2013-04-11

The natural course of chronic myelomonocytic leukemia (CMML) is highly variable but a widely accepted prognostic scoring system for patients with CMML is not available. The main aim of this study was to develop a new CMML-specific prognostic scoring system (CPSS) in a large series of 558 patients with CMML (training cohort, Spanish Group of Myelodysplastic Syndromes) and to validate it in an independent series of 274 patients (validation cohort, Heinrich Heine University Hospital, Düsseldorf, Germany, and San Matteo Hospital, Pavia, Italy). The most relevant variables for overall survival (OS) and evolution to acute myeloblastic leukemia (AML) were FAB and WHO CMML subtypes, CMML-specific cytogenetic risk classification, and red blood cell (RBC) transfusion dependency. CPSS was able to segregate patients into 4 clearly different risk groups for OS (P < .001) and risk of AML evolution (P < .001) and its predictive capability was confirmed in the validation cohort. An alternative CPSS with hemoglobin instead of RBC transfusion dependency offered almost identical prognostic capability. This study confirms the prognostic impact of FAB and WHO subtypes, recognizes the importance of RBC transfusion dependency and cytogenetics, and offers a simple and powerful CPSS for accurately assessing prognosis and planning therapy in patients with CMML.

External validation of a prediction model for surgical site infection after thoracolumbar spine surgery in a Western European cohort.

PubMed

Janssen, Daniël M C; van Kuijk, Sander M J; d'Aumerie, Boudewijn B; Willems, Paul C

2018-05-16

A prediction model for surgical site infection (SSI) after spine surgery was developed in 2014 by Lee et al. This model was developed to compute an individual estimate of the probability of SSI after spine surgery based on the patient's comorbidity profile and invasiveness of surgery. Before any prediction model can be validly implemented in daily medical practice, it should be externally validated to assess how the prediction model performs in patients sampled independently from the derivation cohort. We included 898 consecutive patients who underwent instrumented thoracolumbar spine surgery. To quantify overall performance using Nagelkerke's R 2 statistic, the discriminative ability was quantified as the area under the receiver operating characteristic curve (AUC). We computed the calibration slope of the calibration plot, to judge prediction accuracy. Sixty patients developed an SSI. The overall performance of the prediction model in our population was poor: Nagelkerke's R 2 was 0.01. The AUC was 0.61 (95% confidence interval (CI) 0.54-0.68). The estimated slope of the calibration plot was 0.52. The previously published prediction model showed poor performance in our academic external validation cohort. To predict SSI after instrumented thoracolumbar spine surgery for the present population, a better fitting prediction model should be developed.

A novel classifier based on three preoperative tumor markers predicting the cancer-specific survival of gastric cancer (CEA, CA19-9 and CA72-4).

PubMed

Guo, Jing; Chen, Shangxiang; Li, Shun; Sun, Xiaowei; Li, Wei; Zhou, Zhiwei; Chen, Yingbo; Xu, Dazhi

2018-01-12

Several studies have highlighted the prognostic value of the individual and the various combinations of the tumor markers for gastric cancer (GC). Our study was designed to assess establish a new novel model incorporating carcino-embryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 72-4 (CA72-4). A total of 1,566 GC patients (Primary cohort) between Jan 2000 and July 2013 were analyzed. The Primary cohort was randomly divided into Training set (n=783) and Validation set (n=783). A three-tumor marker classifier was developed in the Training set and validated in the Validation set by multivariate regression and risk-score analysis. We have identified a three-tumor marker classifier (including CEA, CA19-9 and CA72-4) for the cancer specific survival (CSS) of GC (p<0.001). Consistent results were obtained in the both Training set and Validation set. Multivariate analysis showed that the classifier was an independent predictor of GC (All p value <0.001 in the Training set, Validation set and Primary cohort). Furthermore, when the leave-one-out approach was performed, the classifier showed superior predictive value to the individual or two of them (with the highest AUC (Area Under Curve); 0.618 for the Training set, and 0.625 for the Validation set), which ascertained its predictive value. Our three-tumor marker classifier is closely associated with the CSS of GC and may serve as a novel model for future decisions concerning treatments.

Birth-cohort patterns in Crohn's disease and ulcerative colitis.

PubMed

Sonnenberg, Amnon

2014-01-01

To test the long-term time trends of mortality from inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), for the presence of birth-cohort phenomena. We analyzed mortality data from the national statistical offices of Canada, England and Wales, Italy, the Netherlands, Switzerland, and the USA for the past 60-80 years. Age-specific rates of death were plotted against the period of death, as period-age contours, and against the period of birth, as cohort-age contours. In all six countries alike, the general time trends of IBD have been shaped by an underlying birth-cohort pattern. This pattern was also observed in the data of CD and UC analyzed separately. UC mortality increased in all generations born during the 19th century. It peaked among generations born shortly before the turn of the century and then decreased in all subsequent generations born throughout the 20th century. Compared with UC, the birth-cohort pattern of CD was delayed by 30-50 years. In addition to one risk factor responsible for the general occurrence of IBD and possibly UC alone, there exists at least one additional risk factor responsible for CD. Exposure to both separate risk factors must occur during early life.

Development and validation of a set of six adaptable prognosis prediction (SAP) models based on time-series real-world big data analysis for patients with cancer receiving chemotherapy: A multicenter case crossover study

PubMed Central

Kanai, Masashi; Okamoto, Kazuya; Yamamoto, Yosuke; Yoshioka, Akira; Hiramoto, Shuji; Nozaki, Akira; Nishikawa, Yoshitaka; Yamaguchi, Daisuke; Tomono, Teruko; Nakatsui, Masahiko; Baba, Mika; Morita, Tatsuya; Matsumoto, Shigemi; Kuroda, Tomohiro; Okuno, Yasushi; Muto, Manabu

2017-01-01

Background We aimed to develop an adaptable prognosis prediction model that could be applied at any time point during the treatment course for patients with cancer receiving chemotherapy, by applying time-series real-world big data. Methods Between April 2004 and September 2014, 4,997 patients with cancer who had received systemic chemotherapy were registered in a prospective cohort database at the Kyoto University Hospital. Of these, 2,693 patients with a death record were eligible for inclusion and divided into training (n = 1,341) and test (n = 1,352) cohorts. In total, 3,471,521 laboratory data at 115,738 time points, representing 40 laboratory items [e.g., white blood cell counts and albumin (Alb) levels] that were monitored for 1 year before the death event were applied for constructing prognosis prediction models. All possible prediction models comprising three different items from 40 laboratory items (40C3 = 9,880) were generated in the training cohort, and the model selection was performed in the test cohort. The fitness of the selected models was externally validated in the validation cohort from three independent settings. Results A prognosis prediction model utilizing Alb, lactate dehydrogenase, and neutrophils was selected based on a strong ability to predict death events within 1–6 months and a set of six prediction models corresponding to 1,2, 3, 4, 5, and 6 months was developed. The area under the curve (AUC) ranged from 0.852 for the 1 month model to 0.713 for the 6 month model. External validation supported the performance of these models. Conclusion By applying time-series real-world big data, we successfully developed a set of six adaptable prognosis prediction models for patients with cancer receiving chemotherapy. PMID:28837592

Genome-Wide miRNA Analysis Identifies miR-188-3p as a Novel Prognostic Marker and Molecular Factor Involved in Colorectal Carcinogenesis

PubMed Central

Pichler, Martin; Stiegelbauer, Verena; Vychytilova-Faltejskova, Petra; Ivan, Cristina; Ling, Hui; Winter, Elke; Zhang, Xinna; Goblirsch, Matthew; Wulf-Goldenberg, Annika; Ohtsuka, Masahisa; Haybaeck, Johannes; Svoboda, Marek; Okugawa, Yoshinaga; Gerger, Armin; Hoefler, Gerald; Goel, Ajay; Slaby, Ondrej; Calin, George Adrian

2017-01-01

Purpose Characterization of colorectal cancer transcriptome by high-throughput techniques has enabled the discovery of several differentially expressed genes involving previously unreported miRNA abnormalities. Here, we followed a systematic approach on a global scale to identify miRNAs as clinical outcome predictors and further validated them in the clinical and experimental setting. Experimental Design Genome-wide miRNA sequencing data of 228 colorectal cancer patients from The Cancer Genome Atlas dataset were analyzed as a screening cohort to identify miRNAs significantly associated with survival according to stringent prespecified criteria. A panel of six miRNAs was further validated for their prognostic utility in a large independent validation cohort (n = 332). In situ hybridization and functional experiments in a panel of colorectal cancer cell lines and xenografts further clarified the role of clinical relevant miRNAs. Results Six miRNAs (miR-92b-3p, miR-188-3p, miR-221-5p, miR-331-3p, miR-425-3p, and miR-497-5p) were identified as strong predictors of survival in the screening cohort. High miR-188-3p expression proves to be an independent prognostic factor [screening cohort: HR = 4.137; 95% confidence interval (CI), 1.568–10.917; P = 0.004; validation cohort: HR = 1.538; 95% CI, 1.107–2.137; P = 0.010, respectively]. Forced miR-188-3p expression increased migratory behavior of colorectal cancer cells in vitro and metastases formation in vivo (P < 0.05). The promigratory role of miR-188-3p is mediated by direct interaction with MLLT4, a novel identified player involved in colorectal cancer cell migration. Conclusions miR-188-3p is a novel independent prognostic factor in colorectal cancer patients, which can be partly explained by its effect on MLLT4 expression and migration of cancer cells. PMID:27601590

Establishment of an Adjusted Prognosis Analysis Model for Initially Diagnosed Non-Small-Cell Lung Cancer With Brain Metastases From Sun Yat-Sen University Cancer Center.

PubMed

Dinglin, Xiao-Xiao; Ma, Shu-Xiang; Wang, Fang; Li, De-Lan; Liang, Jian-Zhong; Chen, Xin-Ru; Liu, Qing; Zeng, Yin-Duo; Chen, Li-Kun

2017-05-01

The current published prognosis models for brain metastases (BMs) from cancer have not addressed the issue of either newly diagnosed non-small-cell lung cancer (NSCLC) with BMs or the lung cancer genotype. We sought to build an adjusted prognosis analysis (APA) model, a new prognosis model specifically for NSCLC patients with BMs at the initial diagnosis using adjusted prognosis analysis (APA). The model was derived using data from 1158 consecutive patients, with 837 in the derivation cohort and 321 in the validation cohort. The patients had initially received a diagnosis of BMs from NSCLC at Sun Yat-Sen University Cancer Center from 1994 to 2015. The prognostic factors analyzed included patient characteristics, disease characteristics, and treatments. The APA model was built according to the numerical score derived from the hazard ratio of each independent prognostic variable. The predictive accuracy of the APA model was determined using a concordance index and was compared with current prognosis models. The results were validated using bootstrap resampling and a validation cohort. We established 2 prognostic models (APA 1 and 2) for the whole group of patients and for those with known epidermal growth factor receptor (EGFR) genotype, respectively. Six factors were independently associated with survival time: Karnofsky performance status, age, smoking history (replaced by EGFR mutation in APA 2), local treatment of intracranial metastases, EGFR-tyrosine kinase inhibitor treatment, and chemotherapy. Patients in the derivation cohort were stratified into low- (score, 0-2), moderate- (score, 3-5), and high-risk (score 6-7) groups according to the median survival time (16.6, 10.3, and 5.2 months, respectively; P < .001). The results were further confirmed in the validation cohort. Compared with recursive partition analysis and graded prognostic assessment, APA seems to be more suitable for initially diagnosed NSCLC with BMs. Copyright © 2017 Elsevier Inc. All rights reserved.

Decision curve analysis and external validation of the postoperative Karakiewicz nomogram for renal cell carcinoma based on a large single-center study cohort.

PubMed

Zastrow, Stefan; Brookman-May, Sabine; Cong, Thi Anh Phuong; Jurk, Stanislaw; von Bar, Immanuel; Novotny, Vladimir; Wirth, Manfred

2015-03-01

To predict outcome of patients with renal cell carcinoma (RCC) who undergo surgical therapy, risk models and nomograms are valuable tools. External validation on independent datasets is crucial for evaluating accuracy and generalizability of these models. The objective of the present study was to externally validate the postoperative nomogram developed by Karakiewicz et al. for prediction of cancer-specific survival. A total of 1,480 consecutive patients with a median follow-up of 82 months (IQR 46-128) were included into this analysis with 268 RCC-specific deaths. Nomogram-estimated survival probabilities were compared with survival probabilities of the actual cohort, and concordance indices were calculated. Calibration plots and decision curve analyses were used for evaluating calibration and clinical net benefit of the nomogram. Concordance between predictions of the nomogram and survival rates of the cohort was 0.911 after 12, 0.909 after 24 months and 0.896 after 60 months. Comparison of predicted probabilities and actual survival estimates with calibration plots showed an overestimation of tumor-specific survival based on nomogram predictions of high-risk patients, although calibration plots showed a reasonable calibration for probability ranges of interest. Decision curve analysis showed a positive net benefit of nomogram predictions for our patient cohort. The postoperative Karakiewicz nomogram provides a good concordance in this external cohort and is reasonably calibrated. It may overestimate tumor-specific survival in high-risk patients, which should be kept in mind when counseling patients. A positive net benefit of nomogram predictions was proven.

Novel risk score of contrast-induced nephropathy after percutaneous coronary intervention.

PubMed

Ji, Ling; Su, XiaoFeng; Qin, Wei; Mi, XuHua; Liu, Fei; Tang, XiaoHong; Li, Zi; Yang, LiChuan

2015-08-01

Contrast-induced nephropathy (CIN) post-percutaneous coronary intervention (PCI) is a major cause of acute kidney injury. In this study, we established a comprehensive risk score model to assess risk of CIN after PCI procedure, which could be easily used in a clinical environment. A total of 805 PCI patients, divided into analysis cohort (70%) and validation cohort (30%), were enrolled retrospectively in this study. Risk factors for CIN were identified using univariate analysis and multivariate logistic regression in the analysis cohort. Risk score model was developed based on multiple regression coefficients. Sensitivity and specificity of the new risk score system was validated in the validation cohort. Comparisons between the new risk score model and previous reported models were applied. The incidence of post-PCI CIN in the analysis cohort (n = 565) was 12%. Considerably high CIN incidence (50%) was observed in patients with chronic kidney disease (CKD). Age >75, body mass index (BMI) >25, myoglobin level, cardiac function level, hypoalbuminaemia, history of chronic kidney disease (CKD), Intra-aortic balloon pump (IABP) and peripheral vascular disease (PVD) were identified as independent risk factors of post-PCI CIN. A novel risk score model was established using multivariate regression coefficients, which showed highest sensitivity and specificity (0.917, 95%CI 0.877-0.957) compared with previous models. A new post-PCI CIN risk score model was developed based on a retrospective study of 805 patients. Application of this model might be helpful to predict CIN in patients undergoing PCI procedure. © 2015 Asian Pacific Society of Nephrology.

Prognostic nomogram for patients with hepatocellular carcinoma underwent adjuvant transarterial chemoembolization following curative resection

PubMed Central

Jing, Chu-Yu; Fu, Yi-Peng; Zheng, Su-Su; Yi, Yong; Shen, Hu-Jia; Huang, Jin-Long; Xu, Xin; Lin, Jia-Jia; Zhou, Jian; Fan, Jia; Ren, Zheng-Gang; Qiu, Shuang-Jian; Zhang, Bo-Heng

2017-01-01

Abstract Adjuvant transarterial chemoembolization (TACE) is a major option for postoperative hepatocellular carcinoma (HCC) patients with recurrence risk factors. However, individualized predictive models for subgroup of these patients are limited. This study aimed to develop a prognostic nomogram for patients with HCC underwent adjuvant TACE following curative resection. A cohort comprising 144 HCC patients who received adjuvant TACE following curative resection in the Zhongshan Hospital were analyzed. The nomogram was formulated based on independent prognostic indicators for overall survival (OS). The performance of the nomogram was evaluated by the concordance index (C-index), calibration curve, and decision curve analysis (DCA) and compared with the conventional staging systems. The results were validated in an independent cohort of 86 patients with the same inclusion criteria. Serum alpha-fetoprotein (AFP), hyper-sensitive C-reactive protein (hs-CRP), incomplete tumor encapsulation, and double positive staining of Cytokeratin 7 and Cytokeratin 19 on tumor cells were identified as independent predictors for OS. The C-indices of the nomogram for OS prediction in the training cohort and validation cohort were 0.787 (95%CI 0.775–0.799) and 0.714 (95%CI 0.695–0.733), respectively. In both the training and validation cohorts, the calibration plot showed good consistency between the nomogram-predicted and the observed survival. Furthermore, the established nomogram was superior to the conventional staging systems in terms of C-index and clinical net benefit on DCA. The proposed nomogram provided an accurate prediction on risk stratification for HCC patients underwent adjuvant TACE following curative resection. PMID:28296727

Patient-Level DNA Damage and Repair Pathway Profiles and Prognosis After Prostatectomy for High-Risk Prostate Cancer.

PubMed

Evans, Joseph R; Zhao, Shuang G; Chang, S Laura; Tomlins, Scott A; Erho, Nicholas; Sboner, Andrea; Schiewer, Matthew J; Spratt, Daniel E; Kothari, Vishal; Klein, Eric A; Den, Robert B; Dicker, Adam P; Karnes, R Jeffrey; Yu, Xiaochun; Nguyen, Paul L; Rubin, Mark A; de Bono, Johann; Knudsen, Karen E; Davicioni, Elai; Feng, Felix Y

2016-04-01

A substantial number of patients diagnosed with high-risk prostate cancer are at risk for metastatic progression after primary treatment. Better biomarkers are needed to identify patients at the highest risk to guide therapy intensification. To create a DNA damage and repair (DDR) pathway profiling method for use as a prognostic signature biomarker in high-risk prostate cancer. A cohort of 1090 patients with high-risk prostate cancer who underwent prostatectomy and were treated at 3 different academic institutions were divided into a training cohort (n = 545) and 3 pooled validation cohorts (n = 232, 130, and 183) assembled for case-control or case-cohort studies. Profiling of 9 DDR pathways using 17 gene sets for GSEA (Gene Set Enrichment Analysis) of high-density microarray gene expression data from formalin-fixed paraffin-embedded prostatectomy samples with median 10.3 years follow-up was performed. Prognostic signature development from DDR pathway profiles was studied, and DDR pathway gene mutation in published cohorts was analyzed. Biochemical recurrence-free, metastasis-free, and overall survival. Across the training cohort and pooled validation cohorts, 1090 men were studied; mean (SD) age at diagnosis was 65.3 (6.4) years. We found that there are distinct clusters of DDR pathways within the cohort, and DDR pathway enrichment is only weakly correlated with clinical variables such as age (Spearman ρ [ρ], range, -0.07 to 0.24), Gleason score (ρ, range, 0.03 to 0.20), prostate-specific antigen level (ρ, range, -0.07 to 0.10), while 13 of 17 DDR gene sets are strongly correlated with androgen receptor pathway enrichment (ρ, range, 0.33 to 0.82). In published cohorts, DDR pathway genes are rarely mutated. A DDR pathway profile prognostic signature built in the training cohort was significantly associated with biochemical recurrence-free, metastasis-free, and overall survival in the pooled validation cohorts independent of standard clinicopathological variables. The prognostic performance of the signature for metastasis-free survival appears to be stronger in the younger patients (HR, 1.67; 95% CI, 1.12-2.50) than in the older patients (HR, 0.77; 95% CI, 0.29-2.07) on multivariate Cox analysis. DNA damage and repair pathway profiling revealed patient-level variations and the DDR pathways are rarely affected by mutation. A DDR pathway signature showed strong prognostic performance with the long-term outcomes of metastasis-free and overall survival that may be useful for risk stratification of high-risk prostate cancer patients.

Validation of a Performance Assessment Instrument in Problem-Based Learning Tutorials Using Two Cohorts of Medical Students

ERIC Educational Resources Information Center

Lee, Ming; Wimmers, Paul F.

2016-01-01

Although problem-based learning (PBL) has been widely used in medical schools, few studies have attended to the assessment of PBL processes using validated instruments. This study examined reliability and validity for an instrument assessing PBL performance in four domains: Problem Solving, Use of Information, Group Process, and Professionalism.…

Derivation and Validation of a Biomarker-Based Clinical Algorithm to Rule Out Sepsis From Noninfectious Systemic Inflammatory Response Syndrome at Emergency Department Admission: A Multicenter Prospective Study.

PubMed

Mearelli, Filippo; Fiotti, Nicola; Giansante, Carlo; Casarsa, Chiara; Orso, Daniele; De Helmersen, Marco; Altamura, Nicola; Ruscio, Maurizio; Castello, Luigi Mario; Colonetti, Efrem; Marino, Rossella; Barbati, Giulia; Bregnocchi, Andrea; Ronco, Claudio; Lupia, Enrico; Montrucchio, Giuseppe; Muiesan, Maria Lorenza; Di Somma, Salvatore; Avanzi, Gian Carlo; Biolo, Gianni

2018-05-07

To derive and validate a predictive algorithm integrating a nomogram-based prediction of the pretest probability of infection with a panel of serum biomarkers, which could robustly differentiate sepsis/septic shock from noninfectious systemic inflammatory response syndrome. Multicenter prospective study. At emergency department admission in five University hospitals. Nine-hundred forty-seven adults in inception cohort and 185 adults in validation cohort. None. A nomogram, including age, Sequential Organ Failure Assessment score, recent antimicrobial therapy, hyperthermia, leukocytosis, and high C-reactive protein values, was built in order to take data from 716 infected patients and 120 patients with noninfectious systemic inflammatory response syndrome to predict pretest probability of infection. Then, the best combination of procalcitonin, soluble phospholypase A2 group IIA, presepsin, soluble interleukin-2 receptor α, and soluble triggering receptor expressed on myeloid cell-1 was applied in order to categorize patients as "likely" or "unlikely" to be infected. The predictive algorithm required only procalcitonin backed up with soluble phospholypase A2 group IIA determined in 29% of the patients to rule out sepsis/septic shock with a negative predictive value of 93%. In a validation cohort of 158 patients, predictive algorithm reached 100% of negative predictive value requiring biomarker measurements in 18% of the population. We have developed and validated a high-performing, reproducible, and parsimonious algorithm to assist emergency department physicians in distinguishing sepsis/septic shock from noninfectious systemic inflammatory response syndrome.

A novel accelerometer-based method to describe day-to-day exposure to potentially osteogenic vertical impacts in older adults: findings from a multi-cohort study.

PubMed

Hannam, K; Deere, K C; Hartley, A; Clark, E M; Coulson, J; Ireland, A; Moss, C; Edwards, M H; Dennison, E; Gaysin, T; Cooper, R; Wong, A; McPhee, J S; Cooper, C; Kuh, D; Tobias, J H

2017-03-01

This observational study assessed vertical impacts experienced in older adults as part of their day-to-day physical activity using accelerometry and questionnaire data. Population-based older adults experienced very limited high-impact activity. The accelerometry method utilised appeared to be valid based on comparisons between different cohorts and with self-reported activity. We aimed to validate a novel method for evaluating day-to-day higher impact weight-bearing physical activity (PA) in older adults, thought to be important in protecting against osteoporosis, by comparing results between four cohorts varying in age and activity levels, and with self-reported PA levels. Participants were from three population-based cohorts, MRC National Survey of Health and Development (NSHD), Hertfordshire Cohort Study (HCS) and Cohort for Skeletal Health in Bristol and Avon (COSHIBA), and the Master Athlete Cohort (MAC). Y-axis peaks (reflecting the vertical when an individual is upright) from a triaxial accelerometer (sampling frequency 50 Hz, range 0-16 g) worn at the waist for 7 days were classified as low (0.5-1.0 g), medium (1.0-1.5 g) or higher (≥1.5 g) impacts. There were a median of 90, 41 and 39 higher impacts/week in NSHD (age 69.5), COSHIBA (age 76.8) and HCS (age 78.5) participants, respectively (total n = 1512). In contrast, MAC participants (age 68.5) had a median of 14,322 higher impacts/week. In the three population cohorts combined, based on comparison of beta coefficients, moderate-high-impact activities as assessed by PA questionnaire were suggestive of stronger association with higher impacts from accelerometers (0.25 [0.17, 0.34]), compared with medium (0.18 [0.09, 0.27]) and low impacts (0.13 [0.07,0.19]) (beta coefficient, with 95 % CI). Likewise in MAC, reported moderate-high-impact activities showed a stronger association with higher impacts (0.26 [0.14, 0.37]), compared with medium (0.14 [0.05, 0.22]) and low impacts (0.03 [-0.02, 0.08]). Our new accelerometer method appears to provide valid measures of higher vertical impacts in older adults. Results obtained from the three population-based cohorts indicate that older adults generally experience very limited higher impact weight-bearing PA.

Alcoholism and Timing of Separation in Parents: Findings in a Midwestern Birth Cohort

PubMed Central

Waldron, Mary; Bucholz, Kathleen K.; Lynskey, Michael T.; Madden, Pamela A. F.; Heath, Andrew C.

2013-01-01

Objective: We examined history of alcoholism and occurrence and timing of separation in parents of a female twin cohort. Method: Parental separation (never-together; never-married cohabitants who separated; married who separated) was predicted from maternal and paternal alcoholism in 326 African ancestry (AA) and 1,849 European/other ancestry (EA) families. Broad (single-informant, reported in abstract) and narrow (self-report or two-informant) measures of alcoholism were compared. Results: Parental separation was more common in families with parental alcoholism: By the time twins were 18 years of age, parents had separated in only 24% of EA families in which neither parent was alcoholic, contrasted with 58% of families in which only the father was (father-only), 61% of families in which only the mother was (mother-only), and 75% in which both parents were alcoholic (two-parent); corresponding AA percentages were 59%, 71%, 82%, and 86%, respectively. Maternal alcoholism was more common in EA never-together couples (mother-only: odds ratio [OR] = 5.95; two parent: OR = 3.69). In ever-together couples, alcoholism in either parent predicted elevated risk of separation, with half of EA relationships ending in separation within 12 years of twins’ birth for father-only families, 9 years for mother-only families, and 4 years for both parents alcoholic; corresponding median survival times for AA couples were 9, 4, and 2 years, respectively. EA maternal alcoholism was especially strongly associated with separation in the early postnatal years (mother-only: birth—5 years, hazard ratio [HR] = 4.43; 6 years on, HR = 2.52; two-parent: HRs = 5.76, 3.68, respectively). Conclusions: Parental separation is a childhood environmental exposure that is more common in children of alcoholics, with timing of separation highly dependent on alcoholic parent gender. PMID:23384382

Alcoholism and timing of separation in parents: findings in a midwestern birth cohort.

PubMed

Waldron, Mary; Bucholz, Kathleen K; Lynskey, Michael T; Madden, Pamela A F; Heath, Andrew C

2013-03-01

We examined history of alcoholism and occurrence and timing of separation in parents of a female twin cohort. Parental separation (never-together; never-married cohabitants who separated; married who separated) was predicted from maternal and paternal alcoholism in 326 African ancestry (AA) and 1,849 European/ other ancestry (EA) families. Broad (single-informant, reported in abstract) and narrow (self-report or two-informant) measures of alcoholism were compared. Parental separation was more common in families with parental alcoholism: By the time twins were 18 years of age, parents had separated in only 24% of EA families in which neither parent was alcoholic, contrasted with 58% of families in which only the father was (father-only), 61% of families in which only the mother was (mother-only), and 75% in which both parents were alcoholic (two-parent); corresponding AA percentages were 59%, 71%, 82%, and 86%, respectively. Maternal alcoholism was more common in EA nevertogether couples (mother-only: odds ratio [OR] = 5.95; two parent: OR = 3.69). In ever-together couples, alcoholism in either parent predicted elevated risk of separation, with half of EA relationships ending in separation within 12 years of twins' birth for father-only families, 9 years for mother-only families, and 4 years for both parents alcoholic; corresponding median survival times for AA couples were 9, 4, and 2 years, respectively. EA maternal alcoholism was especially strongly associated with separation in the early postnatal years (mother-only: birth-5 years, hazard ratio [HR] = 4.43; 6 years on, HR = 2.52; two-parent: HRs = 5.76, 3.68, respectively). Parental separation is a childhood environmental exposure that is more common in children of alcoholics, with timing of separation highly dependent on alcoholic parent gender.

Validated Risk Score for Predicting 6-Month Mortality in Infective Endocarditis.

PubMed

Park, Lawrence P; Chu, Vivian H; Peterson, Gail; Skoutelis, Athanasios; Lejko-Zupa, Tatjana; Bouza, Emilio; Tattevin, Pierre; Habib, Gilbert; Tan, Ren; Gonzalez, Javier; Altclas, Javier; Edathodu, Jameela; Fortes, Claudio Querido; Siciliano, Rinaldo Focaccia; Pachirat, Orathai; Kanj, Souha; Wang, Andrew

2016-04-18

Host factors and complications have been associated with higher mortality in infective endocarditis (IE). We sought to develop and validate a model of clinical characteristics to predict 6-month mortality in IE. Using a large multinational prospective registry of definite IE (International Collaboration on Endocarditis [ICE]-Prospective Cohort Study [PCS], 2000-2006, n=4049), a model to predict 6-month survival was developed by Cox proportional hazards modeling with inverse probability weighting for surgery treatment and was internally validated by the bootstrapping method. This model was externally validated in an independent prospective registry (ICE-PLUS, 2008-2012, n=1197). The 6-month mortality was 971 of 4049 (24.0%) in the ICE-PCS cohort and 342 of 1197 (28.6%) in the ICE-PLUS cohort. Surgery during the index hospitalization was performed in 48.1% and 54.0% of the cohorts, respectively. In the derivation model, variables related to host factors (age, dialysis), IE characteristics (prosthetic or nosocomial IE, causative organism, left-sided valve vegetation), and IE complications (severe heart failure, stroke, paravalvular complication, and persistent bacteremia) were independently associated with 6-month mortality, and surgery was associated with a lower risk of mortality (Harrell's C statistic 0.715). In the validation model, these variables had similar hazard ratios (Harrell's C statistic 0.682), with a similar, independent benefit of surgery (hazard ratio 0.74, 95% CI 0.62-0.89). A simplified risk model was developed by weight adjustment of these variables. Six-month mortality after IE is ≈25% and is predicted by host factors, IE characteristics, and IE complications. Surgery during the index hospitalization is associated with lower mortality but is performed less frequently in the highest risk patients. A simplified risk model may be used to identify specific risk subgroups in IE. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Modeling Major Adverse Outcomes of Pediatric and Adult Patients With Congenital Heart Disease Undergoing Cardiac Catheterization: Observations From the NCDR IMPACT Registry (National Cardiovascular Data Registry Improving Pediatric and Adult Congenital Treatment).

PubMed

Jayaram, Natalie; Spertus, John A; Kennedy, Kevin F; Vincent, Robert; Martin, Gerard R; Curtis, Jeptha P; Nykanen, David; Moore, Phillip M; Bergersen, Lisa

2017-11-21

Risk standardization for adverse events after congenital cardiac catheterization is needed to equitably compare patient outcomes among different hospitals as a foundation for quality improvement. The goal of this project was to develop a risk-standardization methodology to adjust for patient characteristics when comparing major adverse outcomes in the NCDR's (National Cardiovascular Data Registry) IMPACT Registry (Improving Pediatric and Adult Congenital Treatment). Between January 2011 and March 2014, 39 725 consecutive patients within IMPACT undergoing cardiac catheterization were identified. Given the heterogeneity of interventional procedures for congenital heart disease, new procedure-type risk categories were derived with empirical data and expert opinion, as were markers of hemodynamic vulnerability. A multivariable hierarchical logistic regression model to identify patient and procedural characteristics predictive of a major adverse event or death after cardiac catheterization was derived in 70% of the cohort and validated in the remaining 30%. The rate of major adverse event or death was 7.1% and 7.2% in the derivation and validation cohorts, respectively. Six procedure-type risk categories and 6 independent indicators of hemodynamic vulnerability were identified. The final risk adjustment model included procedure-type risk category, number of hemodynamic vulnerability indicators, renal insufficiency, single-ventricle physiology, and coagulation disorder. The model had good discrimination, with a C-statistic of 0.76 and 0.75 in the derivation and validation cohorts, respectively. Model calibration in the validation cohort was excellent, with a slope of 0.97 (standard error, 0.04; P value [for difference from 1] =0.53) and an intercept of 0.007 (standard error, 0.12; P value [for difference from 0] =0.95). The creation of a validated risk-standardization model for adverse outcomes after congenital cardiac catheterization can support reporting of risk-adjusted outcomes in the IMPACT Registry as a foundation for quality improvement. © 2017 American Heart Association, Inc.

Derivation and validation of the prolonged length of stay score in acute stroke patients.

PubMed

Koton, S; Bornstein, N M; Tsabari, R; Tanne, D

2010-05-11

Length of stay (LOS) is the main cost-determining factor of hospitalization of stroke patients. Our aim was to derive and validate a simple score for the assessment of the risk of prolonged LOS for acute stroke patients in a national setting. Ischemic stroke (IS) and intracerebral hemorrhage (ICH) patients in the National Acute Stroke Israeli Surveys (NASIS 2004 and 2007) were included. Predictors of prolonged LOS (LOS > or =7 days) in the NASIS 2004 (n = 1,700) were identified with logistic regression analysis and used for the derivation of the Prolonged Length of Stay (PLOS) score. The score was validated in the NASIS 2007 (n = 1,648). Median (interquartile range) LOS was 6 (3-10) days in the derivation cohort (42.3% prolonged LOS) and 5 (3-8) in the validation cohort (35.7% prolonged LOS). The derivation cohort included 54.8% men, 90.8% IS and 9.2% ICH, with a mean (SD) age of 71.2 (12.5) years. Stroke severity was the strongest multivariable predictor of prolonged LOS: odds ratio (95% confidence interval [CI]) increased from 2.6 (2.0-3.3) for NIH Stroke Scale score (NIHSS) 6-10 to 4.9 (3.0-8.0) for NIHSS 16-20, compared with NIHSS < or =5. Stroke severity and type, decreased level of consciousness on admission, history of congestive heart failure, and prior atrial fibrillation were used for the derivation of the PLOS score (c statistics 0.692, 95% CI 0.666-0.718). The score performed similarly well in the validation cohort (c statistics 0.680, 95% CI 0.653-0.707). A simple prolonged length of stay score, based on available baseline information, may be useful for tailoring policy aimed at better use of resources and optimal discharge planning of acute stroke patients.

Model to Determine Risk of Pancreatic Cancer in Patients with New-onset Diabetes.

PubMed

Sharma, Ayush; Kandlakunta, Harika; Singh Nagpal, Sajan Jiv; Ziding, Feng; Hoos, William; Petersen, Gloria M; Chari, Suresh T

2018-05-15

Of subjects with new-onset diabetes (based on glycemia) over the age of 50 years, approximately 1% are diagnosed with pancreatic cancer within 3 years. We aimed to develop and validate a model to determine risk of pancreatic cancer in individuals with new-onset diabetes. We retrospectively collected data from 4 independent, non-overlapping cohorts of patients (n=1561) with new-onset diabetes (based on glycemia; data collected at date of diagnosis and 12 months before) in the Rochester Epidemiology Project, from January 1, 2000 through December 31, 2015 to create our model. The model weighed scores for the 3 factors identified in the discovery cohort to be most strongly associated with pancreatic cancer (64 patients with pancreatic cancer and 192 with type-2 diabetes): change in weight, change in blood glucose, and age at onset of diabetes. We called our model enriching new-onset diabetes for pancreatic cancer (END-PAC). We validated the locked-down model and cutoff score in an independent population-based cohort of 1096 patients with diabetes; of these 9 patients (.82%) had pancreatic within 3 years of meeting the criteria for new-onset diabetes. In the discovery cohort the END-PAC model identified patients who developed pancreatic cancer within 3 years of onset of diabetes with an area under the receiver operating characteristic curve value of 0.87; a score of >3 identified patients who developed pancreatic cancer with 80% sensitivity and specificity. In the validation cohort, a score of >3 identified 7/9 patients with pancreatic cancer (78%), with 85% specificity; the prevalence of pancreatic cancer in subjects with score of >3 (3.6%) was 4.4-fold more than in patients with new-onset diabetes. A high END-PAC score in subjects who did not have pancreatic cancer (false positives) was often due to such factors as recent steroid use or different malignancy. An END-PAC score <0 (in 49% of subjects) meant that patients had an extremely low-risk for pancreatic cancer. An END-PAC score >3 identified 75% of subjects in the discovery cohort >6 months before a diagnosis of pancreatic cancer. Based on change in weight, change in blood glucose, and age at onset of diabetes, we developed and validated a model to determine risk of pancreatic cancer in patients with new-onset diabetes, based on glycemia (the END-PAC model). An independent, prospective study is needed to further validate this model, which could contribute to early detection of pancreatic cancer. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

Development and Validation of a Novel Pediatric Appendicitis Risk Calculator (pARC).

PubMed

Kharbanda, Anupam B; Vazquez-Benitez, Gabriela; Ballard, Dustin W; Vinson, David R; Chettipally, Uli K; Kene, Mamata V; Dehmer, Steven P; Bachur, Richard G; Dayan, Peter S; Kuppermann, Nathan; O'Connor, Patrick J; Kharbanda, Elyse O

2018-04-01

We sought to develop and validate a clinical calculator that can be used to quantify risk for appendicitis on a continuous scale for patients with acute abdominal pain. The pediatric appendicitis risk calculator (pARC) was developed and validated through secondary analyses of 3 distinct cohorts. The derivation sample included visits to 9 pediatric emergency departments between March 2009 and April 2010. The validation sample included visits to a single pediatric emergency department from 2003 to 2004 and 2013 to 2015. Variables evaluated were as follows: age, sex, temperature, nausea and/or vomiting, pain duration, pain location, pain with walking, pain migration, guarding, white blood cell count, and absolute neutrophil count. We used stepwise regression to develop and select the best model. Test performance of the pARC was compared with the Pediatric Appendicitis Score (PAS). The derivation sample included 2423 children, 40% of whom had appendicitis. The validation sample included 1426 children, 35% of whom had appendicitis. The final pARC model included the following variables: sex, age, duration of pain, guarding, pain migration, maximal tenderness in the right-lower quadrant, and absolute neutrophil count. In the validation sample, the pARC exhibited near perfect calibration and a high degree of discrimination (area under the curve: 0.85; 95% confidence interval: 0.83 to 0.87) and outperformed the PAS (area under the curve: 0.77; 95% confidence interval: 0.75 to 0.80). By using the pARC, almost half of patients in the validation cohort could be accurately classified as at <15% risk or ≥85% risk for appendicitis, whereas only 23% would be identified as having a comparable PAS of <3 or >8. In our validation cohort of patients with acute abdominal pain, the pARC accurately quantified risk for appendicitis. Copyright © 2018 by the American Academy of Pediatrics.

Nordic registry-based cohort studies: Possibilities and pitfalls when combining Nordic registry data.

PubMed

Maret-Ouda, John; Tao, Wenjing; Wahlin, Karl; Lagergren, Jesper

2017-07-01

All five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden) have nationwide registries with similar data structure and validity, as well as personal identity numbers enabling linkage between registries. These resources provide opportunities for medical research that is based on large registry-based cohort studies with long and complete follow-up. This review describes practical aspects, opportunities and challenges encountered when setting up all-Nordic registry-based cohort studies. Relevant articles describing registries often used for medical research in the Nordic countries were retrieved. Further, our experiences of conducting this type of study, including planning, acquiring permissions, data retrieval and data cleaning and handling, and the possibilities and challenges we have encountered are described. Combining data from the Nordic countries makes it possible to create large and powerful cohorts. The main challenges include obtaining all permissions within each country, usually in the local language, and retrieving the data. These challenges emphasise the importance of having experienced collaborators within each country. Following the acquisition of data, data management requires the understanding of the differences between the variables to be used in the various countries. A concern is the long time required between initiation and completion. Nationwide Nordic registries can be combined into cohorts with high validity and statistical power, but the considerable expertise, workload and time required to complete such cohorts should not be underestimated.

The effect of two lottery-style incentives on response rates to postal questionnaires in a prospective cohort study in preschool children at high risk of asthma: a randomized trial.

PubMed

van der Mark, Lonneke B; van Wonderen, Karina E; Mohrs, Jacob; Bindels, Patrick Je; Puhan, Milo A; Ter Riet, Gerben

2012-12-18

In research with long-term follow-up and repeated measurements, quick and complete response to questionnaires helps ensure a study's validity, precision and efficiency. Evidence on the effect of non-monetary incentives on response rates in observational longitudinal research is scarce. To study the impact of two strategies to enhance completeness and efficiency in observational cohort studies with follow-up durations of around 2 years. METHOD AND INTERVENTION: In a factorial design, 771 children between 2 and 5 years old and their parents participating in a prospective cohort study were randomized to three intervention groups and a control group. Three types of lotteries were run: (i) daytrip tickets for the whole family to a popular amusement park if they returned all postal questionnaires, (ii) €12.50-worth gift vouchers for sending back the questionnaire on time after each questionnaire round and (iii) a combination of (i) and (ii). Primary outcome was the proportion of participants who returned all questionnaires without any reminder. Secondary outcomes were '100% returned with or without reminder', 'probability of 100% non-response', 'probability of withdrawal', 'proportion of returned questionnaires' and 'overall number of reminders sent'. After testing for interaction between the two lottery interventions, the two trials were analysed separately. We calculated risk differences (RD) and numbers needed to "treat" and their 95% confidence intervals. Daytrip nor voucher intervention had an effect on the proportion of participants who returned all questionnaires (RD -0.01; 95% CI-0.07 - 0.06) and (RD 0.02; 95% CI-0.50 - 0.08), respectively. No effects were found on the secondary outcomes. Our findings do not support the idea that lottery-style incentives lead to more complete response to postal questionnaires in observational cohort studies with repeated data collection and follow-up durations of around 2 years.

Troponin-only Manchester Acute Coronary Syndromes (T-MACS) decision aid: single biomarker re-derivation and external validation in three cohorts

PubMed Central

Body, Richard; Sperrin, Matthew; Lewis, Philip S; Burrows, Gillian; Carley, Simon; McDowell, Garry; Buchan, Iain; Greaves, Kim; Mackway-Jones, Kevin

2017-01-01

Background The original Manchester Acute Coronary Syndromes model (MACS) ‘rules in’ and ‘rules out’ acute coronary syndromes (ACS) using high sensitivity cardiac troponin T (hs-cTnT) and heart-type fatty acid binding protein (H-FABP) measured at admission. The latter is not always available. We aimed to refine and validate MACS as Troponin-only Manchester Acute Coronary Syndromes (T-MACS), cutting down the biomarkers to just hs-cTnT. Methods We present secondary analyses from four prospective diagnostic cohort studies including patients presenting to the ED with suspected ACS. Data were collected and hs-cTnT measured on arrival. The primary outcome was ACS, defined as prevalent acute myocardial infarction (AMI) or incident death, AMI or coronary revascularisation within 30 days. T-MACS was built in one cohort (derivation set) and validated in three external cohorts (validation set). Results At the ‘rule out’ threshold, in the derivation set (n=703), T-MACS had 99.3% (95% CI 97.3% to 99.9%) negative predictive value (NPV) and 98.7% (95.3%–99.8%) sensitivity for ACS, ‘ruling out’ 37.7% patients (specificity 47.6%, positive predictive value (PPV) 34.0%). In the validation set (n=1459), T-MACS had 99.3% (98.3%–99.8%) NPV and 98.1% (95.2%–99.5%) sensitivity, ‘ruling out’ 40.4% (n=590) patients (specificity 47.0%, PPV 23.9%). T-MACS would ‘rule in’ 10.1% and 4.7% patients in the respective sets, of which 100.0% and 91.3% had ACS. C-statistics for the original and refined rules were similar (T-MACS 0.91 vs MACS 0.90 on validation). Conclusions T-MACS could ‘rule out’ ACS in 40% of patients, while ‘ruling in’ 5% at highest risk using a single hs-cTnT measurement on arrival. As a clinical decision aid, T-MACS could therefore help to conserve healthcare resources. PMID:27565197

Development and External Validation of the Korean Prostate Cancer Risk Calculator for High-Grade Prostate Cancer: Comparison with Two Western Risk Calculators in an Asian Cohort

PubMed Central

Yoon, Sungroh; Park, Man Sik; Choi, Hoon; Bae, Jae Hyun; Moon, Du Geon; Hong, Sung Kyu; Lee, Sang Eun; Park, Chanwang

2017-01-01

Purpose We developed the Korean Prostate Cancer Risk Calculator for High-Grade Prostate Cancer (KPCRC-HG) that predicts the probability of prostate cancer (PC) of Gleason score 7 or higher at the initial prostate biopsy in a Korean cohort (http://acl.snu.ac.kr/PCRC/RISC/). In addition, KPCRC-HG was validated and compared with internet-based Western risk calculators in a validation cohort. Materials and Methods Using a logistic regression model, KPCRC-HG was developed based on the data from 602 previously unscreened Korean men who underwent initial prostate biopsies. Using 2,313 cases in a validation cohort, KPCRC-HG was compared with the European Randomized Study of Screening for PC Risk Calculator for high-grade cancer (ERSPCRC-HG) and the Prostate Cancer Prevention Trial Risk Calculator 2.0 for high-grade cancer (PCPTRC-HG). The predictive accuracy was assessed using the area under the receiver operating characteristic curve (AUC) and calibration plots. Results PC was detected in 172 (28.6%) men, 120 (19.9%) of whom had PC of Gleason score 7 or higher. Independent predictors included prostate-specific antigen levels, digital rectal examination findings, transrectal ultrasound findings, and prostate volume. The AUC of the KPCRC-HG (0.84) was higher than that of the PCPTRC-HG (0.79, p<0.001) but not different from that of the ERSPCRC-HG (0.83) on external validation. Calibration plots also revealed better performance of KPCRC-HG and ERSPCRC-HG than that of PCPTRC-HG on external validation. At a cut-off of 5% for KPCRC-HG, 253 of the 2,313 men (11%) would not have been biopsied, and 14 of the 614 PC cases with Gleason score 7 or higher (2%) would not have been diagnosed. Conclusions KPCRC-HG is the first web-based high-grade prostate cancer prediction model in Korea. It had higher predictive accuracy than PCPTRC-HG in a Korean population and showed similar performance with ERSPCRC-HG in a Korean population. This prediction model could help avoid unnecessary biopsy and reduce overdiagnosis and overtreatment in clinical settings. PMID:28046017

Development and External Validation of the Korean Prostate Cancer Risk Calculator for High-Grade Prostate Cancer: Comparison with Two Western Risk Calculators in an Asian Cohort.

PubMed

Park, Jae Young; Yoon, Sungroh; Park, Man Sik; Choi, Hoon; Bae, Jae Hyun; Moon, Du Geon; Hong, Sung Kyu; Lee, Sang Eun; Park, Chanwang; Byun, Seok-Soo

2017-01-01

We developed the Korean Prostate Cancer Risk Calculator for High-Grade Prostate Cancer (KPCRC-HG) that predicts the probability of prostate cancer (PC) of Gleason score 7 or higher at the initial prostate biopsy in a Korean cohort (http://acl.snu.ac.kr/PCRC/RISC/). In addition, KPCRC-HG was validated and compared with internet-based Western risk calculators in a validation cohort. Using a logistic regression model, KPCRC-HG was developed based on the data from 602 previously unscreened Korean men who underwent initial prostate biopsies. Using 2,313 cases in a validation cohort, KPCRC-HG was compared with the European Randomized Study of Screening for PC Risk Calculator for high-grade cancer (ERSPCRC-HG) and the Prostate Cancer Prevention Trial Risk Calculator 2.0 for high-grade cancer (PCPTRC-HG). The predictive accuracy was assessed using the area under the receiver operating characteristic curve (AUC) and calibration plots. PC was detected in 172 (28.6%) men, 120 (19.9%) of whom had PC of Gleason score 7 or higher. Independent predictors included prostate-specific antigen levels, digital rectal examination findings, transrectal ultrasound findings, and prostate volume. The AUC of the KPCRC-HG (0.84) was higher than that of the PCPTRC-HG (0.79, p<0.001) but not different from that of the ERSPCRC-HG (0.83) on external validation. Calibration plots also revealed better performance of KPCRC-HG and ERSPCRC-HG than that of PCPTRC-HG on external validation. At a cut-off of 5% for KPCRC-HG, 253 of the 2,313 men (11%) would not have been biopsied, and 14 of the 614 PC cases with Gleason score 7 or higher (2%) would not have been diagnosed. KPCRC-HG is the first web-based high-grade prostate cancer prediction model in Korea. It had higher predictive accuracy than PCPTRC-HG in a Korean population and showed similar performance with ERSPCRC-HG in a Korean population. This prediction model could help avoid unnecessary biopsy and reduce overdiagnosis and overtreatment in clinical settings.

Development and Validation of a Chronic Pancreatitis Prognosis Score in 2 Independent Cohorts.

PubMed

Beyer, Georg; Mahajan, Ujjwal M; Budde, Christoph; Bulla, Thomas J; Kohlmann, Thomas; Kuhlmann, Louise; Schütte, Kerstin; Aghdassi, Ali A; Weber, Eckhard; Weiss, F Ulrich; Drewes, Asbjørn M; Olesen, Søren S; Lerch, Markus M; Mayerle, Julia

2017-12-01

The clinical course of chronic pancreatitis is unpredictable. There is no model to assess disease severity or progression or predict patient outcomes. We performed a prospective study of 91 patients with chronic pancreatitis; data were collected from patients seen at academic centers in Europe from January 2011 through April 2014. We analyzed correlations between clinical, laboratory, and imaging data with number of hospital readmissions and in-hospital days over the next 12 months; the parameters with the highest degree of correlation were used to develop a 3-stage chronic pancreatitis prognosis score (COPPS). The predictive strength was validated in 129 independent subjects identified from 2 prospective databases. The mean number of hospital admissions was 1.9 (95% confidence interval [CI], 1.39-2.44) and 15.2 for hospital days (95% CI, 10.76-19.71) for the development cohort and 10.9 for the validation cohort (95% CI, 7.54-14.30) (P = .08). Based on bivariate correlations, pain (numeric rating scale), level of glycated hemoglobin A1c, level of C-reactive protein, body mass index, and platelet count were used to develop the COPPS system. The patients' median COPPS was 8.9 points (range, 5-14). The system accurately discriminated stages of disease severity (low to high): A (5-6 points), B (7-9), and C (10-15). In Pearson correlation analysis of the development cohort, the COPPS correlated with hospital admissions (0.39; P < .01) and number of hospital days (0.33; P < .01). The correlation was validated in the validation set (Pearson correlation values of 0.36 and 0.44; P < .01). COPPS did not correlate with results from the Cambridge classification system. We developed and validated an easy to use dynamic multivariate scoring system, similar to the Child-Pugh-Score for liver cirrhosis. The COPPS allows objective monitoring of patients with chronic pancreatitis, determining risk for readmission to hospital and potential length of hospital stay. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Validation of the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) pulmonary hypertension prediction model in a unique population and utility in the prediction of long-term survival.

PubMed

Cogswell, Rebecca; Kobashigawa, Erin; McGlothlin, Dana; Shaw, Robin; De Marco, Teresa

2012-11-01

The Registry to Evaluate Early and Long-Term Pulmonary Arterial (PAH) Hypertension Disease Management (REVEAL) model was designed to predict 1-year survival in patients with PAH. Multivariate prediction models need to be evaluated in cohorts distinct from the derivation set to determine external validity. In addition, limited data exist on the utility of this model in the prediction of long-term survival. REVEAL model performance was assessed to predict 1-year and 5-year outcomes, defined as survival or composite survival or freedom from lung transplant, in 140 patients with PAH. The validation cohort had a higher proportion of human immunodeficiency virus (7.9% vs 1.9%, p < 0.0001), methamphetamine use (19.3% vs 4.9%, p < 0.0001), and portal hypertension PAH (16.4% vs 5.1%, p < 0.0001) compared with the development cohort. The C-index of the model to predict survival was 0.765 at 1 year and 0.712 at 5 years of follow-up. The C-index of the model to predict composite survival or freedom from lung transplant was 0.805 and 0.724 at 1 and 5 years of follow-up, respectively. Prediction by the model, however, was weakest among patients with intermediate-risk predicted survival. The REVEAL model had adequate discrimination to predict 1-year survival in this small but clinically distinct validation cohort. Although the model also had predictive ability out to 5 years, prediction was limited among patients of intermediate risk, suggesting our prediction methods can still be improved. Copyright © 2012. Published by Elsevier Inc.

Predicting prolonged dose titration in patients starting warfarin.

PubMed

Finkelman, Brian S; French, Benjamin; Bershaw, Luanne; Brensinger, Colleen M; Streiff, Michael B; Epstein, Andrew E; Kimmel, Stephen E

2016-11-01

Patients initiating warfarin therapy generally experience a dose-titration period of weeks to months, during which time they are at higher risk of both thromboembolic and bleeding events. Accurate prediction of prolonged dose titration could help clinicians determine which patients might be better treated by alternative anticoagulants that, while more costly, do not require dose titration. A prediction model was derived in a prospective cohort of patients starting warfarin (n = 390), using Cox regression, and validated in an external cohort (n = 663) from a later time period. Prolonged dose titration was defined as a dose-titration period >12 weeks. Predictor variables were selected using a modified best subsets algorithm, using leave-one-out cross-validation to reduce overfitting. The final model had five variables: warfarin indication, insurance status, number of doctor's visits in the previous year, smoking status, and heart failure. The area under the ROC curve (AUC) in the derivation cohort was 0.66 (95%CI 0.60, 0.74) using leave-one-out cross-validation, but only 0.59 (95%CI 0.54, 0.64) in the external validation cohort, and varied across clinics. Including genetic factors in the model did not improve the area under the ROC curve (0.59; 95%CI 0.54, 0.65). Relative utility curves indicated that the model was unlikely to provide a clinically meaningful benefit compared with no prediction. Our results suggest that prolonged dose titration cannot be accurately predicted in warfarin patients using traditional clinical, social, and genetic predictors, and that accurate prediction will need to accommodate heterogeneities across clinical sites and over time. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

A Novel Model for Predicting Incident Moderate to Severe Anemia and Iron Deficiency in Patients with Newly Diagnosed Ulcerative Colitis.

PubMed

Khan, Nabeel; Patel, Dhruvan; Shah, Yash; Yang, Yu-Xiao

2017-05-01

Anemia and iron deficiency are common complications of ulcerative colitis (UC). We aimed to develop and internally validate a prediction model for the incidence of moderate to severe anemia and iron deficiency anemia (IDA) in newly diagnosed patients with UC. Multivariable logistic regression was performed among a nationwide cohort of patients who were newly diagnosed with UC in the VA health-care system. Model development was performed in a random two-third of the total cohort and then validated in the remaining one-third of the cohort. As candidate predictors, we examined routinely available data at the time of UC diagnosis including demographics, medications, laboratory results, and endoscopy findings. A total of 789 patients met the inclusion criteria. For the outcome of moderate to severe anemia, age, albumin level and mild anemia at UC diagnosis were predictors selected for the model. The AUC for this model was 0.69 (95% CI 0.64-0.74). For the outcome of moderate to severe anemia with evidence of iron deficiency, the predictors included African-American ethnicity, mild anemia, age, and albumin level at UC diagnosis. The AUC was 0.76, (95% CI 0.69-0.82). Calibration was consistently good in all models (Hosmer-Lemeshow goodness of fit p > 0.05). The models performed similarly in the internal validation cohort. We developed and internally validated a prognostic model for predicting the risk of moderate to severe anemia and IDA among newly diagnosed patients with UC. This will help identify patients at high risk of these complications, who could benefit from surveillance and preventive measures.

Validation of a screening tool for the rapid and reliable detection of CGG trinucleotide repeat expansions in FMR1.

PubMed

Basehore, Monica J; Marlowe, Natalia M; Jones, Julie R; Behlendorf, Deborah E; Laver, Thomas A; Friez, Michael J

2012-06-01

Most individuals with intellectual disability and/or autism are tested for Fragile X syndrome at some point in their lifetime. Greater than 99% of individuals with Fragile X have an expanded CGG trinucleotide repeat motif in the promoter region of the FMR1 gene, and diagnostic testing involves determining the size of the CGG repeat as well as methylation status when an expansion is present. Using a previously described triplet repeat-primed polymerase chain reaction, we have performed additional validation studies using two cohorts with previous diagnostic testing results available for comparison purposes. The first cohort (n=88) consisted of both males and females and had a high percentage of abnormal samples, while the second cohort (n=624) consisted of only females and was not enriched for expansion mutations. Data from each cohort were completely concordant with the results previously obtained during the course of diagnostic testing. This study further demonstrates the utility of using laboratory-developed triplet repeat-primed FMR1 testing in a clinical setting.

Validity of the SAT® for Predicting First-Year Grades: 2009 SAT Validity Sample. Statistical Report No. 2012-2

ERIC Educational Resources Information Center

Patterson, Brian F.; Mattern, Krista D.

2009-01-01

In an effort to continuously monitor the validity of the SAT for predicting first-year college grades, the College Board has continued its multi-year effort to recruit four-year colleges and universities (henceforth, "institutions") to provide data on the cohorts of first-time, first-year students entering in the fall semester beginning…

A biomarker-based risk score to predict death in patients with atrial fibrillation: the ABC (age, biomarkers, clinical history) death risk score

PubMed Central

Hijazi, Ziad; Oldgren, Jonas; Lindbäck, Johan; Alexander, John H; Connolly, Stuart J; Eikelboom, John W; Ezekowitz, Michael D; Held, Claes; Hylek, Elaine M; Lopes, Renato D; Yusuf, Salim; Granger, Christopher B; Siegbahn, Agneta; Wallentin, Lars

2018-01-01

Abstract Aims In atrial fibrillation (AF), mortality remains high despite effective anticoagulation. A model predicting the risk of death in these patients is currently not available. We developed and validated a risk score for death in anticoagulated patients with AF including both clinical information and biomarkers. Methods and results The new risk score was developed and internally validated in 14 611 patients with AF randomized to apixaban vs. warfarin for a median of 1.9 years. External validation was performed in 8548 patients with AF randomized to dabigatran vs. warfarin for 2.0 years. Biomarker samples were obtained at study entry. Variables significantly contributing to the prediction of all-cause mortality were assessed by Cox-regression. Each variable obtained a weight proportional to the model coefficients. There were 1047 all-cause deaths in the derivation and 594 in the validation cohort. The most important predictors of death were N-terminal pro B-type natriuretic peptide, troponin-T, growth differentiation factor-15, age, and heart failure, and these were included in the ABC (Age, Biomarkers, Clinical history)-death risk score. The score was well-calibrated and yielded higher c-indices than a model based on all clinical variables in both the derivation (0.74 vs. 0.68) and validation cohorts (0.74 vs. 0.67). The reduction in mortality with apixaban was most pronounced in patients with a high ABC-death score. Conclusion A new biomarker-based score for predicting risk of death in anticoagulated AF patients was developed, internally and externally validated, and well-calibrated in two large cohorts. The ABC-death risk score performed well and may contribute to overall risk assessment in AF. ClinicalTrials.gov identifier NCT00412984 and NCT00262600 PMID:29069359

Sewer solids separation by sedimentation--the problem of modeling, validation and transferability.

PubMed

Kutzner, R; Brombach, H; Geiger, W F

2007-01-01

Sedimentation of sewer solids in tanks, ponds and similar devices is the most relevant process for the treatment of stormwater and combined sewer overflows in urban collecting systems. In the past a lot of research work was done to develop deterministic models for the description of this separation process. But these modern models are not commonly accepted in Germany until today. Water Authorities are sceptical with regard to model validation and transferability. Within this paper it is checked whether this scepticism is reasonable. A framework-proposal for the validation of mathematical models with zero or one dimensional spatial resolution for particle separation processes for stormwater and combined sewer overflow treatment is presented. This proposal was applied to publications of repute on sewer solids separation by sedimentation. The result was that none of the investigated models described in literature passed the validation entirely. There is an urgent need for future research in sewer solids sedimentation and remobilization!

The Modified Abbreviated Math Anxiety Scale: A Valid and Reliable Instrument for Use with Children.

PubMed

Carey, Emma; Hill, Francesca; Devine, Amy; Szűcs, Dénes

2017-01-01

Mathematics anxiety (MA) can be observed in children from primary school age into the teenage years and adulthood, but many MA rating scales are only suitable for use with adults or older adolescents. We have adapted one such rating scale, the Abbreviated Math Anxiety Scale (AMAS), to be used with British children aged 8-13. In this study, we assess the scale's reliability, factor structure, and divergent validity. The modified AMAS (mAMAS) was administered to a very large ( n = 1746) cohort of British children and adolescents. This large sample size meant that as well as conducting confirmatory factor analysis on the scale itself, we were also able to split the sample to conduct exploratory and confirmatory factor analysis of items from the mAMAS alongside items from child test anxiety and general anxiety rating scales. Factor analysis of the mAMAS confirmed that it has the same underlying factor structure as the original AMAS, with subscales measuring anxiety about Learning and Evaluation in math. Furthermore, both exploratory and confirmatory factor analysis of the mAMAS alongside scales measuring test anxiety and general anxiety showed that mAMAS items cluster onto one factor (perceived to represent MA). The mAMAS provides a valid and reliable scale for measuring MA in children and adolescents, from a younger age than is possible with the original AMAS. Results from this study also suggest that MA is truly a unique construct, separate from both test anxiety and general anxiety, even in childhood.

Multinational Assessment of Accuracy of Equations for Predicting Risk of Kidney Failure: A Meta-analysis.

PubMed

Tangri, Navdeep; Grams, Morgan E; Levey, Andrew S; Coresh, Josef; Appel, Lawrence J; Astor, Brad C; Chodick, Gabriel; Collins, Allan J; Djurdjev, Ognjenka; Elley, C Raina; Evans, Marie; Garg, Amit X; Hallan, Stein I; Inker, Lesley A; Ito, Sadayoshi; Jee, Sun Ha; Kovesdy, Csaba P; Kronenberg, Florian; Heerspink, Hiddo J Lambers; Marks, Angharad; Nadkarni, Girish N; Navaneethan, Sankar D; Nelson, Robert G; Titze, Stephanie; Sarnak, Mark J; Stengel, Benedicte; Woodward, Mark; Iseki, Kunitoshi

2016-01-12

Identifying patients at risk of chronic kidney disease (CKD) progression may facilitate more optimal nephrology care. Kidney failure risk equations, including such factors as age, sex, estimated glomerular filtration rate, and calcium and phosphate concentrations, were previously developed and validated in 2 Canadian cohorts. Validation in other regions and in CKD populations not under the care of a nephrologist is needed. To evaluate the accuracy of the risk equations across different geographic regions and patient populations through individual participant data meta-analysis. Thirty-one cohorts, including 721,357 participants with CKD stages 3 to 5 in more than 30 countries spanning 4 continents, were studied. These cohorts collected data from 1982 through 2014. Cohorts participating in the CKD Prognosis Consortium with data on end-stage renal disease. Data were obtained and statistical analyses were performed between July 2012 and June 2015. Using the risk factors from the original risk equations, cohort-specific hazard ratios were estimated and combined using random-effects meta-analysis to form new pooled kidney failure risk equations. Original and pooled kidney failure risk equation performance was compared, and the need for regional calibration factors was assessed. Kidney failure (treatment by dialysis or kidney transplant). During a median follow-up of 4 years of 721,357 participants with CKD, 23,829 cases kidney failure were observed. The original risk equations achieved excellent discrimination (ability to differentiate those who developed kidney failure from those who did not) across all cohorts (overall C statistic, 0.90; 95% CI, 0.89-0.92 at 2 years; C statistic at 5 years, 0.88; 95% CI, 0.86-0.90); discrimination in subgroups by age, race, and diabetes status was similar. There was no improvement with the pooled equations. Calibration (the difference between observed and predicted risk) was adequate in North American cohorts, but the original risk equations overestimated risk in some non-North American cohorts. Addition of a calibration factor that lowered the baseline risk by 32.9% at 2 years and 16.5% at 5 years improved the calibration in 12 of 15 and 10 of 13 non-North American cohorts at 2 and 5 years, respectively (P = .04 and P = .02). Kidney failure risk equations developed in a Canadian population showed high discrimination and adequate calibration when validated in 31 multinational cohorts. However, in some regions the addition of a calibration factor may be necessary.

Signatures of subacute potentially catastrophic illness in the intensive care unit: model development and validation

PubMed Central

Moss, Travis J.; Lake, Douglas E.; Forrest Calland, J; Enfield, Kyle B; Delos, John B.; Fairchild, Karen D.; Randall Moorman, J.

2016-01-01

Objective Patients in intensive care units are susceptible to subacute, potentially catastrophic illnesses such as respiratory failure, sepsis, and hemorrhage that present as severe derangements of vital signs. More subtle physiologic signatures may be present before clinical deterioration, when treatment might be more effective. We performed multivariate statistical analyses of bedside physiologic monitoring data to identify such early, subclinical signatures of incipient life-threatening illness. Design We report a study of model development and validation of a retrospective observational cohort using resampling (TRIPOD Type 1b internal validation), and a study of model validation using separate data (Type 2b internal/external validation). Setting University of Virginia Health System (Charlottesville), a tertiary-care, academic medical center. Patients Critically ill patients consecutively admitted between January 2009 and June 2015 to either the neonatal, surgical/trauma/burn, or medical intensive care units with available physiologic monitoring data. Interventions None. Measurements and Main Results We analyzed 146 patient-years of vital sign and electrocardiography waveform time series from the bedside monitors of 9,232 ICU admissions. Calculations from 30-minute windows of the physiologic monitoring data were made every 15 minutes. Clinicians identified 1,206 episodes of respiratory failure leading to urgent, unplanned intubation, sepsis, or hemorrhage leading to multi-unit transfusions from systematic, individual chart reviews. Multivariate models to predict events up to 24 hours prior had internally-validated C-statistics of 0.61 to 0.88. In adults, physiologic signatures of respiratory failure and hemorrhage were distinct from each other but externally consistent across ICUs. Sepsis, on the other hand, demonstrated less distinct and inconsistent signatures. Physiologic signatures of all neonatal illnesses were similar. Conclusions Subacute, potentially catastrophic illnesses in 3 diverse ICU populations have physiologic signatures that are detectable in the hours preceding clinical detection and intervention. Detection of such signatures can draw attention to patients at highest risk, potentially enabling earlier intervention and better outcomes. PMID:27452809

Signatures of Subacute Potentially Catastrophic Illness in the ICU: Model Development and Validation.

PubMed

Moss, Travis J; Lake, Douglas E; Calland, J Forrest; Enfield, Kyle B; Delos, John B; Fairchild, Karen D; Moorman, J Randall

2016-09-01

Patients in ICUs are susceptible to subacute potentially catastrophic illnesses such as respiratory failure, sepsis, and hemorrhage that present as severe derangements of vital signs. More subtle physiologic signatures may be present before clinical deterioration, when treatment might be more effective. We performed multivariate statistical analyses of bedside physiologic monitoring data to identify such early subclinical signatures of incipient life-threatening illness. We report a study of model development and validation of a retrospective observational cohort using resampling (Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis type 1b internal validation) and a study of model validation using separate data (type 2b internal/external validation). University of Virginia Health System (Charlottesville), a tertiary-care, academic medical center. Critically ill patients consecutively admitted between January 2009 and June 2015 to either the neonatal, surgical/trauma/burn, or medical ICUs with available physiologic monitoring data. None. We analyzed 146 patient-years of vital sign and electrocardiography waveform time series from the bedside monitors of 9,232 ICU admissions. Calculations from 30-minute windows of the physiologic monitoring data were made every 15 minutes. Clinicians identified 1,206 episodes of respiratory failure leading to urgent unplanned intubation, sepsis, or hemorrhage leading to multi-unit transfusions from systematic individual chart reviews. Multivariate models to predict events up to 24 hours prior had internally validated C-statistics of 0.61-0.88. In adults, physiologic signatures of respiratory failure and hemorrhage were distinct from each other but externally consistent across ICUs. Sepsis, on the other hand, demonstrated less distinct and inconsistent signatures. Physiologic signatures of all neonatal illnesses were similar. Subacute potentially catastrophic illnesses in three diverse ICU populations have physiologic signatures that are detectable in the hours preceding clinical detection and intervention. Detection of such signatures can draw attention to patients at highest risk, potentially enabling earlier intervention and better outcomes.

Development and Validation of a Scoring System to Predict Outcomes of Vedolizumab Treatment in Patients with Crohn's Disease.

PubMed

Dulai, Parambir S; Boland, Brigid S; Singh, Siddharth; Chaudrey, Khadija; Koliani-Pace, Jenna L; Kochhar, Gursimran; Parikh, Malav P; Shmidt, Eugenia; Hartke, Justin; Chilukuri, Prianka; Meserve, Joseph; Whitehead, Diana; Hirten, Robert; Winters, Adam C; Katta, Leah G; Peerani, Farhad; Narula, Neeraj; Sultan, Keith; Swaminath, Arun; Bohm, Matthew; Lukin, Dana; Hudesman, David; Chang, John T; Rivera-Nieves, Jesus; Jairath, Vipul; Zou, G Y; Feagan, Brian G; Shen, Bo; Siegel, Corey A; Loftus, Edward V; Kane, Sunanda; Sands, Bruce E; Colombel, Jean-Frederic; Sandborn, William J; Lasch, Karen; Cao, Charlie

2018-05-29

As more treatment options for inflammatory bowel diseases become available, it is important to identify patients most likely to respond to different therapies. We created and validated a scoring system to identify patients with Crohn's disease (CD) who respond to vedolizumab. We collected data from GEMINI 2 phase 3 trial of patients with active CD treated with vedolizumab for 26 weeks (n=814) and performed logistic regression analysis to identify factors associated with clinical, steroid-free, and durable remission (derivation set). We used these data to develop a clinical decision support tool, which we validated using data from 366 participants in a separate clinical practice observational cohort of patients with active CD treated with vedolizumab for 26 weeks (the VICTORY cohort). We evaluated the ability of this tool to identify patients in clinical remission or corticosteroid-free remission, or those with mucosal healing (MH), clinical remission with MH, or corticosteroid-free remission with MH after vedolizumab therapy using receiver operating characteristic area under the curve (AUC) analyses. The primary outcome was to develop and validate a list of factors associated with achieving remission by vedolizumab in patients with active CD. In the derivation analysis, we identified absence of previous treatment with a tumor necrosis factor antagonist (+3 points), absence of prior bowel surgery (+2 points), absence of prior fistulizing disease (+2 points), baseline level of albumin (+0.4 points per g/L), and baseline concentration of C-reactive protein (reduction of 0.5 points for values between 3.0-10.0 mg/L and 3.0 points for values > 10.0 mg/L) as factors associated with remission. In the validation set, our model identified patients in clinical remission with an AUC of 0.67, patients in corticosteroid-free remission with an AUC of 0.66, patients with MH with an AUC of 0.72, patients in clinical remission with MH with an AUC of 0.73, and patients in corticosteroid-free clinical remission with MH with an AUC of 0.75. A cut-off value of 13 points identified patients in clinical remission after vedolizumab therapy with 92% sensitivity, patients in corticosteroid-free remission with 94% sensitivity, patients with MH with 98% sensitivity, patients in deep remission with 100% sensitivity, and patients with corticosteroid-free clinical remission with MH with 100% sensitivity. We developed and validated a scoring system to identify patients with CD most likely to respond to 26 weeks of vedolizumab therapy. Further studies are needed to optimize its accuracy in select populations and determine its cost effectiveness. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

Validation of the MOS Social Support Survey 6-item (MOS-SSS-6) measure with two large population-based samples of Australian women.

PubMed

Holden, Libby; Lee, Christina; Hockey, Richard; Ware, Robert S; Dobson, Annette J

2014-12-01

This study aimed to validate a 6-item 1-factor global measure of social support developed from the Medical Outcomes Study Social Support Survey (MOS-SSS) for use in large epidemiological studies. Data were obtained from two large population-based samples of participants in the Australian Longitudinal Study on Women's Health. The two cohorts were aged 53-58 and 28-33 years at data collection (N = 10,616 and 8,977, respectively). Items selected for the 6-item 1-factor measure were derived from the factor structure obtained from unpublished work using an earlier wave of data from one of these cohorts. Descriptive statistics, including polychoric correlations, were used to describe the abbreviated scale. Cronbach's alpha was used to assess internal consistency and confirmatory factor analysis to assess scale validity. Concurrent validity was assessed using correlations between the new 6-item version and established 19-item version, and other concurrent variables. In both cohorts, the new 6-item 1-factor measure showed strong internal consistency and scale reliability. It had excellent goodness-of-fit indices, similar to those of the established 19-item measure. Both versions correlated similarly with concurrent measures. The 6-item 1-factor MOS-SSS measures global functional social support with fewer items than the established 19-item measure.

Measuring Outcomes for Dysphagia: Validity and Reliability of the European Portuguese Eating Assessment Tool (P-EAT-10).

PubMed

Nogueira, Dália Santos; Ferreira, Pedro Lopes; Reis, Elizabeth Azevedo; Lopes, Inês Sousa

2015-10-01

The purpose of this study was to evaluate the validity and the reliability of the European Portuguese version of the EAT-10 (P-EAT-10). This research was conducted in three phases: (i) cultural and linguistic adaptation; (ii) feasibility and reliability test; and (iii) validity tests. The final sample was formed by a cohort of 520 subjects. The P-EAT-10 index was compared for socio-demographic and clinic variables. It was also compared for both dysphagic and non-dysphagic groups as well as for the results of the 3Oz wst. Lastly, the P-EAT-10 scores were correlated with the EuroQol Group Portuguese EQ-5D index. The Cronbach's α obtained for the P-EAT-10 scale was 0.952 and it remained excellent even if any item was deleted. The item-total and the intraclass correlation coefficients were very good. The P-EAT-10 mean of the non-dysphagic cohort was 0.56 and that of the dysphagic cohort was 14.26, the mean comparison between the 3Oz wst groups and the P-EAT-10 scores were significant. A significant higher perception of QoL was also found among the non-dysphagic subjects. P-EAT-10 is a valid and reliable measure that may be used to document dysphagia which makes it useful both for screening in clinical practice and in research.

Derivation and validation of the automated search algorithms to identify cognitive impairment and dementia in electronic health records.

PubMed

Amra, Sakusic; O'Horo, John C; Singh, Tarun D; Wilson, Gregory A; Kashyap, Rahul; Petersen, Ronald; Roberts, Rosebud O; Fryer, John D; Rabinstein, Alejandro A; Gajic, Ognjen

2017-02-01

Long-term cognitive impairment is a common and important problem in survivors of critical illness. We developed electronic search algorithms to identify cognitive impairment and dementia from the electronic medical records (EMRs) that provide opportunity for big data analysis. Eligible patients met 2 criteria. First, they had a formal cognitive evaluation by The Mayo Clinic Study of Aging. Second, they were hospitalized in intensive care unit at our institution between 2006 and 2014. The "criterion standard" for diagnosis was formal cognitive evaluation supplemented by input from an expert neurologist. Using all available EMR data, we developed and improved our algorithms in the derivation cohort and validated them in the independent validation cohort. Of 993 participants who underwent formal cognitive testing and were hospitalized in intensive care unit, we selected 151 participants at random to form the derivation and validation cohorts. The automated electronic search algorithm for cognitive impairment was 94.3% sensitive and 93.0% specific. The search algorithms for dementia achieved respective sensitivity and specificity of 97% and 99%. EMR search algorithms significantly outperformed International Classification of Diseases codes. Automated EMR data extractions for cognitive impairment and dementia are reliable and accurate and can serve as acceptable and efficient alternatives to time-consuming manual data review. Copyright © 2016 Elsevier Inc. All rights reserved.

Added value of shear-wave elastography for evaluation of breast masses detected with screening US imaging.

PubMed

Lee, Su Hyun; Chang, Jung Min; Kim, Won Hwa; Bae, Min Sun; Seo, Mirinae; Koo, Hye Ryoung; Chu, A Jung; Gweon, Hye Mi; Cho, Nariya; Moon, Woo Kyung

2014-10-01

To evaluate the additional value of shear-wave elastography (SWE) to B-mode ultrasonography (US) and to determine an appropriate guideline for the combined assessment of screening US-detected breast masses. This study was conducted with institutional review board approval, and written informed consent was obtained. From March 2010 to February 2012, B-mode US and SWE were performed in 159 US-detected breast masses before biopsy. For each lesion, Breast Imaging Reporting and Data System (BI-RADS) category on B-mode US images and the maximum stiffness color and elasticity values on SWE images were assessed. A guideline for adding SWE data to B-mode US was developed with the retrospective cohort to improve diagnostic performance in sensitivity and specificity and was validated in a distinct prospective cohort of 207 women prior to biopsy. Twenty-one of 159 masses in the development cohort and 12 of 207 breast masses in the validation cohort were malignant. In the development cohort, when BI-RADS category 4a masses showing a dark blue color or a maximum elasticity value of 30 kPa or less on SWE images were downgraded to category 3, specificity increased from 9.4% (13 of 138) to 59.4% (82 of 138) and 57.2% (79 of 138) (P < .001), respectively, without loss in sensitivity (100% [21 of 21]). In the validation cohort, specificity increased from 17.4% (34 of 195) to 62.1% (121 of 195) and 53.3% (104 of 195) (P < .001) respectively, without loss in sensitivity (91.7% [11 of 12]). The addition of SWE to B-mode US improved diagnostic performance with increased specificity for screening US-detected breast masses. BI-RADS category 4a masses detected at US screening that showed a dark blue color or a maximum elasticity value of 30 kPa or less on SWE images can be safely followed up instead of performing biopsy. © RSNA, 2014.

A novel 2-step approach combining the NAFLD fibrosis score and liver stiffness measurement for predicting advanced fibrosis.

PubMed

Chan, Wah-Kheong; Nik Mustapha, Nik Raihan; Mahadeva, Sanjiv

2015-10-01

The non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS) is indeterminate in a proportion of NAFLD patients. Combining the NFS with liver stiffness measurement (LSM) may improve prediction of advanced fibrosis. We aim to evaluate the NFS and LSM in predicting advanced fibrosis in NAFLD patients. The NFS was calculated and LSM obtained for consecutive adult NAFLD patients scheduled for liver biopsy. The accuracy of predicting advanced fibrosis using either modality and in combination were assessed. An algorithm combining the NFS and LSM was developed from a training cohort and subsequently tested in a validation cohort. There were 101 and 46 patients in the training and validation cohort, respectively. In the training cohort, the percentages of misclassifications using the NFS alone, LSM alone, LSM alone (with grey zone), both tests for all patients and a 2-step approach using LSM only for patients with indeterminate and high NFS were 5.0, 28.7, 2.0, 2.0 and 4.0 %, respectively. The percentages of patients requiring liver biopsy were 30.7, 0, 36.6, 36.6 and 18.8 %, respectively. In the validation cohort, the percentages of misclassifications were 8.7, 28.3, 2.2, 2.2 and 8.7 %, respectively. The percentages of patients requiring liver biopsy were 28.3, 0, 41.3, 43.5 and 19.6 %, respectively. The novel 2-step approach further reduced the number of patients requiring a liver biopsy whilst maintaining the accuracy to predict advanced fibrosis. The combination of NFS and LSM for all patients provided no apparent advantage over using either of the tests alone.

A user-friendly risk-score for predicting in-hospital cardiac arrest among patients admitted with suspected non ST-elevation acute coronary syndrome - The SAFER-score.

PubMed

Faxén, Jonas; Hall, Marlous; Gale, Chris P; Sundström, Johan; Lindahl, Bertil; Jernberg, Tomas; Szummer, Karolina

2017-12-01

To develop a simple risk-score model for predicting in-hospital cardiac arrest (CA) among patients hospitalized with suspected non-ST elevation acute coronary syndrome (NSTE-ACS). Using the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART), we identified patients (n=242 303) admitted with suspected NSTE-ACS between 2008 and 2014. Logistic regression was used to assess the association between 26 candidate variables and in-hospital CA. A risk-score model was developed and validated using a temporal cohort (n=126 073) comprising patients from SWEDEHEART between 2005 and 2007 and an external cohort (n=276 109) comprising patients from the Myocardial Ischaemia National Audit Project (MINAP) between 2008 and 2013. The incidence of in-hospital CA for NSTE-ACS and non-ACS was lower in the SWEDEHEART-derivation cohort than in MINAP (1.3% and 0.5% vs. 2.3% and 2.3%). A seven point, five variable risk score (age ≥60 years (1 point), ST-T abnormalities (2 points), Killip Class >1 (1 point), heart rate <50 or ≥100bpm (1 point), and systolic blood pressure <100mmHg (2 points) was developed. Model discrimination was good in the derivation cohort (c-statistic 0.72) and temporal validation cohort (c-statistic 0.74), and calibration was reasonable with a tendency towards overestimation of risk with a higher sum of score points. External validation showed moderate discrimination (c-statistic 0.65) and calibration showed a general underestimation of predicted risk. A simple points score containing five variables readily available on admission predicts in-hospital CA for patients with suspected NSTE-ACS. Copyright © 2017 Elsevier B.V. All rights reserved.

Deep Sequencing of Urinary RNAs for Bladder Cancer Molecular Diagnostics.

PubMed

Sin, Mandy L Y; Mach, Kathleen E; Sinha, Rahul; Wu, Fan; Trivedi, Dharati R; Altobelli, Emanuela; Jensen, Kristin C; Sahoo, Debashis; Lu, Ying; Liao, Joseph C

2017-07-15

Purpose: The majority of bladder cancer patients present with localized disease and are managed by transurethral resection. However, the high rate of recurrence necessitates lifetime cystoscopic surveillance. Developing a sensitive and specific urine-based test would significantly improve bladder cancer screening, detection, and surveillance. Experimental Design: RNA-seq was used for biomarker discovery to directly assess the gene expression profile of exfoliated urothelial cells in urine derived from bladder cancer patients ( n = 13) and controls ( n = 10). Eight bladder cancer specific and 3 reference genes identified by RNA-seq were quantitated by qPCR in a training cohort of 102 urine samples. A diagnostic model based on the training cohort was constructed using multiple logistic regression. The model was further validated in an independent cohort of 101 urines. Results: A total of 418 genes were found to be differentially expressed between bladder cancer and controls. Validation of a subset of these genes was used to construct an equation for computing a probability of bladder cancer score (P BC ) based on expression of three markers ( ROBO1, WNT5A , and CDC42BPB ). Setting P BC = 0.45 as the cutoff for a positive test, urine testing using the three-marker panel had overall 88% sensitivity and 92% specificity in the training cohort. The accuracy of the three-marker panel in the independent validation cohort yielded an AUC of 0.87 and overall 83% sensitivity and 89% specificity. Conclusions: Urine-based molecular diagnostics using this three-marker signature could provide a valuable adjunct to cystoscopy and may lead to a reduction of unnecessary procedures for bladder cancer diagnosis. Clin Cancer Res; 23(14); 3700-10. ©2017 AACR . ©2017 American Association for Cancer Research.

Validation of variants in SLC28A3 and UGT1A6 as genetic markers predictive of anthracycline-induced cardiotoxicity in children.

PubMed

Visscher, H; Ross, C J D; Rassekh, S R; Sandor, G S S; Caron, H N; van Dalen, E C; Kremer, L C; van der Pal, H J; Rogers, P C; Rieder, M J; Carleton, B C; Hayden, M R

2013-08-01

The use of anthracyclines as effective antineoplastic drugs is limited by the occurrence of cardiotoxicity. Multiple genetic variants predictive of anthracycline-induced cardiotoxicity (ACT) in children were recently identified. The current study was aimed to assess replication of these findings in an independent cohort of children. . Twenty-three variants were tested for association with ACT in an independent cohort of 218 patients. Predictive models including genetic and clinical risk factors were constructed in the original cohort and assessed in the current replication cohort. . We confirmed the association of rs17863783 in UGT1A6 and ACT in the replication cohort (P = 0.0062, odds ratio (OR) 7.98). Additional evidence for association of rs7853758 (P = 0.058, OR 0.46) and rs885004 (P = 0.058, OR 0.42) in SLC28A3 was found (combined P = 1.6 × 10(-5) and P = 3.0 × 10(-5), respectively). A previously constructed prediction model did not significantly improve risk prediction in the replication cohort over clinical factors alone. However, an improved prediction model constructed using replicated genetic variants as well as clinical factors discriminated significantly better between cases and controls than clinical factors alone in both original (AUC 0.77 vs. 0.68, P = 0.0031) and replication cohort (AUC 0.77 vs. 0.69, P = 0.060). . We validated genetic variants in two genes predictive of ACT in an independent cohort. A prediction model combining replicated genetic variants as well as clinical risk factors might be able to identify high- and low-risk patients who could benefit from alternative treatment options. Copyright © 2013 Wiley Periodicals, Inc.

Establishment of an 11-year cohort of 8733 pediatric patients hospitalized at United States free-standing children's hospitals with de novo acute lymphoblastic leukemia from health care administrative data.

PubMed

Fisher, Brian T; Harris, Tracey; Torp, Kari; Seif, Alix E; Shah, Ami; Huang, Yuan-Shung V; Bailey, L Charles; Kersun, Leslie S; Reilly, Anne F; Rheingold, Susan R; Walker, Dana; Li, Yimei; Aplenc, Richard

2014-01-01

Acute lymphoblastic leukemia (ALL) accounts for almost one quarter of pediatric cancer in the United States. Despite cooperative group therapeutic trials, there remains a paucity of large cohort data on which to conduct epidemiology and comparative effectiveness research studies. We designed a 3-step process utilizing International Classification of Diseases-9 Clinical Modification (ICD-9) discharge diagnoses codes and chemotherapy exposure data contained in the Pediatric Health Information System administrative database to establish a cohort of children with de novo ALL. This process was validated by chart review at 1 of the pediatric centers. An ALL cohort of 8733 patients was identified with a sensitivity of 88% [95% confidence interval (CI), 83%-92%] and a positive predictive value of 93% (95% CI, 89%-96%). The 30-day all cause inpatient case fatality rate using this 3-step process was 0.80% (95% CI, 0.63%-1.01%), which was significantly different than the case fatality rate of 1.40% (95% CI, 1.23%-1.60%) when ICD-9 codes alone were used. This is the first report of assembly and validation of a cohort of de novo ALL patients from a database representative of free-standing children's hospitals across the United States. Our data demonstrate that the use of ICD-9 codes alone to establish cohorts will lead to substantial patient misclassification and result in biased outcome estimates. Systematic methods beyond the use of just ICD-9 codes must be used before analysis to establish accurate cohorts of patients with malignancy. A similar approach should be followed when establishing future cohorts from administrative data.

An eleven gene molecular signature for extra-capsular spread in oral squamous cell carcinoma serves as a prognosticator of outcome in patients without nodal metastases.

PubMed

Wang, Weining; Lim, Weng Khong; Leong, Hui Sun; Chong, Fui Teen; Lim, Tony K H; Tan, Daniel S W; Teh, Bin Tean; Iyer, N Gopalakrishna

2015-04-01

Extracapsular spread (ECS) is an important prognostic factor for oral squamous cell carcinoma (OSCC) and is used to guide management. In this study, we aimed to identify an expression profile signature for ECS in node-positive OSCC using data derived from two different sources: a cohort of OSCC patients from our institution (National Cancer Centre Singapore) and The Cancer Genome Atlas (TCGA) head and neck squamous cell carcinoma (HNSCC) cohort. We also sought to determine if this signature could serve as a prognostic factor in node negative cancers. Patients with a histological diagnosis of OSCC were identified from an institutional database and fresh tumor samples were retrieved. RNA was extracted and gene expression profiling was performed using the Affymetrix GeneChip Human Genome U133 Plus 2.0 microarray platform. RNA sequence data and corresponding clinical data for the TCGA HNSCC cohort were downloaded from the TCGA Data Portal. All data analyses were conducted using R package and SPSS. We identified an 11 gene signature (GGH, MTFR1, CDKN3, PSRC1, SMIM3, CA9, IRX4, CPA3, ZSCAN16, CBX7 and ZFP3) which was robust in segregating tumors by ECS status. In node negative patients, patients harboring this ECS signature had a significantly worse overall survival (p=0.04). An eleven gene signature for ECS was derived. Our results also suggest that this signature is prognostic in a separate subset of patients with no nodal metastasis Further validation of this signature on other datasets and immunohistochemical studies are required to establish utility of this signature in stratifying early stage OSCC patients. Copyright © 2014 Elsevier Ltd. All rights reserved.

A New Standard in Dementia Knowledge Measurement: Comparative Validation of the Dementia Knowledge Assessment Scale and the Alzheimer's Disease Knowledge Scale.

PubMed

Annear, Michael J; Eccleston, Claire E; McInerney, Frances J; Elliott, Kate-Ellen J; Toye, Christine M; Tranter, Bruce K; Robinson, Andrew L

2016-06-01

To compare the psychometric performance of the Dementia Knowledge Assessment Scale (DKAS) and the Alzheimer's Disease Knowledge Scale (ADKS) when administered to a large international cohort before and after online dementia education. Comparative psychometric analysis with pre- and posteducation scale responses. The setting for this research encompassed 7,909 individuals from 124 countries who completed the 9-week Understanding Dementia Massive Open Online Course (MOOC). Volunteer respondents who completed the DKAS and ADKS before (n = 3,649) and after (n = 878) completion of the Understanding Dementia MOOC. Assessment and comparison of the DKAS and ADKS included evaluation of scale development procedures, interscale correlations, response distribution, internal consistency, and construct validity. The DKAS had superior internal consistency, wider response distribution with less ceiling effect, and better discrimination between pre- and posteducation scores and occupational cohorts than the ADKS. The 27-item DKAS is a reliable and preliminarily valid measure of dementia knowledge that is psychometrically and conceptually sound, overcomes limitations of existing instruments, and can be administered to diverse cohorts to measure baseline understanding and knowledge change. © 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.

Discovery and Validation of Predictive Biomarkers of Survival for Non-small Cell Lung Cancer Patients Undergoing Radical Radiotherapy: Two Proteins With Predictive Value

PubMed Central

Walker, Michael J.; Zhou, Cong; Backen, Alison; Pernemalm, Maria; Williamson, Andrew J.K.; Priest, Lynsey J.C.; Koh, Pek; Faivre-Finn, Corinne; Blackhall, Fiona H.; Dive, Caroline; Whetton, Anthony D.

2015-01-01

Lung cancer is the most frequent cause of cancer-related death world-wide. Radiotherapy alone or in conjunction with chemotherapy is the standard treatment for locally advanced non-small cell lung cancer (NSCLC). Currently there is no predictive marker with clinical utility to guide treatment decisions in NSCLC patients undergoing radiotherapy. Identification of such markers would allow treatment options to be considered for more effective therapy. To enable the identification of appropriate protein biomarkers, plasma samples were collected from patients with non-small cell lung cancer before and during radiotherapy for longitudinal comparison following a protocol that carries sufficient power for effective discovery proteomics. Plasma samples from patients pre- and during radiotherapy who had survived > 18 mo were compared to the same time points from patients who survived < 14 mo using an 8 channel isobaric tagging tandem mass spectrometry discovery proteomics platform. Over 650 proteins were detected and relatively quantified. Proteins which showed a change during radiotherapy were selected for validation using an orthogonal antibody-based approach. Two of these proteins were verified in a separate patient cohort: values of CRP and LRG1 combined gave a highly significant indication of extended survival post one week of radiotherapy treatment. PMID:26425690

Comparison of ICD-9-based, retrospective, and prospective assessments of perioperative complications: assessment of accuracy in reporting.

PubMed

Campbell, Peter G; Malone, Jennifer; Yadla, Sanjay; Chitale, Rohan; Nasser, Rani; Maltenfort, Mitchell G; Vaccaro, Alex; Ratliff, John K

2011-01-01

large studies of ICD-9-based complication and hospital-acquired condition (HAC) chart reviews have not been validated through a comparison with prospective assessments of perioperative adverse event occurrence. Retrospective chart review, while generally assumed to underreport complication occurrence, has not been subjected to prospective study. It is unclear whether ICD-9-based population studies are more accurate than retrospective reviews or are perhaps equally susceptible to bias. To determine the validity of an ICD-9-based assessment of perioperative complications, the authors compared a prospective independent evaluation of such complications with ICD-9-based HAC data in a cohort of patients who underwent spine surgery. For further comparison, a separate retrospective review of the same cohort of patients was completed as well. a prospective assessment of complications in spine surgery over a 6-month period (May to December 2008) was completed using an independent auditor and a validated definition of perioperative complications. The auditor maintained a prospective database, which included complications occurring in the initial 30 days after surgery. All medical adverse events were included in the assessment. All patients undergoing spine surgery during the study period were eligible for inclusion; the only exclusionary criterion used was the availability of the auditor for patient assessment. From the overall patient database, 100 patients were randomly extracted for further review; in these patients ICD-9-based HAC data were obtained from coder data. Separately, a retrospective assessment of complication incidence was completed using chart and electronic medical record review. The same definition of perioperative adverse events and the inclusion of medical adverse events were applied in the prospective, ICD-9-based, and retrospective assessments. ninety-two patients had adequate records for the ICD-9 assessment, whereas 98 patients had adequate chart information for retrospective review. The overall complication incidence among the groups was similar (major complications: ICD-9 17.4%, retrospective 19.4%, and prospective 22.4%; minor complications: ICD-9 43.8%, retrospective 31.6%, and prospective 42.9%). However, the ICD-9-based assessment included many minor medical events not deemed complications by the auditor. Rates of specific complications were consistently underreported in both the ICD-9 and the retrospective assessments. The ICD-9 assessment underreported infection, the need for reoperation, deep wound infection, deep venous thrombosis, and new neurological deficits (p = 0.003, p < 0.0001, p < 0.0001, p = 0.0025, and p = 0.04, respectively). The retrospective review underestimated incidences of infection, the need for revision, and deep wound infection (p < 0.0001 for each). Only in the capture of new cardiac events was ICD-9-based reporting more accurate than prospective data accrual (p = 0.04). The most sensitive measure for the appreciation of complication occurrence was the prospective review, followed by the ICD-9-based assessment (p = 0.05). an ICD-9-based coding of perioperative adverse events and major complications in a cohort of spine surgery patients revealed an overall complication incidence similar to that in a prospectively executed measure. In contrast, a retrospective review underestimated complication incidence. The ICD-9-based review captured many medical events of limited clinical import, inflating the overall incidence of adverse events demonstrated by this approach. In multiple categories of major, clinically significant perioperative complications, ICD-9-based and retrospective assessments significantly underestimated complication incidence. These findings illustrate a significant potential weakness and source of inaccuracy in the use of population-based ICD-9 and retrospective complication recording.

Development of a novel score for the prediction of hospital mortality in patients with severe sepsis: the use of electronic healthcare records with LASSO regression.

PubMed

Zhang, Zhongheng; Hong, Yucai

2017-07-25

There are several disease severity scores being used for the prediction of mortality in critically ill patients. However, none of them was developed and validated specifically for patients with severe sepsis. The present study aimed to develop a novel prediction score for severe sepsis. A total of 3206 patients with severe sepsis were enrolled, including 1054 non-survivors and 2152 survivors. The LASSO score showed the best discrimination (area under curve: 0.772; 95% confidence interval: 0.735-0.810) in the validation cohort as compared with other scores such as simplified acute physiology score II, acute physiological score III, Logistic organ dysfunction system, sequential organ failure assessment score, and Oxford Acute Severity of Illness Score. The calibration slope was 0.889 and Brier value was 0.173. The study employed a single center database called Medical Information Mart for Intensive Care-III) MIMIC-III for analysis. Severe sepsis was defined as infection and acute organ dysfunction. Clinical and laboratory variables used in clinical routines were included for screening. Subjects without missing values were included, and the whole dataset was split into training and validation cohorts. The score was coined LASSO score because variable selection was performed using the least absolute shrinkage and selection operator (LASSO) technique. Finally, the LASSO score was evaluated for its discrimination and calibration in the validation cohort. The study developed the LASSO score for mortality prediction in patients with severe sepsis. Although the score had good discrimination and calibration in a randomly selected subsample, external validations are still required.

WHipple-ABACUS, a simple, validated risk score for 30-day mortality after pancreaticoduodenectomy developed using the ACS-NSQIP database.

PubMed

Gleeson, Elizabeth M; Shaikh, Mohammad F; Shewokis, Patricia A; Clarke, John R; Meyers, William C; Pitt, Henry A; Bowne, Wilbur B

2016-11-01

Pancreaticoduodenectomy needs simple, validated risk models to better identify 30-day mortality. The goal of this study is to develop a simple risk score to predict 30-day mortality after pancreaticoduodenectomy. We reviewed cases of pancreaticoduodenectomy from 2005-2012 in the American College of Surgeons-National Surgical Quality Improvement Program databases. Logistic regression was used to identify preoperative risk factors for morbidity and mortality from a development cohort. Scores were created using weighted beta coefficients, and predictive accuracy was assessed on the validation cohort using receiver operator characteristic curves and measuring area under the curve. The 30-day mortality rate was 2.7% for patients who underwent pancreaticoduodenectomy (n = 14,993). We identified 8 independent risk factors. The score created from weighted beta coefficients had an area under the curve of 0.71 (95% confidence interval, 0.66-0.77) on the validation cohort. Using the score WHipple-ABACUS (hypertension With medication + History of cardiac surgery + Age >62 + 2 × Bleeding disorder + Albumin <3.5 g/dL + 2 × disseminated Cancer + 2 × Use of steroids + 2 × Systemic inflammatory response syndrome), mortality rates increase with increasing score (P < .001). While other risk scores exist for 30-day mortality after pancreaticoduodenectomy, we present a simple, validated score developed using exclusively preoperative predictors surgeons could use to identify patients at risk for this procedure. Copyright © 2016 Elsevier Inc. All rights reserved.

Effect of Social Support and Marital Status on Perceived Surgical Effectiveness and 30-Day Hospital Readmission.

PubMed

Adogwa, Owoicho; Elsamadicy, Aladine A; Vuong, Victoria D; Mehta, Ankit I; Vasquez, Raul A; Cheng, Joseph; Bagley, Carlos A; Karikari, Isaac O

2017-12-01

Retrospective cohort review. To determine whether higher levels of social support are associated with improved surgical outcomes after elective spine surgery. The medical records of 430 patients (married, n = 313; divorced/separated/widowed, n = 71; single, n = 46) undergoing elective spine surgery at a major academic medical center were reviewed. Patients were categorized by their marital status at the time of surgery. Patient demographics, comorbidities, and postoperative complication rates were collected. All patients had prospectively collected outcomes measures and a minimum of 1-year follow-up. Patient reported outcomes instruments (Oswestry Disability Index, Short Form-36, and visual analog scale-back pain/leg pain) were completed before surgery, then at 1 year after surgery. Baseline characteristics were similar in all cohorts. There was no statistically significant difference in the length of hospital stay across all 3 cohorts, although "single patients" had longer duration of in-hospital stays that trended toward significance (single 6.24 days vs married 4.53 days vs divorced/separated/widowed 4.55 days, P = .05). Thirty-day readmission rates were similar across all cohorts (married 7.03% vs divorced/separated/widowed 7.04% vs single 6.52%, P = .99). Additionally, there were no significant differences in baseline and 1-year patient reported outcomes measures between all groups. Increased social support did not appear to be associated with superior short and long-term clinical outcomes after spine surgery; however, it was associated with a shorter duration of in-hospital stay with no increase in 30-day readmission rates.

MABAL: a Novel Deep-Learning Architecture for Machine-Assisted Bone Age Labeling.

PubMed

Mutasa, Simukayi; Chang, Peter D; Ruzal-Shapiro, Carrie; Ayyala, Rama

2018-02-05

Bone age assessment (BAA) is a commonly performed diagnostic study in pediatric radiology to assess skeletal maturity. The most commonly utilized method for assessment of BAA is the Greulich and Pyle method (Pediatr Radiol 46.9:1269-1274, 2016; Arch Dis Child 81.2:172-173, 1999) atlas. The evaluation of BAA can be a tedious and time-consuming process for the radiologist. As such, several computer-assisted detection/diagnosis (CAD) methods have been proposed for automation of BAA. Classical CAD tools have traditionally relied on hard-coded algorithmic features for BAA which suffer from a variety of drawbacks. Recently, the advent and proliferation of convolutional neural networks (CNNs) has shown promise in a variety of medical imaging applications. There have been at least two published applications of using deep learning for evaluation of bone age (Med Image Anal 36:41-51, 2017; JDI 1-5, 2017). However, current implementations are limited by a combination of both architecture design and relatively small datasets. The purpose of this study is to demonstrate the benefits of a customized neural network algorithm carefully calibrated to the evaluation of bone age utilizing a relatively large institutional dataset. In doing so, this study will aim to show that advanced architectures can be successfully trained from scratch in the medical imaging domain and can generate results that outperform any existing proposed algorithm. The training data consisted of 10,289 images of different skeletal age examinations, 8909 from the hospital Picture Archiving and Communication System at our institution and 1383 from the public Digital Hand Atlas Database. The data was separated into four cohorts, one each for male and female children above the age of 8, and one each for male and female children below the age of 10. The testing set consisted of 20 radiographs of each 1-year-age cohort from 0 to 1 years to 14-15+ years, half male and half female. The testing set included left-hand radiographs done for bone age assessment, trauma evaluation without significant findings, and skeletal surveys. A 14 hidden layer-customized neural network was designed for this study. The network included several state of the art techniques including residual-style connections, inception layers, and spatial transformer layers. Data augmentation was applied to the network inputs to prevent overfitting. A linear regression output was utilized. Mean square error was used as the network loss function and mean absolute error (MAE) was utilized as the primary performance metric. MAE accuracies on the validation and test sets for young females were 0.654 and 0.561 respectively. For older females, validation and test accuracies were 0.662 and 0.497 respectively. For young males, validation and test accuracies were 0.649 and 0.585 respectively. Finally, for older males, validation and test set accuracies were 0.581 and 0.501 respectively. The female cohorts were trained for 900 epochs each and the male cohorts were trained for 600 epochs. An eightfold cross-validation set was employed for hyperparameter tuning. Test error was obtained after training on a full data set with the selected hyperparameters. Using our proposed customized neural network architecture on our large available data, we achieved an aggregate validation and test set mean absolute errors of 0.637 and 0.536 respectively. To date, this is the best published performance on utilizing deep learning for bone age assessment. Our results support our initial hypothesis that customized, purpose-built neural networks provide improved performance over networks derived from pre-trained imaging data sets. We build on that initial work by showing that the addition of state-of-the-art techniques such as residual connections and inception architecture further improves prediction accuracy. This is important because the current assumption for use of residual and/or inception architectures is that a large pre-trained network is required for successful implementation given the relatively small datasets in medical imaging. Instead we show that a small, customized architecture incorporating advanced CNN strategies can indeed be trained from scratch, yielding significant improvements in algorithm accuracy. It should be noted that for all four cohorts, testing error outperformed validation error. One reason for this is that our ground truth for our test set was obtained by averaging two pediatric radiologist reads compared to our training data for which only a single read was used. This suggests that despite relatively noisy training data, the algorithm could successfully model the variation between observers and generate estimates that are close to the expected ground truth.

Patient-Level DNA Damage and Repair Pathway Profiles and Prognosis After Prostatectomy for High-Risk Prostate Cancer

PubMed Central

Evans, Joseph R.; Zhao, Shuang G.; Chang, S. Laura; Tomlins, Scott A.; Erho, Nicholas; Sboner, Andrea; Schiewer, Matthew J.; Spratt, Daniel E.; Kothari, Vishal; Klein, Eric A.; Den, Robert B.; Dicker, Adam P.; Karnes, R. Jeffrey; Yu, Xiaochun; Nguyen, Paul L.; Rubin, Mark A.; de Bono, Johann; Knudsen, Karen E.; Davicioni, Elai; Feng, Felix Y.

2017-01-01

IMPORTANCE A substantial number of patients diagnosed with high-risk prostate cancer are at risk for metastatic progression after primary treatment. Better biomarkers are needed to identify patients at the highest risk to guide therapy intensification. OBJECTIVE To create a DNA damage and repair (DDR) pathway profiling method for use as a prognostic signature biomarker in high-risk prostate cancer. DESIGN, SETTING, AND PARTICIPANTS A cohort of 1090 patients with high-risk prostate cancer who underwent prostatectomy and were treated at 3 different academic institutions were divided into a training cohort (n = 545) and 3 pooled validation cohorts (n = 232, 130, and 183) assembled for case-control or case-cohort studies. Profiling of 9 DDR pathways using 17 gene sets for GSEA (Gene Set Enrichment Analysis) of high-density microarray gene expression data from formalin-fixed paraffin-embedded prostatectomy samples with median 10.3 years follow-up was performed. Prognostic signature development from DDR pathway profiles was studied, and DDR pathway gene mutation in published cohorts was analyzed. MAIN OUTCOMES AND MEASURES Biochemical recurrence-free, metastasis-free, and overall survival. RESULTS Across the training cohort and pooled validation cohorts, 1090 men were studied; mean (SD) age at diagnosis was 65.3 (6.4) years. We found that there are distinct clusters of DDR pathways within the cohort, and DDR pathway enrichment is only weakly correlated with clinical variables such as age (Spearman ρ [ρ], range, −0.07 to 0.24), Gleason score (ρ, range, 0.03 to 0.20), prostate-specific antigen level (ρ, range, −0.07 to 0.10), while 13 of 17 DDR gene sets are strongly correlated with androgen receptor pathway enrichment (ρ, range, 0.33 to 0.82). In published cohorts, DDR pathway genes are rarely mutated. A DDR pathway profile prognostic signature built in the training cohort was significantly associated with biochemical recurrence-free, metastasis-free, and overall survival in the pooled validation cohorts independent of standard clinicopathological variables. The prognostic performance of the signature for metastasis-free survival appears to be stronger in the younger patients (HR, 1.67; 95%CI, 1.12–2.50) than in the older patients (HR, 0.77; 95%CI, 0.29–2.07) on multivariate Cox analysis. CONCLUSIONS AND RELEVANCE DNA damage and repair pathway profiling revealed patient-level variations and the DDR pathways are rarely affected by mutation. A DDR pathway signature showed strong prognostic performance with the long-term outcomes of metastasis-free and overall survival that may be useful for risk stratification of high-risk prostate cancer patients. PMID:26746117

Prediction of five-year all-cause mortality in Chinese patients with type 2 diabetes mellitus - A population-based retrospective cohort study.

PubMed

Wan, Eric Yuk Fai; Fong, Daniel Yee Tak; Fung, Colman Siu Cheung; Yu, Esther Yee Tak; Chin, Weng Yee; Chan, Anca Ka Chun; Lam, Cindy Lo Kuen

2017-06-01

This study aimed to develop and validate an all-cause mortality risk prediction model for Chinese primary care patients with type 2 diabetes mellitus(T2DM) in Hong Kong. A population-based retrospective cohort study was conducted on 132,462 Chinese patients who had received public primary care services during 2010. Each gender sample was randomly split on a 2:1 basis into derivation and validation cohorts and was followed-up for a median period of 5years. Gender-specific mortality risk prediction models showing the interaction effect between predictors and age were derived using Cox proportional hazards regression with forward stepwise approach. Developed models were compared with pre-existing models by Harrell's C-statistic and calibration plot using validation cohort. Common predictors of increased mortality risk in both genders included: age; smoking habit; diabetes duration; use of anti-hypertensive agents, insulin and lipid-lowering drugs; body mass index; hemoglobin A1c; systolic blood pressure(BP); total cholesterol to high-density lipoprotein-cholesterol ratio; urine albumin to creatinine ratio(urine ACR); and estimated glomerular filtration rate(eGFR). Prediction models showed better discrimination with Harrell"'s C-statistics of 0.768(males) and 0.782(females) and calibration power from the plots than previously established models. Our newly developed gender-specific models provide a more accurate predicted 5-year mortality risk for Chinese diabetic patients than other established models. Copyright © 2017 Elsevier Inc. All rights reserved.

Common Polymorphisms in the PKP3-SIGIRR-TMEM16J Gene Region Are Associated With Susceptibility to Tuberculosis

PubMed Central

Randhawa, April K.; Chau, Tran T. H.; Bang, Nguyen D.; Yen, Nguyen T. B.; Farrar, Jeremy J.; Dunstan, Sarah J.; Hawn, Thomas R.

2012-01-01

(See the editorial commentary by Wilkinson, on pages 525–7.) Background. Tuberculosis has been associated with genetic variation in host immunity. We hypothesized that single-nucleotide polymorphisms (SNPs) in SIGIRR, a negative regulator of Toll-like receptor/IL-1R signaling, are associated with susceptibility to tuberculosis. Methods. We used a case-population study design in Vietnam with cases that had either tuberculous meningitis or pulmonary tuberculosis. We genotyped 6 SNPs in the SIGIRR gene region (including the adjacent genes PKP3 and TMEM16J) in a discovery cohort of 352 patients with tuberculosis and 382 controls. Significant associations were genotyped in a validation cohort (339 patients with tuberculosis, 376 controls). Results. Three SNPs (rs10902158, rs7105848, rs7111432) were associated with tuberculosis in discovery and validation cohorts. The polymorphisms were associated with both tuberculous meningitis and pulmonary tuberculosis and were strongest with a recessive genetic model (odds ratios, 1.5–1.6; P = .0006–.001). Coinheritance of these polymorphisms with previously identified risk alleles in Toll-like receptor 2 and TIRAP was associated with an additive risk of tuberculosis susceptibility. Conclusions. These results demonstrate a strong association of SNPs in the PKP3-SIGIRR-TMEM16J gene region and tuberculosis in discovery and validation cohorts. To our knowledge, these are the first associations of polymorphisms in this region with any disease. PMID:22223854

Rates and risk factors of unplanned 30-day readmission following general and thoracic pediatric surgical procedures.

PubMed

Polites, Stephanie F; Potter, Donald D; Glasgow, Amy E; Klinkner, Denise B; Moir, Christopher R; Ishitani, Michael B; Habermann, Elizabeth B

2017-08-01

Postoperative unplanned readmissions are costly and decrease patient satisfaction; however, little is known about this complication in pediatric surgery. The purpose of this study was to determine rates and predictors of unplanned readmission in a multi-institutional cohort of pediatric surgical patients. Unplanned 30-day readmissions following general and thoracic surgical procedures in children <18 were identified from the 2012-2014 National Surgical Quality Improvement Program- Pediatric. Time-dependent rates of readmission per 30 person-days were determined to account for varied postoperative length of stay (pLOS). Patients were randomly divided into 70% derivation and 30% validation cohorts which were used for creation and validation of a risk model for readmission. Readmission occurred in 1948 (3.6%) of 54,870 children for a rate of 4.3% per 30 person-days. Adjusted predictors of readmission included hepatobiliary procedures, increased wound class, operative duration, complications, and pLOS. The predictive model discriminated well in the derivation and validation cohorts (AUROC 0.710 and 0.701) with good calibration between observed and expected readmission events in both cohorts (p>.05). Unplanned readmission occurs less frequently in pediatric surgery than what is described in adults, calling into question its use as a quality indicator in this population. Factors that predict readmission including type of procedure, complications, and pLOS can be used to identify at-risk children and develop prevention strategies. III. Copyright © 2017 Elsevier Inc. All rights reserved.

Estimating residual kidney function in dialysis patients without urine collection

PubMed Central

Shafi, Tariq; Michels, Wieneke M.; Levey, Andrew S.; Inker, Lesley A.; Dekker, Friedo W.; Krediet, Raymond T.; Hoekstra, Tiny; Schwartz, George J.; Eckfeldt, John H.; Coresh, Josef

2016-01-01

Residual kidney function contributes substantially to solute clearance in dialysis patients but cannot be assessed without urine collection. We used serum filtration markers to develop dialysis-specific equations to estimate urinary urea clearance without the need for urine collection. In our development cohort, we measured 24-hour urine clearances under close supervision in 44 patients and validated these equations in 826 patients from the Netherlands Cooperative Study on the Adequacy of Dialysis. For the development and validation cohorts, median urinary urea clearance was 2.6 and 2.4 mL/min, respectively. During the 24-hour visit in the development cohort, serum β-trace protein concentrations remained in steady state but concentrations of all other markers increased. In the validation cohort, bias (median measured minus estimated clearance) was low for all equations. Precision was significantly better for β-trace protein and β2-microglobulin equations and the accuracy was significantly greater for β-trace protein, β2-microglobulin and cystatin C equations, compared with the urea plus creatinine equation. Area under the receiver operator characteristic curve for detecting measured urinary urea clearance by equation-estimated urinary urea clearance (both 2 mL/min or more) were 0.821, 0.850 and 0.796 for β-trace protein, β2-microglobulin and cystatin C equations, respectively; significantly greater than the 0.663 for the urea plus creatinine equation. Thus, residual renal function can be estimated in dialysis patients without urine collections. PMID:26924062

Estimating residual kidney function in dialysis patients without urine collection.

PubMed

Shafi, Tariq; Michels, Wieneke M; Levey, Andrew S; Inker, Lesley A; Dekker, Friedo W; Krediet, Raymond T; Hoekstra, Tiny; Schwartz, George J; Eckfeldt, John H; Coresh, Josef

2016-05-01

Residual kidney function contributes substantially to solute clearance in dialysis patients but cannot be assessed without urine collection. We used serum filtration markers to develop dialysis-specific equations to estimate urinary urea clearance without the need for urine collection. In our development cohort, we measured 24-hour urine clearances under close supervision in 44 patients and validated these equations in 826 patients from the Netherlands Cooperative Study on the Adequacy of Dialysis. For the development and validation cohorts, median urinary urea clearance was 2.6 and 2.4 ml/min, respectively. During the 24-hour visit in the development cohort, serum β-trace protein concentrations remained in steady state but concentrations of all other markers increased. In the validation cohort, bias (median measured minus estimated clearance) was low for all equations. Precision was significantly better for β-trace protein and β2-microglobulin equations and the accuracy was significantly greater for β-trace protein, β2-microglobulin, and cystatin C equations, compared with the urea plus creatinine equation. Area under the receiver operator characteristic curve for detecting measured urinary urea clearance by equation-estimated urinary urea clearance (both 2 ml/min or more) were 0.821, 0.850, and 0.796 for β-trace protein, β2-microglobulin, and cystatin C equations, respectively; significantly greater than the 0.663 for the urea plus creatinine equation. Thus, residual renal function can be estimated in dialysis patients without urine collections. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Derivation and Evaluation of a Risk-Scoring Tool to Predict Participant Attrition in a Lifestyle Intervention Project.

PubMed

Jiang, Luohua; Yang, Jing; Huang, Haixiao; Johnson, Ann; Dill, Edward J; Beals, Janette; Manson, Spero M; Roubideaux, Yvette

2016-05-01

Participant attrition in clinical trials and community-based interventions is a serious, common, and costly problem. In order to develop a simple predictive scoring system that can quantify the risk of participant attrition in a lifestyle intervention project, we analyzed data from the Special Diabetes Program for Indians Diabetes Prevention Program (SDPI-DP), an evidence-based lifestyle intervention to prevent diabetes in 36 American Indian and Alaska Native communities. SDPI-DP participants were randomly divided into a derivation cohort (n = 1600) and a validation cohort (n = 801). Logistic regressions were used to develop a scoring system from the derivation cohort. The discriminatory power and calibration properties of the system were assessed using the validation cohort. Seven independent factors predicted program attrition: gender, age, household income, comorbidity, chronic pain, site's user population size, and average age of site staff. Six factors predicted long-term attrition: gender, age, marital status, chronic pain, site's user population size, and average age of site staff. Each model exhibited moderate to fair discriminatory power (C statistic in the validation set: 0.70 for program attrition, and 0.66 for long-term attrition) and excellent calibration. The resulting scoring system offers a low-technology approach to identify participants at elevated risk for attrition in future similar behavioral modification intervention projects, which may inform appropriate allocation of retention resources. This approach also serves as a model for other efforts to prevent participant attrition.

Measuring the impact and distress of osteoarthritis from the patients' perspective

PubMed Central

Pallant, Julie F; Keenan, Anne-Maree; Misajon, Roseanne; Conaghan, Philip G; Tennant, Alan

2009-01-01

Background To assess the internal construct validity of the Perceived Impact of Problem Profile (PIPP), a patient based outcome measure based on the International Classification of Functioning, Disability and Health (ICF), which assesses impact and distress, in an osteoarthritis (OA) cohort. Methods A questionnaire comprising the 23-item PIPP, which assesses five domains (mobility, participation, self care, psychological well being and relationships), the Western Ontario McMasters University Osteoarthritis Index (WOMAC), the General Well-Being Index (GWBI), and the Hospital Anxiety and Depression Scale (HADS) was posted to people with clinician diagnosed OA. Assessment of the internal construct validity of the PIPP was undertaken using Rasch analysis performed with RUMM2020 software and concurrent validity through comparator measures. Results Two hundred and fifty-nine participants with OA responded. Analysis of the five individual domains of the PIPP indicated that there was good fit to the Rasch model, with high person separation reliability. One item required removal from the Mobility subscale and the Participation subscale. There were strong correlations between the PIPP Mobility scores and the WOMAC disability and pain subscales (rho = .73 and rho = .68), and between the PIPP Psychological well-being and HADS Depression (rho = .71) and GWBI (rho = -.69). High inter-correlations between the impact and distress subscales for each domain (range rho = .85 to .96), suggested redundancy of the latter. Conclusion This study demonstrates that the PIPP has good psychometric properties in an OA population. The PIPP, using just the impact subscales, provides a brief, reliable and valid means of assessing the impact of OA from the individual's perspective and operationalizing the bio-psychosocial model by the application of a single multi-domain questionnaire. PMID:19400966

Development and validation of a clinical prediction rule to identify suspected breast cancer: a prospective cohort study.

PubMed

Galvin, Rose; Joyce, Doireann; Downey, Eithne; Boland, Fiona; Fahey, Tom; Hill, Arnold K

2014-10-03

The number of primary care referrals of women with breast symptoms to symptomatic breast units (SBUs) has increased exponentially in the past decade in Ireland. The aim of this study is to develop and validate a clinical prediction rule (CPR) to identify women with breast cancer so that a more evidence based approach to referral from primary care to these SBUs can be developed. We analysed routine data from a prospective cohort of consecutive women reviewed at a SBU with breast symptoms. The dataset was split into a derivation and validation cohort. Regression analysis was used to derive a CPR from the patient's history and clinical findings. Validation of the CPR consisted of estimating the number of breast cancers predicted to occur compared with the actual number of observed breast cancers across deciles of risk. A total of 6,590 patients were included in the derivation study and 4.9% were diagnosed with breast cancer. Independent clinical predictors for breast cancer were: increasing age by year (adjusted odds ratio 1.08, 95% CI 1.07-1.09); presence of a lump (5.63, 95% CI 4.2-7.56); nipple change (2.77, 95% CI 1.68-4.58) and nipple discharge (2.09, 95% CI 1.1-3.97). Validation of the rule (n = 911) demonstrated that the probability of breast cancer was higher with an increasing number of these independent variables. The Hosmer-Lemeshow goodness of fit showed no overall significant difference between the expected and the observed numbers of breast cancer (χ(2)HL: 6.74, p-value: 0.56). This study derived and validated a CPR for breast cancer in women attending an Irish national SBU. We found that increasing age, presence of a lump, nipple discharge and nipple change are all associated with increased risk of breast cancer. Further validation of the rule is necessary as well as an assessment of its impact on referral practice.

Development and Validation of an Individualized Immune Prognostic Signature in Early-Stage Nonsquamous Non-Small Cell Lung Cancer.

PubMed

Li, Bailiang; Cui, Yi; Diehn, Maximilian; Li, Ruijiang

2017-11-01

The prevalence of early-stage non-small cell lung cancer (NSCLC) is expected to increase with recent implementation of annual screening programs. Reliable prognostic biomarkers are needed to identify patients at a high risk for recurrence to guide adjuvant therapy. To develop a robust, individualized immune signature that can estimate prognosis in patients with early-stage nonsquamous NSCLC. This retrospective study analyzed the gene expression profiles of frozen tumor tissue samples from 19 public NSCLC cohorts, including 18 microarray data sets and 1 RNA-Seq data set for The Cancer Genome Atlas (TCGA) lung adenocarcinoma cohort. Only patients with nonsquamous NSCLC with clinical annotation were included. Samples were from 2414 patients with nonsquamous NSCLC, divided into a meta-training cohort (729 patients), meta-testing cohort (716 patients), and 3 independent validation cohorts (439, 323, and 207 patients). All patients underwent surgery with a negative surgical margin, received no adjuvant or neoadjuvant therapy, and had publicly available gene expression data and survival information. Data were collected from July 22 through September 8, 2016. Overall survival. Of 2414 patients (1205 men [50%], 1111 women [46%], and 98 of unknown sex [4%]; median age [range], 64 [15-90] years), a prognostic immune signature of 25 gene pairs consisting of 40 unique genes was constructed using the meta-training data set. In the meta-testing and validation cohorts, the immune signature significantly stratified patients into high- vs low-risk groups in terms of overall survival across and within subpopulations with stage I, IA, IB, or II disease and remained as an independent prognostic factor in multivariate analyses (hazard ratio range, 1.72 [95% CI, 1.26-2.33; P < .001] to 2.36 [95% CI, 1.47-3.79; P < .001]) after adjusting for clinical and pathologic factors. Several biological processes, including chemotaxis, were enriched among genes in the immune signature. The percentage of neutrophil infiltration (5.6% vs 1.8%) and necrosis (4.6% vs 1.5%) was significantly higher in the high-risk immune group compared with the low-risk groups in TCGA data set (P < .003). The immune signature achieved a higher accuracy (mean concordance index [C-index], 0.64) than 2 commercialized multigene signatures (mean C-index, 0.53 and 0.61) for estimation of survival in comparable validation cohorts. When integrated with clinical characteristics such as age and stage, the composite clinical and immune signature showed improved prognostic accuracy in all validation data sets relative to molecular signatures alone (mean C-index, 0.70 vs 0.63) and another commercialized clinical-molecular signature (mean C-index, 0.68 vs 0.65). The proposed clinical-immune signature is a promising biomarker for estimating overall survival in nonsquamous NSCLC, including early-stage disease. Prospective studies are needed to test the clinical utility of the biomarker in individualized management of nonsquamous NSCLC.

A Comparison of Live Classroom Instruction and Internet-Based Lessons for a Preparatory Training Course Delivered to 4th Year Pharmacy Students

ERIC Educational Resources Information Center

Nuffer, Wesley; Duke, Jodi

2013-01-01

To compare the effectiveness of an internet-based training series with a traditional live classroom session in preparing pharmacy students to oversee a diabetes management program in community settings. Two cohorts of students were identified that prepared by utilizing a recorded online training exclusively, and two separate cohorts of students…

Theoretical validation for changing magnetic fields of systems of permanent magnets of drum separators

NASA Astrophysics Data System (ADS)

Lozovaya, S. Y.; Lozovoy, N. M.; Okunev, A. N.

2018-03-01

This article is devoted to the theoretical validation of the change in magnetic fields created by the permanent magnet systems of the drum separators. In the article, using the example of a magnetic separator for enrichment of highly magnetic ores, the method of analytical calculation of the magnetic fields of systems of permanent magnets based on the Biot-Savart-Laplace law, the equivalent solenoid method, and the superposition principle of fields is considered.

Search Strategy to Identify Dental Survival Analysis Articles Indexed in MEDLINE.

PubMed

Layton, Danielle M; Clarke, Michael

2016-01-01

Articles reporting survival outcomes (time-to-event outcomes) in patients over time are challenging to identify in the literature. Research shows the words authors use to describe their dental survival analyses vary, and that allocation of medical subject headings by MEDLINE indexers is inconsistent. Together, this undermines accurate article identification. The present study aims to develop and validate a search strategy to identify dental survival analyses indexed in MEDLINE (Ovid). A gold standard cohort of articles was identified to derive the search terms, and an independent gold standard cohort of articles was identified to test and validate the proposed search strategies. The first cohort included all 6,955 articles published in the 50 dental journals with the highest impact factors in 2008, of which 95 articles were dental survival articles. The second cohort included all 6,514 articles published in the 50 dental journals with the highest impact factors for 2012, of which 148 were dental survival articles. Each cohort was identified by a systematic hand search. Performance parameters of sensitivity, precision, and number needed to read (NNR) for the search strategies were calculated. Sensitive, precise, and optimized search strategies were developed and validated. The performances of the search strategy maximizing sensitivity were 92% sensitivity, 14% precision, and 7.11 NNR; the performances of the strategy maximizing precision were 93% precision, 10% sensitivity, and 1.07 NNR; and the performances of the strategy optimizing the balance between sensitivity and precision were 83% sensitivity, 24% precision, and 4.13 NNR. The methods used to identify search terms were objective, not subjective. The search strategies were validated in an independent group of articles that included different journals and different publication years. Across the three search strategies, dental survival articles can be identified with sensitivity up to 92%, precision up to 93%, and NNR of less than two articles to identify relevant records. This research has highlighted the impact that variation in reporting and indexing has on article identification and has improved researchers' ability to identify dental survival articles.

Validated and longitudinally stable asthma phenotypes based on cluster analysis of the ADEPT study.

PubMed

Loza, Matthew J; Djukanovic, Ratko; Chung, Kian Fan; Horowitz, Daniel; Ma, Keying; Branigan, Patrick; Barnathan, Elliot S; Susulic, Vedrana S; Silkoff, Philip E; Sterk, Peter J; Baribaud, Frédéric

2016-12-15

Asthma is a disease of varying severity and differing disease mechanisms. To date, studies aimed at stratifying asthma into clinically useful phenotypes have produced a number of phenotypes that have yet to be assessed for stability and to be validated in independent cohorts. The aim of this study was to define and validate, for the first time ever, clinically driven asthma phenotypes using two independent, severe asthma cohorts: ADEPT and U-BIOPRED. Fuzzy partition-around-medoid clustering was performed on pre-specified data from the ADEPT participants (n = 156) and independently on data from a subset of U-BIOPRED asthma participants (n = 82) for whom the same variables were available. Models for cluster classification probabilities were derived and applied to the 12-month longitudinal ADEPT data and to a larger subset of the U-BIOPRED asthma dataset (n = 397). High and low type-2 inflammation phenotypes were defined as high or low Th2 activity, indicated by endobronchial biopsies gene expression changes downstream of IL-4 or IL-13. Four phenotypes were identified in the ADEPT (training) cohort, with distinct clinical and biomarker profiles. Phenotype 1 was "mild, good lung function, early onset", with a low-inflammatory, predominantly Type-2, phenotype. Phenotype 2 had a "moderate, hyper-responsive, eosinophilic" phenotype, with moderate asthma control, mild airflow obstruction and predominant Type-2 inflammation. Phenotype 3 had a "mixed severity, predominantly fixed obstructive, non-eosinophilic and neutrophilic" phenotype, with moderate asthma control and low Type-2 inflammation. Phenotype 4 had a "severe uncontrolled, severe reversible obstruction, mixed granulocytic" phenotype, with moderate Type-2 inflammation. These phenotypes had good longitudinal stability in the ADEPT cohort. They were reproduced and demonstrated high classification probability in two subsets of the U-BIOPRED asthma cohort. Focusing on the biology of the four clinical independently-validated easy-to-assess ADEPT asthma phenotypes will help understanding the unmet need and will aid in developing tailored therapies. NCT01274507 (ADEPT), registered October 28, 2010 and NCT01982162 (U-BIOPRED), registered October 30, 2013.

Genome-Wide miRNA Analysis Identifies miR-188-3p as a Novel Prognostic Marker and Molecular Factor Involved in Colorectal Carcinogenesis.

PubMed

Pichler, Martin; Stiegelbauer, Verena; Vychytilova-Faltejskova, Petra; Ivan, Cristina; Ling, Hui; Winter, Elke; Zhang, Xinna; Goblirsch, Matthew; Wulf-Goldenberg, Annika; Ohtsuka, Masahisa; Haybaeck, Johannes; Svoboda, Marek; Okugawa, Yoshinaga; Gerger, Armin; Hoefler, Gerald; Goel, Ajay; Slaby, Ondrej; Calin, George Adrian

2017-03-01

Purpose: Characterization of colorectal cancer transcriptome by high-throughput techniques has enabled the discovery of several differentially expressed genes involving previously unreported miRNA abnormalities. Here, we followed a systematic approach on a global scale to identify miRNAs as clinical outcome predictors and further validated them in the clinical and experimental setting. Experimental Design: Genome-wide miRNA sequencing data of 228 colorectal cancer patients from The Cancer Genome Atlas dataset were analyzed as a screening cohort to identify miRNAs significantly associated with survival according to stringent prespecified criteria. A panel of six miRNAs was further validated for their prognostic utility in a large independent validation cohort ( n = 332). In situ hybridization and functional experiments in a panel of colorectal cancer cell lines and xenografts further clarified the role of clinical relevant miRNAs. Results: Six miRNAs (miR-92b-3p, miR-188-3p, miR-221-5p, miR-331-3p, miR-425-3p, and miR-497-5p) were identified as strong predictors of survival in the screening cohort. High miR-188-3p expression proves to be an independent prognostic factor [screening cohort: HR = 4.137; 95% confidence interval (CI), 1.568-10.917; P = 0.004; validation cohort: HR = 1.538; 95% CI, 1.107-2.137; P = 0.010, respectively]. Forced miR-188-3p expression increased migratory behavior of colorectal cancer cells in vitro and metastases formation in vivo ( P < 0.05). The promigratory role of miR-188-3p is mediated by direct interaction with MLLT4, a novel identified player involved in colorectal cancer cell migration. Conclusions: miR-188-3p is a novel independent prognostic factor in colorectal cancer patients, which can be partly explained by its effect on MLLT4 expression and migration of cancer cells. Clin Cancer Res; 23(5); 1323-33. ©2016 AACR . ©2016 American Association for Cancer Research.

PLCO Ovarian Phase III Validation Study — EDRN Public Portal

Cancer.gov

Our preliminary data indicate that the performance of CA 125 as a screening test for ovarian cancer can be improved upon by additional biomarkers. With completion of one additional validation step, we will be ready to test the performance of a consensus marker panel in a phase III validation study. Given the original aims of the PLCO trial, we believe that the PLCO represents an ideal longitudinal cohort offering specimens for phase III validation of ovarian cancer biomarkers.

Optimal reproducibility of gated sestamibi and thallium myocardial perfusion study left ventricular ejection fractions obtained on a solid-state CZT cardiac camera requires operator input.

PubMed

Cherk, Martin H; Ky, Jason; Yap, Kenneth S K; Campbell, Patrina; McGrath, Catherine; Bailey, Michael; Kalff, Victor

2012-08-01

To evaluate the reproducibility of serial re-acquisitions of gated Tl-201 and Tc-99m sestamibi left ventricular ejection fraction (LVEF) measurements obtained on a new generation solid-state cardiac camera system during myocardial perfusion imaging and the importance of manual operator optimization of left ventricular wall tracking. Resting blinded automated (auto) and manual operator optimized (opt) LVEF measurements were measured using ECT toolbox (ECT) and Cedars-Sinai QGS software in two separate cohorts of 55 Tc-99m sestamibi (MIBI) and 50 thallium (Tl-201) myocardial perfusion studies (MPS) acquired in both supine and prone positions on a cadmium zinc telluride (CZT) solid-state camera system. Resting supine and prone automated LVEF measurements were similarly obtained in a further separate cohort of 52 gated cardiac blood pool scans (GCBPS) for validation of methodology and comparison. Appropriate use of Bland-Altman, chi-squared and Levene's equality of variance tests was used to analyse the resultant data comparisons. For all radiotracer and software combinations, manual checking and optimization of valve planes (+/- centre radius with ECT software) resulted in significant improvement in MPS LVEF reproducibility that approached that of planar GCBPS. No difference was demonstrated between optimized MIBI/Tl-201 QGS and planar GCBPS LVEF reproducibility (P = .17 and P = .48, respectively). ECT required significantly more manual optimization compared to QGS software in both supine and prone positions independent of radiotracer used (P < .02). Reproducibility of gated sestamibi and Tl-201 LVEF measurements obtained during myocardial perfusion imaging with ECT toolbox or QGS software packages using a new generation solid-state cardiac camera with improved image quality approaches that of planar GCBPS however requires visual quality control and operator optimization of left ventricular wall tracking for best results. Using this superior cardiac technology, Tl-201 reproducibility also appears at least equivalent to sestamibi for measuring LVEF.

A 2-Stage Genome-Wide Association Study to Identify Single Nucleotide Polymorphisms Associated With Development of Erectile Dysfunction Following Radiation Therapy for Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kerns, Sarah L.; Departments of Pathology and Genetics, Albert Einstein College of Medicine, Bronx, New York; Stock, Richard

2013-01-01

Purpose: To identify single nucleotide polymorphisms (SNPs) associated with development of erectile dysfunction (ED) among prostate cancer patients treated with radiation therapy. Methods and Materials: A 2-stage genome-wide association study was performed. Patients were split randomly into a stage I discovery cohort (132 cases, 103 controls) and a stage II replication cohort (128 cases, 102 controls). The discovery cohort was genotyped using Affymetrix 6.0 genome-wide arrays. The 940 top ranking SNPs selected from the discovery cohort were genotyped in the replication cohort using Illumina iSelect custom SNP arrays. Results: Twelve SNPs identified in the discovery cohort and validated in themore » replication cohort were associated with development of ED following radiation therapy (Fisher combined P values 2.1 Multiplication-Sign 10{sup -5} to 6.2 Multiplication-Sign 10{sup -4}). Notably, these 12 SNPs lie in or near genes involved in erectile function or other normal cellular functions (adhesion and signaling) rather than DNA damage repair. In a multivariable model including nongenetic risk factors, the odds ratios for these SNPs ranged from 1.6 to 5.6 in the pooled cohort. There was a striking relationship between the cumulative number of SNP risk alleles an individual possessed and ED status (Sommers' D P value = 1.7 Multiplication-Sign 10{sup -29}). A 1-allele increase in cumulative SNP score increased the odds for developing ED by a factor of 2.2 (P value = 2.1 Multiplication-Sign 10{sup -19}). The cumulative SNP score model had a sensitivity of 84% and specificity of 75% for prediction of developing ED at the radiation therapy planning stage. Conclusions: This genome-wide association study identified a set of SNPs that are associated with development of ED following radiation therapy. These candidate genetic predictors warrant more definitive validation in an independent cohort.« less

The Perils of Ignoring Design Effects in Experimental Studies: Lessons from a Mammography Screening Trial

PubMed Central

Glenn, Beth A.; Bastani, Roshan; Maxwell, Annette E.

2013-01-01

Objective Threats to external validity including pretest sensitization and the interaction of selection and an intervention are frequently overlooked by researchers despite their potential to significantly influence study outcomes. The purpose of this investigation was to conduct secondary data analyses to assess the presence of external validity threats in the setting of a randomized trial designed to promote mammography use in a high risk sample of women. Design During the trial, recruitment and intervention implementation took place in three cohorts (with different ethnic composition), utilizing two different designs (pretest-posttest control group design; posttest only control group design). Results Results reveal that the intervention produced different outcomes across cohorts, dependent upon the research design used and the characteristics of the sample. Conclusion These results illustrate the importance of weighing the pros and cons of potential research designs before making a selection and attending more closely to issues of external validity. PMID:23289517

Reliability and validity of the Modified Erikson Psychosocial Stage Inventory in diverse samples.

PubMed

Leidy, N K; Darling-Fisher, C S

1995-04-01

The Modified Erikson Psychosocial Stage Inventory (MEPSI) is a relatively simple survey measure designed to assess the strength of psychosocial attributes that arise from progression through Erikson's eight stages of development. The purpose of this study was to employ secondary analysis to evaluate the internal-consistency reliability and construct validity of the MEPSI across four diverse samples: healthy young adults, hemophilic men, healthy older adults, and older adults with chronic obstructive pulmonary disease. Special attention was given to the performance of the measure across gender, with exploratory analyses examining possible age cohort and health status effects. Internal-consistency estimates for the aggregate measure were high, whereas subscale reliability levels varied across age groups. Construct validity was supported across samples. Gender, cohort, and health effects offered interesting psychometric and theoretical insights and direction for further research. Findings indicated that the MEPSI might be a useful instrument for operationalizing and testing Eriksonian developmental theory in adults.

The perils of ignoring design effects in experimental studies: lessons from a mammography screening trial.

PubMed

Glenn, Beth A; Bastani, Roshan; Maxwell, Annette E

2013-01-01

Threats to external validity, including pretest sensitisation and the interaction of selection and an intervention, are frequently overlooked by researchers despite their potential to significantly influence study outcomes. The purpose of this investigation was to conduct secondary data analyses to assess the presence of external validity threats in the setting of a randomised trial designed to promote mammography use in a high-risk sample of women. During the trial, recruitment and intervention, implementation took place in three cohorts (with different ethnic composition), utilising two different designs (pretest-posttest control group design and posttest only control group design). Results reveal that the intervention produced different outcomes across cohorts, dependent upon the research design used and the characteristics of the sample. These results illustrate the importance of weighing the pros and cons of potential research designs before making a selection and attending more closely to issues of external validity.

Budget Impact of a Comprehensive Nutrition-Focused Quality Improvement Program for Malnourished Hospitalized Patients

PubMed Central

Sulo, Suela; Feldstein, Josh; Partridge, Jamie; Schwander, Bjoern; Sriram, Krishnan; Summerfelt, Wm. Thomas

2017-01-01

Background Nutrition interventions can alleviate the burden of malnutrition by improving patient outcomes; however, evidence on the economic impact of medical nutrition intervention remains limited. A previously published nutrition-focused quality improvement program targeting malnourished hospitalized patients showed that screening patients with a validated screening tool at admission, rapidly administering oral nutritional supplements, and educating patients on supplement adherence result in significant reductions in 30-day unplanned readmissions and hospital length of stay. Objectives To assess the potential cost-savings associated with decreased 30-day readmissions and hospital length of stay in malnourished inpatients through a nutrition-focused quality improvement program using a web-based budget impact model, and to demonstrate the clinical and fiscal value of the intervention. Methods The reduction in readmission rate and length of stay for 1269 patients enrolled in the quality improvement program (between October 13, 2014, and April 2, 2015) were compared with the pre–quality improvement program baseline and validation cohorts (4611 patients vs 1319 patients, respectively) to calculate potential cost-savings as well as to inform the design of the budget impact model. Readmission rate and length-of-stay reductions were calculated by determining the change from baseline to post–quality improvement program as well as the difference between the validation cohort and the post–quality improvement program, respectively. Results As a result of improved health outcomes for the treated patients, the nutrition-focused quality improvement program led to a reduction in 30-day hospital readmissions and length of stay. The avoided hospital readmissions and reduced number of days in the hospital for the patients in the quality improvement program resulted in cost-savings of $1,902,933 versus the pre–quality improvement program baseline cohort, and $4,896,758 versus the pre–quality improvement program in the validation cohort. When these costs were assessed across the entire patient population enrolled in the quality improvement program, per-patient net savings of $1499 when using the baseline cohort as the comparator and savings per patient treated of $3858 when using the validated cohort as the comparator were achieved. Conclusion The nutrition-focused quality improvement program reduced the per-patient healthcare costs by avoiding 30-day readmissions and through reduced length of hospital stay. These clinical and economic outcomes provide a rationale for merging patient care and financial modeling to advance the delivery of value-based medicine in a malnourished hospitalized population. The use of a novel web-based budget impact model supports the integration of comparative effectiveness analytics and healthcare resource management in the hospital setting to provide optimal quality of care at a reduced overall cost. PMID:28975010

Budget Impact of a Comprehensive Nutrition-Focused Quality Improvement Program for Malnourished Hospitalized Patients.

PubMed

Sulo, Suela; Feldstein, Josh; Partridge, Jamie; Schwander, Bjoern; Sriram, Krishnan; Summerfelt, Wm Thomas

2017-07-01

Nutrition interventions can alleviate the burden of malnutrition by improving patient outcomes; however, evidence on the economic impact of medical nutrition intervention remains limited. A previously published nutrition-focused quality improvement program targeting malnourished hospitalized patients showed that screening patients with a validated screening tool at admission, rapidly administering oral nutritional supplements, and educating patients on supplement adherence result in significant reductions in 30-day unplanned readmissions and hospital length of stay. To assess the potential cost-savings associated with decreased 30-day readmissions and hospital length of stay in malnourished inpatients through a nutrition-focused quality improvement program using a web-based budget impact model, and to demonstrate the clinical and fiscal value of the intervention. The reduction in readmission rate and length of stay for 1269 patients enrolled in the quality improvement program (between October 13, 2014, and April 2, 2015) were compared with the pre-quality improvement program baseline and validation cohorts (4611 patients vs 1319 patients, respectively) to calculate potential cost-savings as well as to inform the design of the budget impact model. Readmission rate and length-of-stay reductions were calculated by determining the change from baseline to post-quality improvement program as well as the difference between the validation cohort and the post-quality improvement program, respectively. As a result of improved health outcomes for the treated patients, the nutrition-focused quality improvement program led to a reduction in 30-day hospital readmissions and length of stay. The avoided hospital readmissions and reduced number of days in the hospital for the patients in the quality improvement program resulted in cost-savings of $1,902,933 versus the pre-quality improvement program baseline cohort, and $4,896,758 versus the pre-quality improvement program in the validation cohort. When these costs were assessed across the entire patient population enrolled in the quality improvement program, per-patient net savings of $1499 when using the baseline cohort as the comparator and savings per patient treated of $3858 when using the validated cohort as the comparator were achieved. The nutrition-focused quality improvement program reduced the per-patient healthcare costs by avoiding 30-day readmissions and through reduced length of hospital stay. These clinical and economic outcomes provide a rationale for merging patient care and financial modeling to advance the delivery of value-based medicine in a malnourished hospitalized population. The use of a novel web-based budget impact model supports the integration of comparative effectiveness analytics and healthcare resource management in the hospital setting to provide optimal quality of care at a reduced overall cost.

Validity of empirical models of exposure in asphalt paving

PubMed Central

Burstyn, I; Boffetta, P; Burr, G; Cenni, A; Knecht, U; Sciarra, G; Kromhout, H

2002-01-01

Aims: To investigate the validity of empirical models of exposure to bitumen fume and benzo(a)pyrene, developed for a historical cohort study of asphalt paving in Western Europe. Methods: Validity was evaluated using data from the USA, Italy, and Germany not used to develop the original models. Correlation between observed and predicted exposures was examined. Bias and precision were estimated. Results: Models were imprecise. Furthermore, predicted bitumen fume exposures tended to be lower (-70%) than concentrations found during paving in the USA. This apparent bias might be attributed to differences between Western European and USA paving practices. Evaluation of the validity of the benzo(a)pyrene exposure model revealed a similar to expected effect of re-paving and a larger than expected effect of tar use. Overall, benzo(a)pyrene models underestimated exposures by 51%. Conclusions: Possible bias as a result of underestimation of the impact of coal tar on benzo(a)pyrene exposure levels must be explored in sensitivity analysis of the exposure–response relation. Validation of the models, albeit limited, increased our confidence in their applicability to exposure assessment in the historical cohort study of cancer risk among asphalt workers. PMID:12205236

Decreasing Sports Activity with Increasing Age? Findings from a 20-Year Longitudinal and Cohort Sequence Analysis

ERIC Educational Resources Information Center

Breuer, Christoph; Wicker, Pamela

2009-01-01

According to cross-sectional studies in sport science literature, decreasing sports activity with increasing age is generally assumed. In this paper, the validity of this assumption is checked by applying more effective methods of analysis, such as longitudinal and cohort sequence analyses. With the help of 20 years' worth of data records from the…

Development and External Validation of a Prognostic Nomogram for Metastatic Uveal Melanoma

PubMed Central

Valpione, Sara; Moser, Justin C.; Parrozzani, Raffaele; Bazzi, Marco; Mansfield, Aaron S.; Mocellin, Simone; Pigozzo, Jacopo; Midena, Edoardo; Markovic, Svetomir N.; Aliberti, Camillo; Campana, Luca G.; Chiarion-Sileni, Vanna

2015-01-01

Background Approximately 50% of patients with uveal melanoma (UM) will develop metastatic disease, usually involving the liver. The outcome of metastatic UM (mUM) is generally poor and no standard therapy has been established. Additionally, clinicians lack a validated prognostic tool to evaluate these patients. The aim of this work was to develop a reliable prognostic nomogram for clinicians. Patients and Methods Two cohorts of mUM patients, from Veneto Oncology Institute (IOV) (N=152) and Mayo Clinic (MC) (N=102), were analyzed to develop and externally validate, a prognostic nomogram. Results The median survival of mUM was 17.2 months in the IOV cohort and 19.7 in the MC cohort. Percentage of liver involvement (HR 1.6), elevated levels of serum LDH (HR 1.6), and a WHO performance status=1 (HR 1.5) or 2–3 (HR 4.6) were associated with worse prognosis. Longer disease-free interval from diagnosis of UM to that of mUM conferred a survival advantage (HR 0.9). The nomogram had a concordance probability of 0.75 (SE .006) in the development dataset (IOV), and 0.80 (SE .009) in the external validation (MC). Nomogram predictions were well calibrated. Conclusions The nomogram, which includes percentage of liver involvement, LDH levels, WHO performance status and disease free-interval accurately predicts the prognosis of mUM and could be useful for decision-making and risk stratification for clinical trials. PMID:25780931

Enjoying mathematics or feeling competent in mathematics? Reciprocal effects on mathematics achievement and perceived math effort expenditure.

PubMed

Pinxten, Maarten; Marsh, Herbert W; De Fraine, Bieke; Van Den Noortgate, Wim; Van Damme, Jan

2014-03-01

The multidimensionality of the academic self-concept in terms of domain specificity has been well established in previous studies, whereas its multidimensionality in terms of motivational functions (the so-called affect-competence separation) needs further examination. This study aims at exploring differential effects of enjoyment and competence beliefs on two external validity criteria in the field of mathematics. Data analysed in this study were part of a large-scale longitudinal research project. Following a five-wave design, math enjoyment, math competence beliefs, math achievement, and perceived math effort expenditure measures were repeatedly collected from a cohort of 4,724 pupils in Grades 3-7. Confirmatory factor analysis (CFA) was used to test the internal factor structure of the math self-concept. Additionally, a series of nested models was tested using structural equation modelling to examine longitudinal reciprocal interrelations between math competence beliefs and math enjoyment on the one hand and math achievement and perceived math effort expenditure on the other. Our results showed that CFA models with separate factors for math enjoyment and math competence beliefs fit the data substantially better than models without it. Furthermore, differential relationships between both constructs and the two educational outcomes were observed. Math competence beliefs had positive effects on math achievement and negative effects on perceived math effort expenditure. Math enjoyment had (mild) positive effects on subsequent perceived effort expenditure and math competence beliefs. This study provides further support for the affect-competence separation. Theoretical issues regarding adequate conceptualization and practical consequences for practitioners are discussed. © 2013 The British Psychological Society.

Chronic lymphocytic leukemia: A prognostic model comprising only two biomarkers (IGHV mutational status and FISH cytogenetics) separates patients with different outcome and simplifies the CLL-IPI.

PubMed

Delgado, Julio; Doubek, Michael; Baumann, Tycho; Kotaskova, Jana; Molica, Stefano; Mozas, Pablo; Rivas-Delgado, Alfredo; Morabito, Fortunato; Pospisilova, Sarka; Montserrat, Emili

2017-04-01

Rai and Binet staging systems are important to predict the outcome of patients with chronic lymphocytic leukemia (CLL) but do not reflect the biologic diversity of the disease nor predict response to therapy, which ultimately shape patients' outcome. We devised a biomarkers-only CLL prognostic system based on the two most important prognostic parameters in CLL (i.e., IGHV mutational status and fluorescence in situ hybridization [FISH] cytogenetics), separating three different risk groups: (1) low-risk (mutated IGHV + no adverse FISH cytogenetics [del(17p), del(11q)]); (2) intermediate-risk (either unmutated IGHV or adverse FISH cytogenetics) and (3) high-risk (unmutated IGHV + adverse FISH cytogenetics). In 524 unselected subjects with CLL, the 10-year overall survival was 82% (95% CI 76%-88%), 52% (45%-62%), and 27% (17%-42%) for the low-, intermediate-, and high-risk groups, respectively. Patients with low-risk comprised around 50% of the series and had a life expectancy comparable to the general population. The prognostic model was fully validated in two independent cohorts, including 417 patients representative of general CLL population and 337 patients with Binet stage A CLL. The model had a similar discriminatory value as the CLL-IPI. Moreover, it applied to all patients with CLL independently of age, and separated patients with different risk within Rai or Binet clinical stages. The biomarkers-only CLL prognostic system presented here simplifies the CLL-IPI and could be useful in daily practice and to stratify patients in clinical trials. © 2017 Wiley Periodicals, Inc.

The Fit for School Health Outcome Study - a longitudinal survey to assess health impacts of an integrated school health programme in the Philippines.

PubMed

Monse, Bella; Benzian, Habib; Naliponguit, Ella; Belizario, Vincente; Schratz, Alexander; van Palenstein Helderman, Wim

2013-03-21

Child health in many low- and middle-income countries lags behind international goals and affects children's education, well-being, and general development. Large-scale school health programmes can be effective in reducing preventable diseases through cost-effective interventions. This paper outlines the baseline and 1-year results of a longitudinal health study assessing the impact of the Fit for School Programme in the Philippines. A longitudinal 4-year cohort study was conducted in the province of Camiguin, Mindanao (experimental group); an external concurrent control group was studied in Gingoog, Mindanao. The study has three experimental groups: group 1-daily handwashing with soap, daily brushing with fluoride toothpaste, biannual deworming with 400 mg albendazole (Essential Health Care Program [EHCP]); group 2-EHCP plus twice-a-year access to school-based Oral Urgent Treatment; group 3-EHCP plus weekly toothbrushing with high-fluoride concentration gel. A non-concurrent internal control group was also included. Baseline data on anthropometric indicators to calculate body mass index (BMI), soil-transmitted helminths (STH) infection in stool samples, and dental caries were collected in August 2009 and August 2010. Data were analysed to assess validity of the control group design, baseline, and 1-year results. In the cohort study, 412 children were examined at baseline and 341 1 year after intervention. The baseline results were in line with national averages for STH infection, BMI, and dental caries in group 1 and the control groups. Children lost to follow-up had similar baseline characteristics in the experimental and control groups. After 1 year, group 1 showed a significantly higher increase in mean BMI and lower prevalence of moderate to heavy STH infection than the external concurrent control group. The increases in caries and dental infections were reduced but not statistically significant. The results for groups 2 and 3 will be reported separately. Despite the short 1-year observation period, the study found a reduction in the prevalence of moderate to heavy STH infections, a rise in mean BMI, and a (statistically non-significant) reduction in dental caries and infections. The study design proved functional in actual field conditions. Critical aspects affecting the validity of cohort studies are analysed and discussed. DRKS00003431 WHO Universal Trial Number U1111-1126-0718.

Application of a High Throughput Method of Biomarker Discovery to Improvement of the EarlyCDT®-Lung Test

PubMed Central

Macdonald, Isabel K.; Murray, Andrea; Healey, Graham F.; Parsy-Kowalska, Celine B.; Allen, Jared; McElveen, Jane; Robertson, Chris; Sewell, Herbert F.; Chapman, Caroline J.; Robertson, John F. R.

2012-01-01

Background The National Lung Screening Trial showed that CT screening for lung cancer led to a 20% reduction in mortality. However, CT screening has a number of disadvantages including low specificity. A validated autoantibody assay is available commercially (EarlyCDT®-Lung) to aid in the early detection of lung cancer and risk stratification in patients with pulmonary nodules detected by CT. Recent advances in high throughput (HTP) cloning and expression methods have been developed into a discovery pipeline to identify biomarkers that detect autoantibodies. The aim of this study was to demonstrate the successful clinical application of this strategy to add to the EarlyCDT-Lung panel in order to improve its sensitivity and specificity (and hence positive predictive value, (PPV)). Methods and Findings Serum from two matched independent cohorts of lung cancer patients were used (n = 100 and n = 165). Sixty nine proteins were initially screened on an abridged HTP version of the autoantibody ELISA using protein prepared on small scale by a HTP expression and purification screen. Promising leads were produced in shake flask culture and tested on the full assay. These results were analyzed in combination with those from the EarlyCDT-Lung panel in order to provide a set of re-optimized cut-offs. Five proteins that still displayed cancer/normal differentiation were tested for reproducibility and validation on a second batch of protein and a separate patient cohort. Addition of these proteins resulted in an improvement in the sensitivity and specificity of the test from 38% and 86% to 49% and 93% respectively (PPV improvement from 1 in 16 to 1 in 7). Conclusion This is a practical example of the value of investing resources to develop a HTP technology. Such technology may lead to improvement in the clinical utility of the EarlyCDT­-Lung test, and so further aid the early detection of lung cancer. PMID:23272083

SMAD4 gene mutation predicts poor prognosis in patients undergoing resection for colorectal liver metastases.

PubMed

Mizuno, Takashi; Cloyd, Jordan M; Vicente, Diego; Omichi, Kiyohiko; Chun, Yun Shin; Kopetz, Scott E; Maru, Dipen; Conrad, Claudius; Tzeng, Ching-Wei D; Wei, Steven H; Aloia, Thomas A; Vauthey, Jean-Nicolas

2018-05-01

Dorsophilia protein, mothers against decapentaplegic homolog 4 (SMAD4) is a key mediator in the transforming growth factor (TGF)-β signaling pathway and SMAD4 gene mutations are thought to play a critical role in colorectal cancer (CRC) progression. However, little is known about its influence on survival in patients undergoing resection for colorectal liver metastases (CLM). Between 2005 and 2015, all patients with known SMAD4 mutation status who underwent resection of CLM were identified. Patients with SMAD4 mutation were compared to those with SMAD4 wild type. Next, the prognostic value of SMAD4 mutation was validated in a separate cohort of patients with synchronous stage IV CRC who underwent systemic therapy alone. Of 278 patients, 37 (13%) were SMAD4 mutant while 241 (87%) were wild type. Overall survival (OS) after hepatic resection was worse in SMAD4-mutant patients compared to SMAD4 wild type (OS rate at 3 years, 62% vs. 82%; P < 0.0001). Independent predictors for worse OS were poor differentiation (hazard ratio [HR] 2.586; P = 0.007), multiple tumors (HR 1.970; P = 0.01), diameter greater than 3 cm (HR 1.752; P = 0.017), R1 margin status (HR 2.452; P = 0.014), RAS mutation (HR 2.044; P = 0.002), and SMAD4 mutation (HR 2.773; P < 0.0001). Among 237 patients in the validation cohort, SMAD4-mutations were significantly associated with worse 3-year OS rate (22% vs. 38%; P = 0.012) and was an independent predictor for worse OS (HR, 1.647; P = 0.032). SMAD4 mutation is independently associated with worse outcomes among patients undergoing resection of CLM. Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Impact of sex on prognostic host factors in surgical patients with lung cancer.

PubMed

Wainer, Zoe; Wright, Gavin M; Gough, Karla; Daniels, Marissa G; Choong, Peter; Conron, Matthew; Russell, Prudence A; Alam, Naveed Z; Ball, David; Solomon, Benjamin

2017-12-01

Lung cancer has markedly poorer survival in men. Recognized important prognostic factors are divided into host, tumour and environmental factors. Traditional staging systems that use only tumour factors to predict prognosis are of limited accuracy. By examining sex-based patterns of disease-specific survival in non-small cell lung cancer patients, we determined the effect of sex on the prognostic value of additional host factors. Two cohorts of patients treated surgically with curative intent between 2000 and 2009 were utilized. The primary cohort was from Melbourne, Australia, with an independent validation set from the American Surveillance, Epidemiology and End Results (SEER) database. Univariate and multivariate analyses of validated host-related prognostic factors were performed in both cohorts to investigate the differences in survival between men and women. The Melbourne cohort had 605 patients (61% men) and SEER cohort comprised 55 681 patients (51% men). Disease-specific 5-year survival showed men had statistically significant poorer survival in both cohorts (P < 0.001); Melbourne men at 53.2% compared with women at 68.3%, and SEER 53.3% men and 62.0% women were alive at 5 years. Being male was independently prognostic for disease-specific mortality in the Melbourne cohort after adjustment for ethnicity, smoking history, performance status, age, pathological stage and histology (hazard ratio = 1.54, 95% confidence interval: 1.10-2.16, P = 0.012). Sex differences in non-small cell lung cancer are important irrespective of age, ethnicity, smoking, performance status and tumour, node and metastasis stage. Epidemiological findings such as these should be translated into research and clinical paradigms to determine the factors that influence the survival disadvantage experienced by men. © 2016 Royal Australasian College of Surgeons.

Complete Versus Staged Repair for Neonates With Tetralogy of Fallot: Establishment and Validation of a Cohort of 2235 Patients Using Detailed Surgery Sequence Review of Health Care Administrative Data.

PubMed

Savla, Jill J; Fisher, Brian T; Faerber, Jennifer A; Huang, Yuan-Shung V; Mercer-Rosa, Laura

2017-12-12

The surgical strategy for neonates with tetralogy of Fallot (TOF) consists of complete or staged repair. Assessing the comparative effectiveness of these approaches is facilitated by a large multicenter cohort. We propose a novel process for cohort assembly using the Pediatric Health Information System (PHIS), an administrative database that contains clinical and billing data for inpatient and emergency department stays from tertiary children's hospitals. A 4-step process was used to identify neonates with TOF: (1) screen neonates in PHIS with International Classification of Diseases-9 (ICD-9) diagnosis or procedure codes for TOF; (2) include patients with TOF procedures before 30 days of age; (3) exclude patients with missing 2-year follow-up data; (4) analyze patients' 2-year surgery sequence patterns, exclude patients inconsistent with a treatment strategy for TOF, and designate patients as complete or staged repair. Manual chart review at 1 PHIS center was performed to validate this process. Between January 2004 and March 2015, 5862 patients were identified in step 1. Step 2 of cohort assembly excluded 3425 patients (58%); step 3 excluded 148 patients (3%); and step 4 excluded 54 patients (1%). The final cohort consisted of 2235 neonates with TOF from 45 hospitals. Manual chart review of 336 patients showed a positive predictive value for accurate PHIS identification of 44% after step 1 and 97% after step 4. This systematic cohort identification algorithm resulted in a high positive predictive value to appropriately categorize patients. This carefully assembled cohort offers a unique opportunity for future studies in neonatal TOF outcomes.

Natural Language Processing for Asthma Ascertainment in Different Practice Settings.

PubMed

Wi, Chung-Il; Sohn, Sunghwan; Ali, Mir; Krusemark, Elizabeth; Ryu, Euijung; Liu, Hongfang; Juhn, Young J

We developed and validated NLP-PAC, a natural language processing (NLP) algorithm based on predetermined asthma criteria (PAC) for asthma ascertainment using electronic health records at Mayo Clinic. To adapt NLP-PAC in a different health care setting, Sanford Children Hospital, by assessing its external validity. The study was designed as a retrospective cohort study that used a random sample of 2011-2012 Sanford Birth cohort (n = 595). Manual chart review was performed on the cohort for asthma ascertainment on the basis of the PAC. We then used half of the cohort as a training cohort (n = 298) and the other half as a blind test cohort to evaluate the adapted NLP-PAC algorithm. Association of known asthma-related risk factors with the Sanford-NLP algorithm-driven asthma ascertainment was tested. Among the eligible test cohort (n = 297), 160 (53%) were males, 268 (90%) white, and the median age was 2.3 years (range, 1.5-3.1 years). NLP-PAC, after adaptation, and the human abstractor identified 74 (25%) and 72 (24%) subjects, respectively, with 66 subjects identified by both approaches. Sensitivity, specificity, positive predictive value, and negative predictive value for the NLP algorithm in predicting asthma status were 92%, 96%, 89%, and 97%, respectively. The known risk factors for asthma identified by NLP (eg, smoking history) were similar to the ones identified by manual chart review. Successful implementation of NLP-PAC for asthma ascertainment in 2 different practice settings demonstrates the feasibility of automated asthma ascertainment leveraging electronic health record data with a potential to enable large-scale, multisite asthma studies to improve asthma care and research. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Novel algorithmic approach predicts tumor mutation load and correlates with immunotherapy clinical outcomes using a defined gene mutation set.

PubMed

Roszik, Jason; Haydu, Lauren E; Hess, Kenneth R; Oba, Junna; Joon, Aron Y; Siroy, Alan E; Karpinets, Tatiana V; Stingo, Francesco C; Baladandayuthapani, Veera; Tetzlaff, Michael T; Wargo, Jennifer A; Chen, Ken; Forget, Marie-Andrée; Haymaker, Cara L; Chen, Jie Qing; Meric-Bernstam, Funda; Eterovic, Agda K; Shaw, Kenna R; Mills, Gordon B; Gershenwald, Jeffrey E; Radvanyi, Laszlo G; Hwu, Patrick; Futreal, P Andrew; Gibbons, Don L; Lazar, Alexander J; Bernatchez, Chantale; Davies, Michael A; Woodman, Scott E

2016-10-25

While clinical outcomes following immunotherapy have shown an association with tumor mutation load using whole exome sequencing (WES), its clinical applicability is currently limited by cost and bioinformatics requirements. We developed a method to accurately derive the predicted total mutation load (PTML) within individual tumors from a small set of genes that can be used in clinical next generation sequencing (NGS) panels. PTML was derived from the actual total mutation load (ATML) of 575 distinct melanoma and lung cancer samples and validated using independent melanoma (n = 312) and lung cancer (n = 217) cohorts. The correlation of PTML status with clinical outcome, following distinct immunotherapies, was assessed using the Kaplan-Meier method. PTML (derived from 170 genes) was highly correlated with ATML in cutaneous melanoma and lung adenocarcinoma validation cohorts (R 2  = 0.73 and R 2  = 0.82, respectively). PTML was strongly associated with clinical outcome to ipilimumab (anti-CTLA-4, three cohorts) and adoptive T-cell therapy (1 cohort) clinical outcome in melanoma. Clinical benefit from pembrolizumab (anti-PD-1) in lung cancer was also shown to significantly correlate with PTML status (log rank P value < 0.05 in all cohorts). The approach of using small NGS gene panels, already applied to guide employment of targeted therapies, may have utility in the personalized use of immunotherapy in cancer.

Development and validation of the Neonatal Mortality Score-9 Mexico to predict mortality in critically ill neonates.

PubMed

Márquez-González, Horacio; Jiménez-Báez, María Valeria; Muñoz-Ramírez, C Mireya; Yáñez-Gutiérrez, Lucelli; Huelgas-Plaza, Ana C; Almeida-Gutiérrez, Eduardo; Villa-Romero, Antonio Rafael

2015-06-01

Prognostic scales or scores are useful for physicians who work in neonatal intensive care units. There are several validated neonatal scores but they are mostly applicable to low birth weight infants. The aim of this study was to develop and validate a mortality prognostic score in newborn infants, that would include new prognostic outcome measures. The study was conducted in a mother and child hospital in the city of Mexico, part of the Instituto Mexicano del Seguro Social (Mexican Institute of Social Security). In the first phase of the study, a nested case-control study was designed (newborn infants admitted on the basis of severity criteria during the first day of life), in which a scale was identified and developed with gradual parameters of cumulative score consisting of nine independent outcome measures to predict death, as follows: weight, metabolic acidemia, lactate, PaO2/FiO2, p(A-a) O2, A/a, platelets and serum glucose.Validation was performed in a matched prospective cohort, using 7-day mortality as an endpoint. The initial cohort consisted of 424 newborn infants. Twenty-two cases and 132 controls were selected; and 9 outcome measures were identified, making up the scale named neonatal mortality score-9 Mexico. The validation cohort consisted of 227 newborn infants. Forty-four (19%) deaths were recorded, with an area under the curve (AUC) of 0.92. With a score between 16 and 18, an 85 (11-102) hazard ratio, 99% specificity, 71% positive predictive value and 90% negative predictive value were reported. Conclusions .The proposed scale is a reliable tool to predict severity in newborn infants.

Validating the TeleStroke Mimic Score: A Prediction Rule for Identifying Stroke Mimics Evaluated Over Telestroke Networks.

PubMed

Ali, Syed F; Hubert, Gordian J; Switzer, Jeffrey A; Majersik, Jennifer J; Backhaus, Roland; Shepard, L Wylie; Vedala, Kishore; Schwamm, Lee H

2018-03-01

Up to 30% of acute stroke evaluations are deemed stroke mimics, and these are common in telestroke as well. We recently published a risk prediction score for use during telestroke encounters to differentiate stroke mimics from ischemic cerebrovascular disease derived and validated in the Partners TeleStroke Network. Using data from 3 distinct US and European telestroke networks, we sought to externally validate the TeleStroke Mimic (TM) score in a broader population. We evaluated the TM score in 1930 telestroke consults from the University of Utah, Georgia Regents University, and the German TeleMedical Project for Integrative Stroke Care Network. We report the area under the curve in receiver-operating characteristic curve analysis with 95% confidence interval for our previously derived TM score in which lower TM scores correspond with a higher likelihood of being a stroke mimic. Based on final diagnosis at the end of the telestroke consultation, there were 630 of 1930 (32.6%) stroke mimics in the external validation cohort. All 6 variables included in the score were significantly different between patients with ischemic cerebrovascular disease versus stroke mimics. The TM score performed well (area under curve, 0.72; 95% confidence interval, 0.70-0.73; P <0.001), similar to our prior external validation in the Partners National Telestroke Network. The TM score's ability to predict the presence of a stroke mimic during telestroke consultation in these diverse cohorts was similar to its performance in our original cohort. Predictive decision-support tools like the TM score may help highlight key clinical differences between mimics and patients with stroke during complex, time-critical telestroke evaluations. © 2018 American Heart Association, Inc.

Validation of the DECAF score to predict hospital mortality in acute exacerbations of COPD

PubMed Central

Echevarria, C; Steer, J; Heslop-Marshall, K; Stenton, SC; Hickey, PM; Hughes, R; Wijesinghe, M; Harrison, RN; Steen, N; Simpson, AJ; Gibson, GJ; Bourke, SC

2016-01-01

Background Hospitalisation due to acute exacerbations of COPD (AECOPD) is common, and subsequent mortality high. The DECAF score was derived for accurate prediction of mortality and risk stratification to inform patient care. We aimed to validate the DECAF score, internally and externally, and to compare its performance to other predictive tools. Methods The study took place in the two hospitals within the derivation study (internal validation) and in four additional hospitals (external validation) between January 2012 and May 2014. Consecutive admissions were identified by screening admissions and searching coding records. Admission clinical data, including DECAF indices, and mortality were recorded. The prognostic value of DECAF and other scores were assessed by the area under the receiver operator characteristic (AUROC) curve. Results In the internal and external validation cohorts, 880 and 845 patients were recruited. Mean age was 73.1 (SD 10.3) years, 54.3% were female, and mean (SD) FEV1 45.5 (18.3) per cent predicted. Overall mortality was 7.7%. The DECAF AUROC curve for inhospital mortality was 0.83 (95% CI 0.78 to 0.87) in the internal cohort and 0.82 (95% CI 0.77 to 0.87) in the external cohort, and was superior to other prognostic scores for inhospital or 30-day mortality. Conclusions DECAF is a robust predictor of mortality, using indices routinely available on admission. Its generalisability is supported by consistent strong performance; it can identify low-risk patients (DECAF 0–1) potentially suitable for Hospital at Home or early supported discharge services, and high-risk patients (DECAF 3–6) for escalation planning or appropriate early palliation. Trial registration number UKCRN ID 14214. PMID:26769015

Validity of Administrative Data in Identifying Cancer-related Events in Adolescents and Young Adults: A Population-based Study Using the IMPACT Cohort.

PubMed

Gupta, Sumit; Nathan, Paul C; Baxter, Nancy N; Lau, Cindy; Daly, Corinne; Pole, Jason D

2018-06-01

Despite the importance of estimating population level cancer outcomes, most registries do not collect critical events such as relapse. Attempts to use health administrative data to identify these events have focused on older adults and have been mostly unsuccessful. We developed and tested administrative data-based algorithms in a population-based cohort of adolescents and young adults with cancer. We identified all Ontario adolescents and young adults 15-21 years old diagnosed with leukemia, lymphoma, sarcoma, or testicular cancer between 1992-2012. Chart abstraction determined the end of initial treatment (EOIT) date and subsequent cancer-related events (progression, relapse, second cancer). Linkage to population-based administrative databases identified fee and procedure codes indicating cancer treatment or palliative care. Algorithms determining EOIT based on a time interval free of treatment-associated codes, and new cancer-related events based on billing codes, were compared with chart-abstracted data. The cohort comprised 1404 patients. Time periods free of treatment-associated codes did not validly identify EOIT dates; using subsequent codes to identify new cancer events was thus associated with low sensitivity (56.2%). However, using administrative data codes that occurred after the EOIT date based on chart abstraction, the first cancer-related event was identified with excellent validity (sensitivity, 87.0%; specificity, 93.3%; positive predictive value, 81.5%; negative predictive value, 95.5%). Although administrative data alone did not validly identify cancer-related events, administrative data in combination with chart collected EOIT dates was associated with excellent validity. The collection of EOIT dates by cancer registries would significantly expand the potential of administrative data linkage to assess cancer outcomes.

Development and validation of the ORACLE score to predict risk of osteoporosis.

PubMed

Richy, Florent; Deceulaer, Fréderic; Ethgen, Olivier; Bruyère, Olivier; Reginster, Jean-Yves

2004-11-01

To develop and validate a composite index, the Osteoporosis Risk Assessment by Composite Linear Estimate (ORACLE), that includes risk factors and ultrasonometric outcomes to screen for osteoporosis. Two cohorts of postmenopausal women aged 45 years and older participated in the development (n = 407) and the validation (n = 202) of ORACLE. Their bone mineral density was determined by dual energy x-ray absorptiometry and quantitative ultrasonometry (QUS), and their historical and clinical risk factors were assessed (January to June 2003). Logistic regression analysis was used to select significant predictors of bone mineral density, whereas receiver operating characteristic (ROC) analysis was used to assess the discriminatory performance of ORACLE. The final logistic regression model retained 4 biometric or historical variables and 1 ultrasonometric outcome. The ROC areas under the curves (AUCs) for ORACLE were 84% for the prediction of osteoporosis and 78% for low bone mass. A sensitivity of 90% corresponded to a specificity of 50% for identification of women at risk of developing osteoporosis. The corresponding positive and negative predictive values were 86% and 54%, respectively, in the development cohort. In the validation cohort, the AUCs for identification of osteoporosis and low bone mass were 81% and 76% for ORACLE, 69% and 64% for QUS T score, 71% and 68% for QUS ultrasonometric bone profile index, and 76% and 75% for Osteoporosis Self-assessment Tool, respectively. ORACLE had the best discriminatory performance in identifying osteoporosis compared with the other approaches (P < .05). ORACLE exhibited the highest discriminatory properties compared with ultrasonography alone or other previously validated risk indices. It may be helpful to enhance the predictive value of QUS.

Retrospective Derivation and Validation of an Automated Electronic Search Algorithm to Identify Post Operative Cardiovascular and Thromboembolic Complications

PubMed Central

Tien, M.; Kashyap, R.; Wilson, G. A.; Hernandez-Torres, V.; Jacob, A. K.; Schroeder, D. R.

2015-01-01

Summary Background With increasing numbers of hospitals adopting electronic medical records, electronic search algorithms for identifying postoperative complications can be invaluable tools to expedite data abstraction and clinical research to improve patient outcomes. Objectives To derive and validate an electronic search algorithm to identify postoperative thromboembolic and cardiovascular complications such as deep venous thrombosis, pulmonary embolism, or myocardial infarction within 30 days of total hip or knee arthroplasty. Methods A total of 34 517 patients undergoing total hip or knee arthroplasty between January 1, 1996 and December 31, 2013 were identified. Using a derivation cohort of 418 patients, several iterations of a free-text electronic search were developed and refined for each complication. Subsequently, the automated search algorithm was validated on an independent cohort of 2 857 patients, and the sensitivity and specificities were compared to the results of manual chart review. Results In the final derivation subset, the automated search algorithm achieved a sensitivity of 91% and specificity of 85% for deep vein thrombosis, a sensitivity of 96% and specificity of 100% for pulmonary embolism, and a sensitivity of 100% and specificity of 95% for myocardial infarction. When applied to the validation cohort, the search algorithm achieved a sensitivity of 97% and specificity of 99% for deep vein thrombosis, a sensitivity of 97% and specificity of 100% for pulmonary embolism, and a sensitivity of 100% and specificity of 99% for myocardial infarction. Conclusions The derivation and validation of an electronic search strategy can accelerate the data abstraction process for research, quality improvement, and enhancement of patient care, while maintaining superb reliability compared to manual review. PMID:26448798

Development and validation of a risk-prediction algorithm for the recurrence of panic disorder.

PubMed

Liu, Yan; Sareen, Jitender; Bolton, James; Wang, JianLi

2015-05-01

To develop and validate a risk prediction algorithm for the recurrence of panic disorder. Three-year longitudinal data were taken from the National Epidemiologic Survey on Alcohol and Related Conditions (2001/2002-2004/2005). One thousand six hundred and eighty one participants with a lifetime panic disorder and who had not had panic attacks for at least 2 months at baseline were included. The development cohort included 949 participants; 732 from different census regions were in the validation cohort. Recurrence of panic disorder over the follow-up period was assessed using the Alcohol Use Disorder and Associated Disabilities Interview Schedule, based on the DSM-IV criteria. Logistic regression was used for deriving the algorithm. Discrimination and calibration were assessed in the development and the validation cohorts. The developed algorithm consisted of 11 predictors: age, sex, panic disorder in the past 12 months, nicotine dependence, rapid heartbeat/tachycardia, taking medication for panic attacks, feelings of choking and persistent worry about having another panic attack, two personality traits, and childhood trauma. The algorithm had good discriminative power (C statistic = 0.7863, 95% CI: 0.7487, 0.8240). The C statistic was 0.7283 (95% CI: 0.6889, 0.7764) in the external validation data set. The developed risk algorithm for predicting the recurrence of panic disorder has good discrimination and excellent calibration. Data related to the predictors can be easily attainable in routine clinical practice. It can be used by clinicians to calculate the probability of recurrence of panic disorder in the next 3 years for individual patients, communicate with patients regarding personal risks, and thus improve personalized treatment approaches. © 2015 Wiley Periodicals, Inc.

Validation of the first peoples cultural capability measurement tool with undergraduate health students: A descriptive cohort study.

PubMed

West, Roianne; Mills, Kyly; Rowland, Dale; Creedy, Debra K

2018-05-01

Health professional graduates require the capacity to work safely, both clinically and culturally, when delivering care to Indigenous peoples worldwide. In the Australian context, the Aboriginal and Torres Strait Islander Health Curriculum Framework (The Framework) provides guidance for health professional programs to integrate, teach and assess Aboriginal and Torres Strait Islander peoples' (First Peoples) health content. There is, however, a lack of validated tools that measure the development of students' cultural capabilities. To validate the Cultural Capability Measurement Tool with a cohort of health professional students. A descriptive cohort design was used. All students (N = 753) enrolled in a discrete First Peoples Health course at an Australian university were invited to complete the Cultural Capability Measurement Tool. The tool was tested for reliability, content and construct validity using confirmatory factor analysis; and concurrent validity using and the Cultural Understanding Self-Assessment Tool. A sample of 418 (73% response rate) was recruited. Most participants were enrolled in the Bachelor of Nursing program (n = 369, 82%). The Cultural Capability Measurement Tool had a Cronbach's alpha coefficient of 0.86. A five-factor solution was confirmed which reflected the cultural capability domains and accounted for 51% of the variance. Scores correlated with students' cultural understanding (r = 0.28, p < 0.001). Successful implementation of The Framework requires instruments to measure changes in students' cultural capabilities. Measuring nursing students' cultural capabilities can inform their development, identify areas of strengths and deficits for educators, and will ultimately contribute to the development of a culturally safe nursing workforce. Copyright © 2018 Elsevier Ltd. All rights reserved.

Development and validation of a prediction model for adenoma detection during screening and surveillance colonoscopy with comparison to actual adenoma detection rates

PubMed Central

Crook, Julia E.; Thomas, Colleen S.; Siersema, Peter D.; Rex, Douglas K.; Wallace, Michael B.

2017-01-01

Objective The adenoma detection rate (ADR) varies widely between physicians, possibly due to patient population differences, hampering direct ADR comparison. We developed and validated a prediction model for adenoma detection in an effort to determine if physicians’ ADRs should be adjusted for patient-related factors. Materials and methods Screening and surveillance colonoscopy data from the cross-sectional multicenter cluster-randomized Endoscopic Quality Improvement Program-3 (EQUIP-3) study (NCT02325635) was used. The dataset was split into two cohorts based on center. A prediction model for detection of ≥1 adenoma was developed using multivariable logistic regression and subsequently internally (bootstrap resampling) and geographically validated. We compared predicted to observed ADRs. Results The derivation (5 centers, 35 physicians, overall-ADR: 36%) and validation (4 centers, 31 physicians, overall-ADR: 40%) cohort included respectively 9934 and 10034 patients (both cohorts: 48% male, median age 60 years). Independent predictors for detection of ≥1 adenoma were: age (optimism-corrected odds ratio (OR): 1.02; 95%-confidence interval (CI): 1.02–1.03), male sex (OR: 1.73; 95%-CI: 1.60–1.88), body mass index (OR: 1.02; 95%-CI: 1.01–1.03), American Society of Anesthesiology physical status class (OR class II vs. I: 1.29; 95%-CI: 1.17–1.43, OR class ≥III vs. I: 1.57; 95%-CI: 1.32–1.86), surveillance versus screening (OR: 1.39; 95%-CI: 1.27–1.53), and Hispanic or Latino ethnicity (OR: 1.13; 95%-CI: 1.00–1.27). The model’s discriminative ability was modest (C-statistic in the derivation: 0.63 and validation cohort: 0.60). The observed ADR was considerably lower than predicted for 12/66 (18.2%) physicians and 2/9 (22.2%) centers, and considerably higher than predicted for 18/66 (27.3%) physicians and 4/9 (44.4%) centers. Conclusion The substantial variation in ADRs could only partially be explained by patient-related factors. These data suggest that ADR variation could likely also be due to other factors, e.g. physician or technical issues. PMID:28957445

Urine specimen detection of zolpidem use in patients with pain.

PubMed

Mann, Lindsey M; Atayee, Rabia S; Best, Brookie M; Morello, Candis M; Ma, Joseph D

2014-01-01

This study examined zolpidem and concurrent opioid, benzodiazepine, other central nervous system (CNS) depressants, and alcohol use. Urine specimens were analyzed using liquid chromatography-mass spectrometry (LC-MS/MS). Specimens were tested for zolpidem (n = 71,919) and separated into a provider-reported medication list documenting (n = 5,257) or not documenting zolpidem use (n = 66,662). Zolpidem-positive specimens were further separated into reported and unreported use cohorts. The total number of zolpidem-positive specimens in the reported and unreported use cohorts was 3,391 and 3,190, respectively. Non-informed prescribers were 4.4% (3,190/71,919) among the general population and 48.5% (3,190/6,581) when only zolpidem users were considered. In the zolpidem user population, the most common concurrent opioids in both cohorts were hydrocodone and oxycodone. Alprazolam and clonazepam were higher in the unreported use cohort (P ≤ 0.05). The unreported use cohort also had a higher detection of zolpidem plus a benzodiazepine (49.7 vs. 46%; P ≤ 0.05), zolpidem plus an opioid and a benzodiazepine (40.8% vs. 37.4%; P ≤ 0.05) and zolpidem plus an opioid, a benzodiazepine, and an other CNS depressant (12.9 vs. 10.9%; P ≤ 0.05). Concurrent use of zolpidem, an opioid, a benzodiazepine and an other CNS depressant is prevalent in a pain patient population. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Development and validation of a Hospital Frailty Risk Score focusing on older people in acute care settings using electronic hospital records: an observational study.

PubMed

Gilbert, Thomas; Neuburger, Jenny; Kraindler, Joshua; Keeble, Eilis; Smith, Paul; Ariti, Cono; Arora, Sandeepa; Street, Andrew; Parker, Stuart; Roberts, Helen C; Bardsley, Martin; Conroy, Simon

2018-05-05

Older people are increasing users of health care globally. We aimed to establish whether older people with characteristics of frailty and who are at risk of adverse health-care outcomes could be identified using routinely collected data. A three-step approach was used to develop and validate a Hospital Frailty Risk Score from International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnostic codes. First, we carried out a cluster analysis to identify a group of older people (≥75 years) admitted to hospital who had high resource use and diagnoses associated with frailty. Second, we created a Hospital Frailty Risk Score based on ICD-10 codes that characterised this group. Third, in separate cohorts, we tested how well the score predicted adverse outcomes and whether it identified similar groups as other frailty tools. In the development cohort (n=22 139), older people with frailty diagnoses formed a distinct group and had higher non-elective hospital use (33·6 bed-days over 2 years compared with 23·0 bed-days for the group with the next highest number of bed-days). In the national validation cohort (n=1 013 590), compared with the 429 762 (42·4%) patients with the lowest risk scores, the 202 718 (20·0%) patients with the highest Hospital Frailty Risk Scores had increased odds of 30-day mortality (odds ratio 1·71, 95% CI 1·68-1·75), long hospital stay (6·03, 5·92-6·10), and 30-day readmission (1·48, 1·46-1·50). The c statistics (ie, model discrimination) between individuals for these three outcomes were 0·60, 0·68, and 0·56, respectively. The Hospital Frailty Risk Score showed fair overlap with dichotomised Fried and Rockwood scales (kappa scores 0·22, 95% CI 0·15-0·30 and 0·30, 0·22-0·38, respectively) and moderate agreement with the Rockwood Frailty Index (Pearson's correlation coefficient 0·41, 95% CI 0·38-0·47). The Hospital Frailty Risk Score provides hospitals and health systems with a low-cost, systematic way to screen for frailty and identify a group of patients who are at greater risk of adverse outcomes and for whom a frailty-attuned approach might be useful. National Institute for Health Research. Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Distinguishing infected from noninfected abdominal fluid collections after surgery: an imaging, clinical, and laboratory-based scoring system.

PubMed

Gnannt, Ralph; Fischer, Michael A; Baechler, Thomas; Clavien, Pierre-Alain; Karlo, Christoph; Seifert, Burkhardt; Lesurtel, Mickael; Alkadhi, Hatem

2015-01-01

Mortality from abdominal abscesses ranges from 30% in treated cases up to 80% to 100% in patients with undrained or nonoperated abscesses. Various computed tomographic (CT) imaging features have been suggested to indicate infection of postoperative abdominal fluid collections; however, features are nonspecific and substantial overlap between infected and noninfected collections exists. The purpose of this study was to develop and validate a scoring system on the basis of CT imaging findings as well as laboratory and clinical parameters for distinguishing infected from noninfected abdominal fluid collections after surgery. The score developmental cohort included 100 consecutive patients (69 men, 31 women; mean age, 58 ± 17 years) who underwent portal-venous phase CT within 24 hours before CT-guided intervention of postoperative abdominal fluid collections. Imaging features included attenuation (Hounsfield unit [HU]), volume, wall enhancement and thickness, fat stranding, as well as entrapped gas of fluid collections. Laboratory and clinical parameters included diabetes, intake of immunosuppressive drugs, body temperature, C-reactive protein, and leukocyte blood cell count. The score was validated in a separate cohort of 30 consecutive patients (17 men, 13 women; mean age, 51 ± 15 years) with postoperative abdominal fluid collections. Microbiologic analysis from fluid samples served as the standard of reference. Diabetes, body temperature, C-reactive protein, attenuation of the fluid collection (in HUs), wall enhancement and thickness of the wall, adjacent fat stranding, as well as entrapped gas within the fluid collection were significantly different between infected and noninfected collections (P < 0.001). Multiple logistic regression analysis revealed diabetes, C-reactive protein, attenuation of the fluid collection (in HUs), as well as entrapped gas as significant independent predictors of infection (P < 0.001) and thus was selected for constructing a scoring system from 0 to 10 (diabetes: 2 points; C-reactive protein, ≥ 100 mg/L: 1 point; attenuation of fluid collection, ≥ 20 HU: 4 points; entrapped gas: 3 points). The model was well calibrated (Hosmer-Lemeshow test, P = 0.36). In the validation cohort, scores of 2 or lower had a 90% (95% confidence interval [CI], 56%-100%) negative predictive value, scores of 3 or higher had an 80% (95% CI, 56%-94%) positive predictive value, and scores of 6 or higher a 100% (95% CI, 74%-100%) positive predictive value for diagnosing infected fluid collections. Receiver operating characteristic analysis revealed an area under the curve of 0.96 (95% CI, 0.88-1.00) for the score. We introduce an accurate scoring system including quantitative radiologic, laboratory, and clinical parameters for distinguishing infected from noninfected fluid collections after abdominal surgery.

Translation, Cross-Cultural Adaptation, and Validation of the Activity Rating Scale for Disorders of the Knee

PubMed Central

Flosadottir, Vala; Roos, Ewa M.; Ageberg, Eva

2017-01-01

Background: The Activity Rating Scale (ARS) for disorders of the knee evaluates the level of activity by the frequency of participation in 4 separate activities with high demands on knee function, with a score ranging from 0 (none) to 16 (pivoting activities 4 times/wk). Purpose: To translate and cross-culturally adapt the ARS into Swedish and to assess measurement properties of the Swedish version of the ARS. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: The COSMIN guidelines were followed. Participants (N = 100 [55 women]; mean age, 27 years) who were undergoing rehabilitation for a knee injury completed the ARS twice for test-retest reliability. The Knee injury and Osteoarthritis Outcome Score (KOOS), Tegner Activity Scale (TAS), and modernized Saltin-Grimby Physical Activity Level Scale (SGPALS) were administered at baseline to validate the ARS. Construct validity and responsiveness of the ARS were evaluated by testing predefined hypotheses regarding correlations between the ARS, KOOS, TAS, and SGPALS. The Cronbach alpha, intraclass correlation coefficients, absolute reliability, standard error of measurement, smallest detectable change, and Spearman rank-order correlation coefficients were calculated. Results: The ARS showed good internal consistency (α ≈ 0.96), good test-retest reliability (intraclass correlation coefficient >0.9), and no systematic bias between measurements. The standard error of measurement was less than 2 points, and the smallest detectable change was less than 1 point at the group level and less than 5 points at the individual level. More than 75% of the hypotheses were confirmed, indicating good construct validity and good responsiveness of the ARS. Conclusion: The Swedish version of the ARS is valid, reliable, and responsive for evaluating the level of activity based on the frequency of participation in high-demand knee sports activities in young adults with a knee injury. PMID:28979920

A Diagnostic Marker to Discriminate Childhood Apraxia of Speech From Speech Delay: II. Validity Studies of the Pause Marker.

PubMed

Shriberg, Lawrence D; Strand, Edythe A; Fourakis, Marios; Jakielski, Kathy J; Hall, Sheryl D; Karlsson, Heather B; Mabie, Heather L; McSweeny, Jane L; Tilkens, Christie M; Wilson, David L

2017-04-14

The purpose of this 2nd article in this supplement is to report validity support findings for the Pause Marker (PM), a proposed single-sign diagnostic marker of childhood apraxia of speech (CAS). PM scores and additional perceptual and acoustic measures were obtained from 296 participants in cohorts with idiopathic and neurogenetic CAS, adult-onset apraxia of speech and primary progressive apraxia of speech, and idiopathic speech delay. Adjusted for questionable specificity disagreements with a pediatric Mayo Clinic diagnostic standard, the estimated sensitivity and specificity, respectively, of the PM were 86.8% and 100% for the CAS cohort, yielding positive and negative likelihood ratios of 56.45 (95% confidence interval [CI]: [1.15, 2763.31]) and 0.13 (95% CI [0.06, 0.30]). Specificity of the PM for 4 cohorts totaling 205 participants with speech delay was 98.5%. These findings are interpreted as providing support for the PM as a near-conclusive diagnostic marker of CAS.

The utility of the Cambridge Behavioural Inventory in neurodegenerative disease.

PubMed

Wedderburn, C; Wear, H; Brown, J; Mason, S J; Barker, R A; Hodges, J; Williams-Gray, C

2008-05-01

We investigated the utility of the Cambridge Behavioural Inventory (CBI), a carer-completed questionnaire, in a large cohort with Parkinson's disease (PD) (n = 215). In a sub-cohort of 112 patients with PD, the CBI was found to be a valid instrument compared with the Neuropsychiatric Inventory, PDQ-39 and UPDRS, with high internal consistency. Furthermore, in the whole cohort, the CBI was sensitive to changes in behaviour with disease progression. Comparison between CBI scores in PD and other neurodegenerative diseases, including Huntington's disease (HD) (n = 75), Alzheimer's disease (AD) (n = 96) and frontal variant frontotemporal dementia (fvFTD) (n = 64), revealed distinct profiles for each disease. Predominant deficits were "sleep"' and "self care" in PD; "memory" in HD and AD; and "motivation" and "stereotypic behaviours" in fvFTD. The CBI is a robust, easy-to-use and valid instrument, which has the capacity to discriminate between neurodegenerative diseases, and may be of value in monitoring therapeutic interventions.

Biological and analytical stability of a peripheral blood gene expression score for obstructive coronary artery disease in the PREDICT and COMPASS studies.

PubMed

Daniels, Susan E; Beineke, Philip; Rhees, Brian; McPherson, John A; Kraus, William E; Thomas, Gregory S; Rosenberg, Steven

2014-10-01

A gene expression score (GES) for obstructive coronary artery disease (CAD) has been validated in two multicenter studies. Receiver-operating characteristics (ROC) analysis of the GES on an expanded Personalized Risk Evaluation and Diagnosis in the Coronary Tree (PREDICT) cohort (NCT no. 00500617) with CAD defined by quantitative coronary angiography (QCA) or clinical reads yielded similar performance (area under the curve (AUC)=0.70, N=1,502) to the original validation cohort (AUC=0.70, N=526). Analysis of 138 non-Caucasian and 1,364 Caucasian patients showed very similar performance (AUCs=0.72 vs. 0.70). To assess analytic stability, stored samples of the original validation cohort (N=526) was re-tested after 5 years, and the mean score changed from 20.3 to 19.8 after 5 years (N=501, 95 %). To assess patient scores over time, GES was determined on samples from 173 Coronary Obstruction Detection by Molecular Personalized Gene Expression (COMPASS) study (NCT no. 01117506) patients at approximately 1 year post-enrollment. Mean scores increased slightly from 15.9 to 17.3, corresponding to a 2.5 % increase in obstructive CAD likelihood. Changes in cardiovascular medications did not show a significant change in GES.

A patient-centered electronic tool for weight loss outcomes after Roux-en-Y gastric bypass.

PubMed

Wood, G Craig; Benotti, Peter; Gerhard, Glenn S; Miller, Elaina K; Zhang, Yushan; Zaccone, Richard J; Argyropoulos, George A; Petrick, Anthony T; Still, Christopher D

2014-01-01

BACKGROUND. Current patient education and informed consent regarding weight loss expectations for bariatric surgery candidates are largely based on averages from large patient cohorts. The variation in weight loss outcomes illustrates the need for establishing more realistic weight loss goals for individual patients. This study was designed to develop a simple web-based tool which provides patient-specific weight loss expectations. METHODS. Postoperative weight measurements after Roux-en-Y gastric bypass (RYGB) were collected and analyzed with patient characteristics known to influence weight loss outcomes. Quantile regression was used to create expected weight loss curves (25th, 50th, and 75th %tile) for the 24 months after RYGB. The resulting equations were validated and used to develop web-based tool for predicting weight loss outcomes. RESULTS. Weight loss data from 2986 patients (2608 in the primary cohort and 378 in the validation cohort) were included. Preoperative body mass index (BMI) and age were found to have a high correlation with weight loss accomplishment (P < 0.0001 for each). An electronic tool was created that provides easy access to patient-specific, 24-month weight loss trajectories based on initial BMI and age. CONCLUSIONS. This validated, patient-centered electronic tool will assist patients and providers in patient teaching, informed consent, and postoperative weight loss management.

Mothers and Children as Informants of Bullying Victimization: Results from an Epidemiological Cohort of Children

ERIC Educational Resources Information Center

Shakoor, Sania; Jaffee, Sara R.; Andreou, Penelope; Bowes, Lucy; Ambler, Antony P.; Caspi, Avshalom; Moffitt, Terrie E.; Arseneault, Louise

2011-01-01

Stressful events early in life can affect children's mental health problems. Collecting valid and reliable information about children's bad experiences is important for research and clinical purposes. This study aimed to (1) investigate whether mothers and children provide valid reports of bullying victimization, (2) examine the inter-rater…

Predictive and construct validity of the Bayley Scales of Infant Development and the Wechsler Preschool and Primary Scale of Intelligence with the Taiwan Birth Cohort Study instrument.

PubMed

Lung, For-Wey; Chen, Po-Fei; Shu, Bih-Ching

2012-08-01

This study aimed to investigate the concurrent validity of the parent-report Taiwan Birth Cohort Study Developmental Instrument (TBCS-DI) with the Bayley Scales of Infant Development-Second Edition (BSID-II) and the Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R) at 6, 18, 36, and 60 months. 100 children were recruited at 6 months, 88 children followed-up at 18 months, 71 at 36 months, and 53 at 60 months. Longitudinally, the parent-report TBCS-DI, with the professional psychological assessments of the BSID-II and the WPPSI-R showed predictive validity. Looking at each time point in cross section, at 6 and 18 months the TBCS-DI had good concurrent validity with the BSID-II, and at 36 and 60 months the TBCS-DI was correlated only with the motor and performance domains of the BSID-II and WPPSI-R. With further investigation, the TBCS-DI may be used both in research and in clinical settings.

Palliative care and prognosis in COPD: a systematic review with a validation cohort.

PubMed

Almagro, Pere; Yun, Sergi; Sangil, Ana; Rodríguez-Carballeira, Mónica; Marine, Meritxell; Landete, Pedro; Soler-Cataluña, Juan José; Soriano, Joan B; Miravitlles, Marc

2017-01-01

Current recommendations to consider initiation of palliative care (PC) in COPD patients are often based on an expected poor prognosis. However, this approach is not evidence-based, and which and when COPD patients should start PC is controversial. We aimed to assess whether current suggested recommendations for initiating PC were sufficiently reliable. We identified prognostic variables proposed in the literature for initiating PC; then, we ascertained their relationship with 1-year mortality, and finally, we validated their utility in our cohort of 697 patients hospitalized for COPD exacerbation. From 24 articles of 499 screened, we selected 20 variables and retrieved 48 original articles in which we were able to calculate the relationship between each of them and 1-year mortality. The number of studies where 1-year mortality was detailed for these variables ranged from 9 for previous hospitalizations or FEV 1 ≤30% to none for albumin ≤25 mg/dL. The percentage of 1-year mortality in the literature for these variables ranged from 5% to 60%. In the validation cohort study, the prevalence of these proposed variables ranged from 8% to 64%; only 10 of the 18 variables analyzed in our cohort reached statistical significance with Cox regression analysis, and none overcame an area under the curve ≥0.7. We conclude that none of the suggested criteria for initiating PC based on an expected poor vital prognosis in COPD patients in the short or medium term offers sufficient reliability, and consequently, they should be avoided as exclusive criteria for considering PC or at least critically appraised.

Palliative care and prognosis in COPD: a systematic review with a validation cohort

PubMed Central

Almagro, Pere; Yun, Sergi; Sangil, Ana; Rodríguez-Carballeira, Mónica; Marine, Meritxell; Landete, Pedro; Soler-Cataluña, Juan José; Soriano, Joan B; Miravitlles, Marc

2017-01-01

Current recommendations to consider initiation of palliative care (PC) in COPD patients are often based on an expected poor prognosis. However, this approach is not evidence-based, and which and when COPD patients should start PC is controversial. We aimed to assess whether current suggested recommendations for initiating PC were sufficiently reliable. We identified prognostic variables proposed in the literature for initiating PC; then, we ascertained their relationship with 1-year mortality, and finally, we validated their utility in our cohort of 697 patients hospitalized for COPD exacerbation. From 24 articles of 499 screened, we selected 20 variables and retrieved 48 original articles in which we were able to calculate the relationship between each of them and 1-year mortality. The number of studies where 1-year mortality was detailed for these variables ranged from 9 for previous hospitalizations or FEV1 ≤30% to none for albumin ≤25 mg/dL. The percentage of 1-year mortality in the literature for these variables ranged from 5% to 60%. In the validation cohort study, the prevalence of these proposed variables ranged from 8% to 64%; only 10 of the 18 variables analyzed in our cohort reached statistical significance with Cox regression analysis, and none overcame an area under the curve ≥0.7. We conclude that none of the suggested criteria for initiating PC based on an expected poor vital prognosis in COPD patients in the short or medium term offers sufficient reliability, and consequently, they should be avoided as exclusive criteria for considering PC or at least critically appraised. PMID:28652724

Vaccination coverage among children in Germany estimated by analysis of health insurance claims data

PubMed Central

Rieck, Thorsten; Feig, Marcel; Eckmanns, Tim; Benzler, Justus; Siedler, Anette; Wichmann, Ole

2014-01-01

In Germany, the national routine childhood immunization schedule comprises 12 vaccinations. Primary immunizations should be completed by 24 mo of age. However, nationwide monitoring of vaccination coverage (VC) is performed only at school entry. We utilized health insurance claims data covering ~85% of the total population with the objectives to (1) assess VC of all recommended childhood vaccinations in birth-cohorts 2004–2009, (2) analyze cross-sectional (at 24 and 36 mo) and longitudinal trends, and (3) validate the method internally and externally. Counting vaccine doses in a retrospective cohort fashion, we assembled individual vaccination histories and summarized VC to nationwide figures. For most long-established vaccinations, VC at 24 mo was at moderate levels (~73–80%) and increased slightly across birth-cohorts. One dose measles VC was high (94%), but low (69%) for the second dose. VC with a full course of recently introduced varicella, pneumococcal, and meningococcal C vaccines increased across birth-cohorts from below 10% above 60%, 70%, and 80%, respectively. At 36 mo, VC had increased further by up to 15 percentage points depending on vaccination. Longitudinal analysis suggested a continued VC increase until school entry. Validation of VC figures with primary data showed an overall good agreement. In conclusion, analysis of health insurance claims data allows for the estimation of VC among children in Germany considering completeness and timeliness of vaccination series. This approach provides valid nationwide VC figures for all currently recommended pediatric vaccinations and fills the information gap between early infancy and late assessment at school entry. PMID:24192604

Development and validation of a surgical-pathologic staging and scoring system for cervical cancer.

PubMed

Li, Shuang; Li, Xiong; Zhang, Yuan; Zhou, Hang; Tang, Fangxu; Jia, Yao; Hu, Ting; Sun, Haiying; Yang, Ru; Chen, Yile; Cheng, Xiaodong; Lv, Weiguo; Wu, Li; Zhou, Jin; Wang, Shaoshuai; Huang, Kecheng; Wang, Lin; Yao, Yuan; Yang, Qifeng; Yang, Xingsheng; Zhang, Qinghua; Han, Xiaobing; Lin, Zhongqiu; Xing, Hui; Qu, Pengpeng; Cai, Hongbing; Song, Xiaojie; Tian, Xiaoyu; Shen, Jian; Xi, Ling; Li, Kezhen; Deng, Dongrui; Wang, Hui; Wang, Changyu; Wu, Mingfu; Zhu, Tao; Chen, Gang; Gao, Qinglei; Wang, Shixuan; Hu, Junbo; Kong, Beihua; Xie, Xing; Ma, Ding

2016-04-12

Most cervical cancer patients worldwide receive surgical treatments, and yet the current International Federation of Gynecology and Obstetrics (FIGO) staging system do not consider surgical-pathologic data. We propose a more comprehensive and prognostically valuable surgical-pathologic staging and scoring system (SPSs). Records from 4,220 eligible cervical cancer cases (Cohort 1) were screened for surgical-pathologic risk factors. We constructed a surgical-pathologic staging and SPSs, which was subsequently validated in a prospective study of 1,104 cervical cancer patients (Cohort 2). In Cohort 1, seven independent risk factors were associated with patient outcome: lymph node metastasis (LNM), parametrial involvement, histological type, grade, tumor size, stromal invasion, and lymph-vascular space invasion (LVSI). The FIGO staging system was revised and expanded into a surgical-pathologic staging system by including additional criteria of LNM, stromal invasion, and LVSI. LNM was subdivided into three categories based on number and location of metastases. Inclusion of all seven prognostic risk factors improves practical applicability. Patients were stratified into three SPSs risk categories: zero-, low-, and high-score with scores of 0, 1 to 3, and ≥4 (P=1.08E-45; P=6.15E-55). In Cohort 2, 5-year overall survival (OS) and disease-free survival (DFS) outcomes decreased with increased SPSs scores (P=9.04E-15; P=3.23E-16), validating the approach. Surgical-pathologic staging and SPSs show greater homogeneity and discriminatory utility than FIGO staging. Surgical-pathologic staging and SPSs improve characterization of tumor severity and disease invasion, which may more accurately predict outcome and guide postoperative therapy.

Integrated multigene expression panel to prognosticate patients with gastric cancer.

PubMed

Kanda, Mitsuro; Murotani, Kenta; Tanaka, Haruyoshi; Miwa, Takashi; Umeda, Shinichi; Tanaka, Chie; Kobayashi, Daisuke; Hayashi, Masamichi; Hattori, Norifumi; Suenaga, Masaya; Yamada, Suguru; Nakayama, Goro; Fujiwara, Michitaka; Kodera, Yasuhiro

2018-04-10

Most of the proposed individual markers had limited clinical utility due to the inherent biological and genetic heterogeneity of gastric cancer. We aimed to build a new molecular-based model to predict prognosis in patients with gastric cancer. A total of 200 patients who underwent gastric resection for gastric cancer were divided into learning and validation cohorts using a table of random numbers in a 1:1 ratio. In the learning cohort, mRNA expression levels of 15 molecular markers in gastric tissues were analyzed and concordance index (C-index) values of all single and combinations of the 15 candidate markers for overall survival were calculated. The multigene expression panel was designed according to C-index values and the subpopulation index. Expression scores were determined with weighting according to the coefficient of each constituent. The reproducibility of the panel was evaluated in the validation cohort. C-index values of the 15 single candidate markers ranged from 0.506-0.653. Among 32,767 combinations, the optimal and balanced expression panel comprised four constituents ( MAGED2, SYT8, BTG1 , and FAM46 ) and the C-index value was 0.793. Using this panel, patients were provisionally categorized with scores of 1-3, and clearly stratified into favorable, intermediate, and poor overall survival groups. In the validation cohort, both overall and disease-free survival rates decreased incrementally with increasing expression scores. Multivariate analysis revealed that the expression score was an independent prognostic factor for overall survival after curative gastrectomy. We developed an integrated multigene expression panel that simply and accurately stratified risk of patients with gastric cancer.

A sensitive NanoString-based assay to score STK11 (LKB1) pathway disruption in lung adenocarcinoma

PubMed Central

Chen, Lu; Engel, Brienne E.; Welsh, Eric A.; Yoder, Sean J.; Brantley, Stephen G.; Chen, Dung-Tsa; Beg, Amer A.; Cao, Chunxia; Kaye, Frederic J.; Haura, Eric B.; Schabath, Matthew B.; Cress, W. Douglas

2016-01-01

Introduction Serine/threonine kinase 11 (STK11), better known as LKB1, is a tumor-suppressor commonly mutated in lung adenocarcinoma (LUAD). Previous work has shown that mutational inactivation of the STK11 pathway may serve as a predictive biomarker for cancer treatments including phenformin and COX-2 inhibition. Although immunohistochemistry and diagnostic sequencing are employed to measure STK11 pathway disruption, there are serious limitations to these methods emphasizing the importance to validate a clinically useful assay. Methods An initial STK11 mutation mRNA signature was generated using cell line data and refined using three large, independent patient databases. The signature was validated as a classifier using The Cancer Genome Anatomy Project (TCGA) LUAD cohort as well as a 442-patient LUAD cohort developed at Moffitt. Finally, the signature was adapted into a NanoString -based format and validated using RNA samples isolated from FFPE tissue blocks corresponding to a cohort of 150 LUAD patients. For comparison, STK11 immunochemistry was also performed. Results The STK11 signature was found to correlate with null mutations identified by exon sequencing in multiple cohorts using both microarray and NanoString formats. While there was a statistically significant correlation between reduced STK11 protein expression by IHC and mutation status, the NanoString-based assay showed superior overall performance with a −0.1588 improvement in area under the curve in receiver-operator characteristic curve analysis (p<0.012). Conclusion The described NanoString-based STK11 assay is a sensitive biomarker to study emerging therapeutic modalities in clinical trials. PMID:26917230

A clinical risk stratification tool for predicting treatment resistance in major depressive disorder.

PubMed

Perlis, Roy H

2013-07-01

Early identification of depressed individuals at high risk for treatment resistance could be helpful in selecting optimal setting and intensity of care. At present, validated tools to facilitate this risk stratification are rarely used in psychiatric practice. Data were drawn from the first two treatment levels of a multicenter antidepressant effectiveness study in major depressive disorder, the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) cohort. This cohort was divided into training, testing, and validation subsets. Only clinical or sociodemographic variables available by or readily amenable to self-report were considered. Multivariate models were developed to discriminate individuals reaching remission with a first or second pharmacological treatment trial from those not reaching remission despite two trials. A logistic regression model achieved an area under the receiver operating characteristic curve exceeding .71 in training, testing, and validation cohorts and maintained good calibration across cohorts. Performance of three alternative models with machine learning approaches--a naïve Bayes classifier and a support vector machine, and a random forest model--was less consistent. Similar performance was observed between more and less severe depression, men and women, and primary versus specialty care sites. A web-based calculator was developed that implements this tool and provides graphical estimates of risk. Risk for treatment resistance among outpatients with major depressive disorder can be estimated with a simple model incorporating baseline sociodemographic and clinical features. Future studies should examine the performance of this model in other clinical populations and its utility in treatment selection or clinical trial design. Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

External validation of anti-Müllerian hormone based prediction of live birth in assisted conception

PubMed Central

2013-01-01

Background Chronological age and oocyte yield are independent determinants of live birth in assisted conception. Anti-Müllerian hormone (AMH) is strongly associated with oocyte yield after controlled ovarian stimulation. We have previously assessed the ability of AMH and age to independently predict live birth in an Italian assisted conception cohort. Herein we report the external validation of the nomogram in 822 UK first in vitro fertilization (IVF) cycles. Methods Retrospective cohort consisting of 822 patients undergoing their first IVF treatment cycle at Glasgow Centre for Reproductive Medicine. Analyses were restricted to women aged between 25 and 42 years of age. All women had an AMH measured prior to commencing their first IVF cycle. The performance of the model was assessed; discrimination by the area under the receiver operator curve (ROCAUC) and model calibration by the predicted probability versus observed probability. Results Live births occurred in 29.4% of the cohort. The observed and predicted outcomes showed no evidence of miscalibration (p = 0.188). The ROCAUC was 0.64 (95% CI: 0.60, 0.68), suggesting moderate and similar discrimination to the original model. The ROCAUC for a continuous model of age and AMH was 0.65 (95% CI 0.61, 0.69), suggesting that the original categories of AMH were appropriate. Conclusions We confirm by external validation that AMH and age are independent predictors of live birth. Although the confidence intervals for each category are wide, our results support the assessment of AMH in larger cohorts with detailed baseline phenotyping for live birth prediction. PMID:23294733

External validation of the CAPRA-S score to predict biochemical recurrence, metastasis and mortality after radical prostatectomy in a European cohort.

PubMed

Tilki, Derya; Mandel, Philipp; Schlomm, Thorsten; Chun, Felix K-H; Tennstedt, Pierre; Pehrke, Dirk; Haese, Alexander; Huland, Hartwig; Graefen, Markus; Salomon, Georg

2015-06-01

The CAPRA-S score predicts prostate cancer recurrence based on pathological information from radical prostatectomy. To our knowledge CAPRA-S has never been externally validated in a European cohort. We independently validated CAPRA-S in a single institution European database. The study cohort comprised 14,532 patients treated with radical prostatectomy between January 1992 and August 2012. Prediction of biochemical recurrence, metastasis and cancer specific mortality by CAPRA-S was assessed by Kaplan-Meier analysis and the c-index. CAPRA-S performance to predict biochemical recurrence was evaluated by calibration plot and decision curve analysis. Median followup was 50.8 months (IQR 25.0-96.0). Biochemical recurrence developed in 20.3% of men at a median of 21.2 months (IQR 7.7-44.9). When stratifying patients by CAPRA-S risk group, estimated 5-year biochemical recurrence-free survival was 91.4%, 70.4% and 29.3% in the low, intermediate and high risk groups, respectively. The CAPRA-S c-index to predict biochemical recurrence, metastasis and cancer specific mortality was 0.80, 0.85 and 0.88, respectively. Metastasis developed in 417 men and 196 men died of prostate cancer. The CAPRA-S score was accurate when applied in a European study cohort. It predicted biochemical recurrence, metastasis and cancer specific mortality after radical prostatectomy with a c-index of greater than 0.80. The score can be valuable in regard to decision making for adjuvant therapy. Copyright © 2015. Published by Elsevier Inc.

Cytoplasmic Estrogen Receptor in breast cancer

PubMed Central

Welsh, Allison W.; Lannin, Donald R.; Young, Gregory S.; Sherman, Mark E.; Figueroa, Jonine D.; Henry, N. Lynn; Ryden, Lisa; Kim, Chungyeul; Love, Richard R.; Schiff, Rachel; Rimm, David L.

2011-01-01

Purpose In addition to genomic signaling, it is accepted that ERα has non-nuclear signaling functions, which correlate with tamoxifen resistance in preclinical models. However, evidence for cytoplasmic ER localization in human breast tumors is less established. We sought to determine the presence and implications of non-nuclear ER in clinical specimens. Experimental Design A panel of ERα-specific antibodies (SP1, MC20, F10, 60c, 1D5) were validated by western blot and quantitative immunofluorescent (QIF) analysis of cell lines and patient controls. Then eight retrospective cohorts collected on tissue microarrays were assessed for cytoplasmic ER. Four cohorts were from Yale (YTMA 49, 107, 130, 128) and four others (NCI YTMA 99, South Swedish Breast Cancer Group SBII, NSABP B14, and a Vietnamese Cohort) from other sites around the world. Results Four of the antibodies specifically recognized ER by western and QIF, showed linear increases in amounts of ER in cell line series with progressively increasing ER, and the antibodies were reproducible on YTMA 49 with pearson’s correlations (r2 values)ranging from 0.87-0.94. One antibody with striking cytoplasmic staining (MC20) failed validation. We found evidence for specific cytoplasmic staining with the other 4 antibodies across eight cohorts. The average incidence was 1.5%, ranging from 0 to 3.2%. Conclusions Our data shows ERα present in the cytoplasm in a number of cases using multiple antibodies, while reinforcing the importance of antibody validation. In nearly 3,200 cases, cytoplasmic ER is present at very low incidence, suggesting its measurement is unlikely to be of routine clinical value. PMID:21980134

Validation of the Long-term Difficulties Inventory (LDI) and the List of Threatening Experiences (LTE) as measures of stress in epidemiological population-based cohort studies.

PubMed

Rosmalen, J G M; Bos, E H; de Jonge, P

2012-12-01

Stress questionnaires are included in many epidemiological cohort studies but the psychometric characteristics of these questionnaires are largely unknown. The aim of this study was to describe these characteristics for two short questionnaires measuring the lifetime and past year occurrence of stress: the List of Threatening Events (LTE) as a measure of acute stress and the Long-term Difficulties Inventory (LDI) as a measure of chronic stress. This study was performed in a general population cohort consisting of 588 females (53.7%) and 506 males (46.3%), with a mean age of 53.5 years (s.d.=11.3 years). Respondents completed the LTE and the LDI for the past year, and for the age categories of 0-12, 13-18, 19-39, 40-60, and >60 years. They also completed questionnaires on perceived stress, psychological distress (the General Health Questionnaire, GHQ-12), anxiety and depression (the Symptom Checklist, SCL-8) and neuroticism (the Eysenck Personality Questionnaire - Revised Short Scale, EPQ-RSS-N). Approximately 2 years later, 976 respondents (89%) completed these questionnaires for a second time. The stability of the retrospective reporting of long-term difficulties and life events was satisfactory: 0.7 for the lifetime LDI and 0.6 for the lifetime LTE scores. The construct validity of these lists is indicated by their positive associations with psychological distress, mental health problems and neuroticism. This study in a large population-based sample shows that the LDI and LTE have sufficient validity and stability to include them in major epidemiological cohort studies.

Person mobility in the design and analysis of cluster-randomized cohort prevention trials.

PubMed

Vuchinich, Sam; Flay, Brian R; Aber, Lawrence; Bickman, Leonard

2012-06-01

Person mobility is an inescapable fact of life for most cluster-randomized (e.g., schools, hospitals, clinic, cities, state) cohort prevention trials. Mobility rates are an important substantive consideration in estimating the effects of an intervention. In cluster-randomized trials, mobility rates are often correlated with ethnicity, poverty and other variables associated with disparity. This raises the possibility that estimated intervention effects may generalize to only the least mobile segments of a population and, thus, create a threat to external validity. Such mobility can also create threats to the internal validity of conclusions from randomized trials. Researchers must decide how to deal with persons who leave study clusters during a trial (dropouts), persons and clusters that do not comply with an assigned intervention, and persons who enter clusters during a trial (late entrants), in addition to the persons who remain for the duration of a trial (stayers). Statistical techniques alone cannot solve the key issues of internal and external validity raised by the phenomenon of person mobility. This commentary presents a systematic, Campbellian-type analysis of person mobility in cluster-randomized cohort prevention trials. It describes four approaches for dealing with dropouts, late entrants and stayers with respect to data collection, analysis and generalizability. The questions at issue are: 1) From whom should data be collected at each wave of data collection? 2) Which cases should be included in the analyses of an intervention effect? and 3) To what populations can trial results be generalized? The conclusions lead to recommendations for the design and analysis of future cluster-randomized cohort prevention trials.

Machine Learning Algorithms Outperform Conventional Regression Models in Predicting Development of Hepatocellular Carcinoma

PubMed Central

Singal, Amit G.; Mukherjee, Ashin; Elmunzer, B. Joseph; Higgins, Peter DR; Lok, Anna S.; Zhu, Ji; Marrero, Jorge A; Waljee, Akbar K

2015-01-01

Background Predictive models for hepatocellular carcinoma (HCC) have been limited by modest accuracy and lack of validation. Machine learning algorithms offer a novel methodology, which may improve HCC risk prognostication among patients with cirrhosis. Our study's aim was to develop and compare predictive models for HCC development among cirrhotic patients, using conventional regression analysis and machine learning algorithms. Methods We enrolled 442 patients with Child A or B cirrhosis at the University of Michigan between January 2004 and September 2006 (UM cohort) and prospectively followed them until HCC development, liver transplantation, death, or study termination. Regression analysis and machine learning algorithms were used to construct predictive models for HCC development, which were tested on an independent validation cohort from the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial. Both models were also compared to the previously published HALT-C model. Discrimination was assessed using receiver operating characteristic curve analysis and diagnostic accuracy was assessed with net reclassification improvement and integrated discrimination improvement statistics. Results After a median follow-up of 3.5 years, 41 patients developed HCC. The UM regression model had a c-statistic of 0.61 (95%CI 0.56-0.67), whereas the machine learning algorithm had a c-statistic of 0.64 (95%CI 0.60–0.69) in the validation cohort. The machine learning algorithm had significantly better diagnostic accuracy as assessed by net reclassification improvement (p<0.001) and integrated discrimination improvement (p=0.04). The HALT-C model had a c-statistic of 0.60 (95%CI 0.50-0.70) in the validation cohort and was outperformed by the machine learning algorithm (p=0.047). Conclusion Machine learning algorithms improve the accuracy of risk stratifying patients with cirrhosis and can be used to accurately identify patients at high-risk for developing HCC. PMID:24169273

Validation of the Framingham Heart Study and CHARGE-AF Risk Scores for Atrial Fibrillation in Hispanics, African-Americans, and Non-Hispanic Whites.

PubMed

Shulman, Eric; Kargoli, Faraj; Aagaard, Philip; Hoch, Ethan; Di Biase, Luigi; Fisher, John; Gross, Jay; Kim, Soo; Krumerman, Andrew; Ferrick, Kevin J

2016-01-01

A risk score for atrial fibrillation (AF) has been developed by the Framingham Heart Study and Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)-AF consortium. However, validation of these risk scores in an inner-city population is uncertain. Thus, a validation model was built using the Framingham Risk Score for AF and CHARGE-AF covariates. An in and outpatient electrocardiographic database was interrogated from 2000 to 2013 for the development of AF. Patients were included if their age was >45 and <95 years, had <10-year follow-up, if their initial electrocardiogram was without AF, had ≥ 2 electrocardiograms, and declared a race and/or ethnicity as non-Hispanic white, African-American, or Hispanic. For the Framingham Heart Study, 49,599 patients met inclusion criteria, of which 4,860 developed AF. Discrimination analysis using area under the curve (AUC) for original risk equations: non-Hispanic white AUC = 0.712 (95% confidence interval [CI] 0.694 to 0.731), African-American AUC = 0.733 (95% CI 0.716 to 0.751), and Hispanic AUC = 0.740 (95% CI 0.723 to 0.757). For the CHARGE-AF, 45,571 patients met inclusion criteria, of which 4,512 developed AF. Non-Hispanic white AUC = 0.673 (95% CI 0.652 to 0.694), African-American AUC = 0.706 (95% CI 0.685 to 0.727), and Hispanic AUC = 0.711 (95% CI 0.691 to 0.732). Calibration analysis showed qualitative similarities between cohorts. In conclusion, this is the first study to validate both the Framingham Heart Study and CHARGE-AF risk scores in both a Hispanic and African-American cohort. All models predicted AF well across all race and ethnic cohorts. Copyright © 2016 Elsevier Inc. All rights reserved.

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy.

PubMed

Bharamgoudar, Reshma; Sonsale, Aniket; Hodson, James; Griffiths, Ewen

2018-07-01

The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45-85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p < 0.001), with the proportions of operations lasting > 90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care.

Automated chart review utilizing natural language processing algorithm for asthma predictive index.

PubMed

Kaur, Harsheen; Sohn, Sunghwan; Wi, Chung-Il; Ryu, Euijung; Park, Miguel A; Bachman, Kay; Kita, Hirohito; Croghan, Ivana; Castro-Rodriguez, Jose A; Voge, Gretchen A; Liu, Hongfang; Juhn, Young J

2018-02-13

Thus far, no algorithms have been developed to automatically extract patients who meet Asthma Predictive Index (API) criteria from the Electronic health records (EHR) yet. Our objective is to develop and validate a natural language processing (NLP) algorithm to identify patients that meet API criteria. This is a cross-sectional study nested in a birth cohort study in Olmsted County, MN. Asthma status ascertained by manual chart review based on API criteria served as gold standard. NLP-API was developed on a training cohort (n = 87) and validated on a test cohort (n = 427). Criterion validity was measured by sensitivity, specificity, positive predictive value and negative predictive value of the NLP algorithm against manual chart review for asthma status. Construct validity was determined by associations of asthma status defined by NLP-API with known risk factors for asthma. Among the eligible 427 subjects of the test cohort, 48% were males and 74% were White. Median age was 5.3 years (interquartile range 3.6-6.8). 35 (8%) had a history of asthma by NLP-API vs. 36 (8%) by abstractor with 31 by both approaches. NLP-API predicted asthma status with sensitivity 86%, specificity 98%, positive predictive value 88%, negative predictive value 98%. Asthma status by both NLP and manual chart review were significantly associated with the known asthma risk factors, such as history of allergic rhinitis, eczema, family history of asthma, and maternal history of smoking during pregnancy (p value < 0.05). Maternal smoking [odds ratio: 4.4, 95% confidence interval 1.8-10.7] was associated with asthma status determined by NLP-API and abstractor, and the effect sizes were similar between the reviews with 4.4 vs 4.2 respectively. NLP-API was able to ascertain asthma status in children mining from EHR and has a potential to enhance asthma care and research through population management and large-scale studies when identifying children who meet API criteria.

A combined analysis of genome-wide expression profiling of bipolar disorder in human prefrontal cortex.

PubMed

Wang, Jinglu; Qu, Susu; Wang, Weixiao; Guo, Liyuan; Zhang, Kunlin; Chang, Suhua; Wang, Jing

2016-11-01

Numbers of gene expression profiling studies of bipolar disorder have been published. Besides different array chips and tissues, variety of the data processes in different cohorts aggravated the inconsistency of results of these genome-wide gene expression profiling studies. By searching the gene expression databases, we obtained six data sets for prefrontal cortex (PFC) of bipolar disorder with raw data and combinable platforms. We used standardized pre-processing and quality control procedures to analyze each data set separately and then combined them into a large gene expression matrix with 101 bipolar disorder subjects and 106 controls. A standard linear mixed-effects model was used to calculate the differentially expressed genes (DEGs). Multiple levels of sensitivity analyses and cross validation with genetic data were conducted. Functional and network analyses were carried out on basis of the DEGs. In the result, we identified 198 unique differentially expressed genes in the PFC of bipolar disorder and control. Among them, 115 DEGs were robust to at least three leave-one-out tests or different pre-processing methods; 51 DEGs were validated with genetic association signals. Pathway enrichment analysis showed these DEGs were related with regulation of neurological system, cell death and apoptosis, and several basic binding processes. Protein-protein interaction network further identified one key hub gene. We have contributed the most comprehensive integrated analysis of bipolar disorder expression profiling studies in PFC to date. The DEGs, especially those with multiple validations, may denote a common signature of bipolar disorder and contribute to the pathogenesis of disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

Utility of a New Model to Diagnose an Alcohol Basis for Steatohepatitis

PubMed Central

Dunn, Winston; Angulo, Paul; Sanderson, Schuyler; Jamil, Laith H.; Stadheim, Linda; Rosen, Charles; Malinchoc, Michael; Kamath, Patrick S.; Shah, Vijay

2007-01-01

Background and Aims Distinguishing an alcohol basis from a nonalcoholic basis for the clinical and histological spectrum of steatohepatitic liver disease is difficult owing to unreliability of alcohol consumption history. Unfortunately, various biomarkers have had limited utility in distinguishing alcoholic liver disease (ALD) from nonalcoholic fatty liver disease (NAFLD). Thus, the aim of our study was to create and validate a model to diagnose ALD in patients with steatohepatitis. Methods Cross-sectional cohort study was performed at Mayo Clinic; Rochester, Minnesota to create a model using multivariable logistic regression analysis. This model was validated in three independent data-sets comprising patients of varying severity of steatohepatitis spanning over 10 years. Results Logistic regression identified mean corpuscular volume, AST/ALT ratio, body-mass index, and gender as the most important variables that separated patients with ALD from NAFLD. These variables were used to generate the ALD/NAFLD Index (ANI); with ANI of greater than 0 incrementally favoring ALD, and ANI of less than 0 incrementally favoring a diagnosis of NAFLD, thus making ALD unlikely. ANI had a c-statistic of 0.989 in the derivation sample, and 0.974, 0.989, 0.767 in the three validation samples. ANI performance characteristics were significantly better than several conventional and recently proposed biomarkers used to differentiate ALD from NAFLD including the histopathological marker Protein Tyrosine Phosphatase 1b, AST/ALT ratio, gamma-glutamyl transferase and Carbohydrate Deficient Transferrin. Conclusion ANI, derived from easily available objective variables, accurately differentiates ALD from NAFLD in hospitalized, ambulatory and pre-transplant patients and compares favorably to other traditional and proposed biomarkers. PMID:17030176

Correlation of X-ray computed tomography with quantitative nuclear magnetic resonance methods for pre-clinical measurement of adipose and lean tissues in living mice.

PubMed

Metzinger, Matthew N; Miramontes, Bernadette; Zhou, Peng; Liu, Yueying; Chapman, Sarah; Sun, Lucy; Sasser, Todd A; Duffield, Giles E; Stack, M Sharon; Leevy, W Matthew

2014-10-08

Numerous obesity studies have coupled murine models with non-invasive methods to quantify body composition in longitudinal experiments, including X-ray computed tomography (CT) or quantitative nuclear magnetic resonance (QMR). Both microCT and QMR have been separately validated with invasive techniques of adipose tissue quantification, like post-mortem fat extraction and measurement. Here we report a head-to-head study of both protocols using oil phantoms and mouse populations to determine the parameters that best align CT data with that from QMR. First, an in vitro analysis of oil/water mixtures was used to calibrate and assess the overall accuracy of microCT vs. QMR data. Next, experiments were conducted with two cohorts of living mice (either homogenous or heterogeneous by sex, age and genetic backgrounds) to assess the microCT imaging technique for adipose tissue segmentation and quantification relative to QMR. Adipose mass values were obtained from microCT data with three different resolutions, after which the data were analyzed with different filter and segmentation settings. Strong linearity was noted between the adipose mass values obtained with microCT and QMR, with optimal parameters and scan conditions reported herein. Lean tissue (muscle, internal organs) was also segmented and quantified using the microCT method relative to the analogous QMR values. Overall, the rigorous calibration and validation of the microCT method for murine body composition, relative to QMR, ensures its validity for segmentation, quantification and visualization of both adipose and lean tissues.

Peripheral blood microRNA and VEGFA mRNA changes following electroconvulsive therapy: implications for psychotic depression.

PubMed

Kolshus, E; Ryan, K M; Blackshields, G; Smyth, P; Sheils, O; McLoughlin, D M

2017-12-01

MicroRNAs are short, non-coding molecules that regulate gene expression. Here, we investigate the role of microRNAs in depression and electroconvulsive therapy (ECT). We performed three studies: a deep sequencing discovery-phase study of miRNA changes in whole blood following ECT (n = 16), followed by a validation study in a separate cohort of patients pre-/post-ECT (n = 37) and matched healthy controls (n = 34). Changes in an experimentally validated gene target (VEGFA) were then analysed in patients pre-/post-ECT (n = 97) and in matched healthy controls (n = 53). In the discovery-phase study, we found no statistically significant differences in miRNA expression from baseline to end of treatment in the group as a whole, but post hoc analysis indicated a difference in patients with psychotic depression (n = 3). In a follow-up validation study, patients with psychotic depression (n = 7) had elevated baseline levels of miR-126-3p (t = 3.015, P = 0.006) and miR-106a-5p (t = 2.598, P = 0.025) compared to healthy controls. Following ECT, these differences disappeared. Baseline VEGFA levels were significantly higher in depressed patients compared to healthy controls (F(1,144) = 27.688, P = <0.001). Following ECT, there was a significant change in VEGFA levels in the psychotic group only (t = 2.915, P = 0.010). Molecular differences (miRNA and VEGFA) may exist between psychotic and non-psychotic depression treated with ECT. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Epstein-Barr virus glycoprotein gH/gL antibodies complement IgA-viral capsid antigen for diagnosis of nasopharyngeal carcinoma

PubMed Central

Tang, Lin-Quan; Zhang, Hua; Li, Yan; Liu, Wan-Li; Zhong, Qian; Zeng, Mu-Sheng; Huang, Xiao-Ming

2016-01-01

To determine whether measuring antibodies against Epstein-Barr virus (EBV) glycoprotein gH/gL in serum could improve diagnostic accuracy in nasopharyngeal carcinoma (NPC) cases, gH/gL expressed in a recombinant baculovirus system was used in an enzyme-linked immunosorbent assay (ELISA) to detect antibodies in two independent cohorts. Binary logistic regression analyses were performed using results from a training cohort (n = 406) to establish diagnostic mathematical models, which were validated in a second independent cohort (n = 279). Levels of serum gH/gL antibodies were higher in NPC patients than in healthy controls (p < 0.001). In the training cohort, the IgA-gH/gL ELISA had a sensitivity of 83.7%, specificity of 82.3% and area under the curve (AUC) of 0.893 (95% CI, 0.862-0.924) for NPC diagnosis. Furthermore, gH/gL maintained diagnostic capacity in IgA-VCA negative NPC patients (sensitivity = 78.1%, specificity = 82.3%, AUC = 0.879 [95% CI, 0.820 - 0.937]). Combining gH/gL and viral capsid antigen (VCA) detection improved diagnostic capacity as compared to individual tests alone in both the training cohort (sensitivity = 88.5%, specificity = 97%, AUC = 0.98 [95% CI, 0.97 - 0.991]), and validation cohort (sensitivity = 91.2%, specificity = 96.5%, AUC = 0.97 [95% CI, 0.951-0.988]). These findings suggest that EBV gH/gL detection complements VCA detection in the diagnosis of NPC and aids in the identification of patients with VCA-negative NPC. PMID:27093005

A reference equation for maximal aerobic power for treadmill and cycle ergometer exercise testing: Analysis from the FRIEND registry.

PubMed

de Souza E Silva, Christina G; Kaminsky, Leonard A; Arena, Ross; Christle, Jeffrey W; Araújo, Claudio Gil S; Lima, Ricardo M; Ashley, Euan A; Myers, Jonathan

2018-05-01

Background Maximal oxygen uptake (VO 2 max) is a powerful predictor of health outcomes. Valid and portable reference values are integral to interpreting measured VO 2 max; however, available reference standards lack validation and are specific to exercise mode. This study was undertaken to develop and validate a single equation for normal standards for VO 2 max for the treadmill or cycle ergometer in men and women. Methods Healthy individuals ( N = 10,881; 67.8% men, 20-85 years) who performed a maximal cardiopulmonary exercise test on either a treadmill or a cycle ergometer were studied. Of these, 7617 and 3264 individuals were randomly selected for development and validation of the equation, respectively. A Brazilian sample (1619 individuals) constituted a second validation cohort. The prediction equation was determined using multiple regression analysis, and comparisons were made with the widely-used Wasserman and European equations. Results Age, sex, weight, height and exercise mode were significant predictors of VO 2 max. The regression equation was: VO 2 max (ml kg -1  min -1 ) = 45.2 - 0.35*Age - 10.9*Sex (male = 1; female = 2) - 0.15*Weight (pounds) + 0.68*Height (inches) - 0.46*Exercise Mode (treadmill = 1; bike = 2) ( R = 0.79, R 2  = 0.62, standard error of the estimate = 6.6 ml kg -1  min -1 ). Percentage predicted VO 2 max for the US and Brazilian validation cohorts were 102.8% and 95.8%, respectively. The new equation performed better than traditional equations, particularly among women and individuals ≥60 years old. Conclusion A combined equation was developed for normal standards for VO 2 max for different exercise modes derived from a US national registry. The equation provided a lower average error between measured and predicted VO 2 max than traditional equations even when applied to an independent cohort. Additional studies are needed to determine its portability.

Establishment and Validation of GV-SAPS II Scoring System for Non-Diabetic Critically Ill Patients.

PubMed

Liu, Wen-Yue; Lin, Shi-Gang; Zhu, Gui-Qi; Poucke, Sven Van; Braddock, Martin; Zhang, Zhongheng; Mao, Zhi; Shen, Fei-Xia; Zheng, Ming-Hua

2016-01-01

Recently, glucose variability (GV) has been reported as an independent risk factor for mortality in non-diabetic critically ill patients. However, GV is not incorporated in any severity scoring system for critically ill patients currently. The aim of this study was to establish and validate a modified Simplified Acute Physiology Score II scoring system (SAPS II), integrated with GV parameters and named GV-SAPS II, specifically for non-diabetic critically ill patients to predict short-term and long-term mortality. Training and validation cohorts were exacted from the Multiparameter Intelligent Monitoring in Intensive Care database III version 1.3 (MIMIC-III v1.3). The GV-SAPS II score was constructed by Cox proportional hazard regression analysis and compared with the original SAPS II, Sepsis-related Organ Failure Assessment Score (SOFA) and Elixhauser scoring systems using area under the curve of the receiver operator characteristic (auROC) curve. 4,895 and 5,048 eligible individuals were included in the training and validation cohorts, respectively. The GV-SAPS II score was established with four independent risk factors, including hyperglycemia, hypoglycemia, standard deviation of blood glucose levels (GluSD), and SAPS II score. In the validation cohort, the auROC values of the new scoring system were 0.824 (95% CI: 0.813-0.834, P< 0.001) and 0.738 (95% CI: 0.725-0.750, P< 0.001), respectively for 30 days and 9 months, which were significantly higher than other models used in our study (all P < 0.001). Moreover, Kaplan-Meier plots demonstrated significantly worse outcomes in higher GV-SAPS II score groups both for 30-day and 9-month mortality endpoints (all P< 0.001). We established and validated a modified prognostic scoring system that integrated glucose variability for non-diabetic critically ill patients, named GV-SAPS II. It demonstrated a superior prognostic capability and may be an optimal scoring system for prognostic evaluation in this patient group.

Development of the Galaxy Chronic Obstructive Pulmonary Disease (COPD) Model Using Data from ECLIPSE: Internal Validation of a Linked-Equations Cohort Model.

PubMed

Briggs, Andrew H; Baker, Timothy; Risebrough, Nancy A; Chambers, Mike; Gonzalez-McQuire, Sebastian; Ismaila, Afisi S; Exuzides, Alex; Colby, Chris; Tabberer, Maggie; Muellerova, Hana; Locantore, Nicholas; Rutten van Mölken, Maureen P M H; Lomas, David A

2017-05-01

The recent joint International Society for Pharmacoeconomics and Outcomes Research / Society for Medical Decision Making Modeling Good Research Practices Task Force emphasized the importance of conceptualizing and validating models. We report a new model of chronic obstructive pulmonary disease (COPD) (part of the Galaxy project) founded on a conceptual model, implemented using a novel linked-equation approach, and internally validated. An expert panel developed a conceptual model including causal relationships between disease attributes, progression, and final outcomes. Risk equations describing these relationships were estimated using data from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study, with costs estimated from the TOwards a Revolution in COPD Health (TORCH) study. Implementation as a linked-equation model enabled direct estimation of health service costs and quality-adjusted life years (QALYs) for COPD patients over their lifetimes. Internal validation compared 3 years of predicted cohort experience with ECLIPSE results. At 3 years, the Galaxy COPD model predictions of annual exacerbation rate and annual decline in forced expiratory volume in 1 second fell within the ECLIPSE data confidence limits, although 3-year overall survival was outside the observed confidence limits. Projections of the risk equations over time permitted extrapolation to patient lifetimes. Averaging the predicted cost/QALY outcomes for the different patients within the ECLIPSE cohort gives an estimated lifetime cost of £25,214 (undiscounted)/£20,318 (discounted) and lifetime QALYs of 6.45 (undiscounted/5.24 [discounted]) per ECLIPSE patient. A new form of model for COPD was conceptualized, implemented, and internally validated, based on a series of linked equations using epidemiological data (ECLIPSE) and cost data (TORCH). This Galaxy model predicts COPD outcomes from treatment effects on disease attributes such as lung function, exacerbations, symptoms, or exercise capacity; further external validation is required.

Intergenerational Class Mobility in Britain: A Comparative Look across Three Generations in the Lothian Birth Cohort 1936

ERIC Educational Resources Information Center

Johnson, Wendy; Brett, Caroline E.; Deary, Ian J.

2010-01-01

The Lothian Birth Cohort 1936 sample is in a uniquely good position to provide relevant data on social class mobility patterns over most of the last century. These participants, with known ultimate social class attainment, took a validated mental test in the Scottish Mental Survey of 1947 and were followed up at approximately age 70. Then, besides…

Epidemiology and Long-term Clinical and Biologic Risk Factors for Pneumonia in Community-Dwelling Older Americans

PubMed Central

Alvarez, Karina; Loehr, Laura; Folsom, Aaron R.; Newman, Anne B.; Weissfeld, Lisa A.; Wunderink, Richard G.; Kritchevsky, Stephen B.; Mukamal, Kenneth J.; London, Stephanie J.; Harris, Tamara B.; Bauer, Doug C.; Angus, Derek C.

2013-01-01

Background: Preventing pneumonia requires better understanding of incidence, mortality, and long-term clinical and biologic risk factors, particularly in younger individuals. Methods: This was a cohort study in three population-based cohorts of community-dwelling individuals. A derivation cohort (n = 16,260) was used to determine incidence and survival and develop a risk prediction model. The prediction model was validated in two cohorts (n = 8,495). The primary outcome was 10-year risk of pneumonia hospitalization. Results: The crude and age-adjusted incidences of pneumonia were 6.71 and 9.43 cases/1,000 person-years (10-year risk was 6.15%). The 30-day and 1-year mortality were 16.5% and 31.5%. Although age was the most important risk factor (range of crude incidence rates, 1.69-39.13 cases/1,000 person-years for each 5-year increment from 45-85 years), 38% of pneumonia cases occurred in adults < 65 years of age. The 30-day and 1-year mortality were 12.5% and 25.7% in those < 65 years of age. Although most comorbidities were associated with higher risk of pneumonia, reduced lung function was the most important risk factor (relative risk = 6.61 for severe reduction based on FEV1 by spirometry). A clinical risk prediction model based on age, smoking, and lung function predicted 10-year risk (area under curve [AUC] = 0.77 and Hosmer-Lemeshow [HL] C statistic = 0.12). Model discrimination and calibration were similar in the internal validation cohort (AUC = 0.77; HL C statistic, 0.65) but lower in the external validation cohort (AUC = 0.62; HL C statistic, 0.45). The model also calibrated well in blacks and younger adults. C-reactive protein and IL-6 were associated with higher pneumonia risk but did not improve model performance. Conclusions: Pneumonia hospitalization is common and associated with high mortality, even in younger healthy adults. Long-term risk of pneumonia can be predicted in community-dwelling adults with a simple clinical risk prediction model. PMID:23744106

Methods to Develop an Electronic Medical Record Phenotype Algorithm to Compare the Risk of Coronary Artery Disease across 3 Chronic Disease Cohorts.

PubMed

Liao, Katherine P; Ananthakrishnan, Ashwin N; Kumar, Vishesh; Xia, Zongqi; Cagan, Andrew; Gainer, Vivian S; Goryachev, Sergey; Chen, Pei; Savova, Guergana K; Agniel, Denis; Churchill, Susanne; Lee, Jaeyoung; Murphy, Shawn N; Plenge, Robert M; Szolovits, Peter; Kohane, Isaac; Shaw, Stanley Y; Karlson, Elizabeth W; Cai, Tianxi

2015-01-01

Typically, algorithms to classify phenotypes using electronic medical record (EMR) data were developed to perform well in a specific patient population. There is increasing interest in analyses which can allow study of a specific outcome across different diseases. Such a study in the EMR would require an algorithm that can be applied across different patient populations. Our objectives were: (1) to develop an algorithm that would enable the study of coronary artery disease (CAD) across diverse patient populations; (2) to study the impact of adding narrative data extracted using natural language processing (NLP) in the algorithm. Additionally, we demonstrate how to implement CAD algorithm to compare risk across 3 chronic diseases in a preliminary study. We studied 3 established EMR based patient cohorts: diabetes mellitus (DM, n = 65,099), inflammatory bowel disease (IBD, n = 10,974), and rheumatoid arthritis (RA, n = 4,453) from two large academic centers. We developed a CAD algorithm using NLP in addition to structured data (e.g. ICD9 codes) in the RA cohort and validated it in the DM and IBD cohorts. The CAD algorithm using NLP in addition to structured data achieved specificity >95% with a positive predictive value (PPV) 90% in the training (RA) and validation sets (IBD and DM). The addition of NLP data improved the sensitivity for all cohorts, classifying an additional 17% of CAD subjects in IBD and 10% in DM while maintaining PPV of 90%. The algorithm classified 16,488 DM (26.1%), 457 IBD (4.2%), and 245 RA (5.0%) with CAD. In a cross-sectional analysis, CAD risk was 63% lower in RA and 68% lower in IBD compared to DM (p<0.0001) after adjusting for traditional cardiovascular risk factors. We developed and validated a CAD algorithm that performed well across diverse patient populations. The addition of NLP into the CAD algorithm improved the sensitivity of the algorithm, particularly in cohorts where the prevalence of CAD was low. Preliminary data suggest that CAD risk was significantly lower in RA and IBD compared to DM.

Methods to Develop an Electronic Medical Record Phenotype Algorithm to Compare the Risk of Coronary Artery Disease across 3 Chronic Disease Cohorts

PubMed Central

Liao, Katherine P.; Ananthakrishnan, Ashwin N.; Kumar, Vishesh; Xia, Zongqi; Cagan, Andrew; Gainer, Vivian S.; Goryachev, Sergey; Chen, Pei; Savova, Guergana K.; Agniel, Denis; Churchill, Susanne; Lee, Jaeyoung; Murphy, Shawn N.; Plenge, Robert M.; Szolovits, Peter; Kohane, Isaac; Shaw, Stanley Y.; Karlson, Elizabeth W.; Cai, Tianxi

2015-01-01

Background Typically, algorithms to classify phenotypes using electronic medical record (EMR) data were developed to perform well in a specific patient population. There is increasing interest in analyses which can allow study of a specific outcome across different diseases. Such a study in the EMR would require an algorithm that can be applied across different patient populations. Our objectives were: (1) to develop an algorithm that would enable the study of coronary artery disease (CAD) across diverse patient populations; (2) to study the impact of adding narrative data extracted using natural language processing (NLP) in the algorithm. Additionally, we demonstrate how to implement CAD algorithm to compare risk across 3 chronic diseases in a preliminary study. Methods and Results We studied 3 established EMR based patient cohorts: diabetes mellitus (DM, n = 65,099), inflammatory bowel disease (IBD, n = 10,974), and rheumatoid arthritis (RA, n = 4,453) from two large academic centers. We developed a CAD algorithm using NLP in addition to structured data (e.g. ICD9 codes) in the RA cohort and validated it in the DM and IBD cohorts. The CAD algorithm using NLP in addition to structured data achieved specificity >95% with a positive predictive value (PPV) 90% in the training (RA) and validation sets (IBD and DM). The addition of NLP data improved the sensitivity for all cohorts, classifying an additional 17% of CAD subjects in IBD and 10% in DM while maintaining PPV of 90%. The algorithm classified 16,488 DM (26.1%), 457 IBD (4.2%), and 245 RA (5.0%) with CAD. In a cross-sectional analysis, CAD risk was 63% lower in RA and 68% lower in IBD compared to DM (p<0.0001) after adjusting for traditional cardiovascular risk factors. Conclusions We developed and validated a CAD algorithm that performed well across diverse patient populations. The addition of NLP into the CAD algorithm improved the sensitivity of the algorithm, particularly in cohorts where the prevalence of CAD was low. Preliminary data suggest that CAD risk was significantly lower in RA and IBD compared to DM. PMID:26301417

Whole Blood Gene Expression Profiles to Assess Pathogenesis and Disease Severity in Infants with Respiratory Syncytial Virus Infection

PubMed Central

Mejias, Asuncion; Dimo, Blerta; Suarez, Nicolas M.; Garcia, Carla; Suarez-Arrabal, M. Carmen; Jartti, Tuomas; Blankenship, Derek; Jordan-Villegas, Alejandro; Ardura, Monica I.; Xu, Zhaohui; Banchereau, Jacques; Chaussabel, Damien; Ramilo, Octavio

2013-01-01

Background Respiratory syncytial virus (RSV) is the leading cause of viral lower respiratory tract infection (LRTI) and hospitalization in infants. Mostly because of the incomplete understanding of the disease pathogenesis, there is no licensed vaccine, and treatment remains symptomatic. We analyzed whole blood transcriptional profiles to characterize the global host immune response to acute RSV LRTI in infants, to characterize its specificity compared with influenza and human rhinovirus (HRV) LRTI, and to identify biomarkers that can objectively assess RSV disease severity. Methods and Findings This was a prospective observational study over six respiratory seasons including a cohort of infants hospitalized with RSV (n = 135), HRV (n = 30), and influenza (n = 16) LRTI, and healthy age- and sex-matched controls (n = 39). A specific RSV transcriptional profile was identified in whole blood (training cohort, n = 45 infants; Dallas, Texas, US) and validated in three different cohorts (test cohort, n = 46, Dallas, Texas, US; validation cohort A, n = 16, Turku, Finland; validation cohort B, n = 28, Columbus, Ohio, US) with high sensitivity (94% [95% CI 87%–98%]) and specificity (98% [95% CI 88%–99%]). It classified infants with RSV LRTI versus HRV or influenza LRTI with 95% accuracy. The immune dysregulation induced by RSV (overexpression of neutrophil, inflammation, and interferon genes, and suppression of T and B cell genes) persisted beyond the acute disease, and immune dysregulation was greatly impaired in younger infants (<6 mo). We identified a genomic score that significantly correlated with outcomes of care including a clinical disease severity score and, more importantly, length of hospitalization and duration of supplemental O2. Conclusions Blood RNA profiles of infants with RSV LRTI allow specific diagnosis, better understanding of disease pathogenesis, and assessment of disease severity. This study opens new avenues for biomarker discovery and identification of potential therapeutic or preventive targets, and demonstrates that large microarray datasets can be translated into a biologically meaningful context and applied to the clinical setting. Please see later in the article for the Editors' Summary PMID:24265599

Obesity and the risk of systemic lupus erythematosus among women in the Nurses' Health Studies.

PubMed

Tedeschi, Sara K; Barbhaiya, Medha; Malspeis, Susan; Lu, Bing; Sparks, Jeffrey A; Karlson, Elizabeth W; Willett, Walter; Costenbader, Karen H

2017-12-01

Obesity is increasingly prevalent and related to increased risk of several autoimmune diseases, likely via generation of inflammatory adipokines. Prior studies have not evaluated obesity in relation to systemic lupus erythematosus (SLE) risk. We prospectively evaluated whether obesity was associated with increased SLE risk among women in the U.S. Nurses' Health Study cohorts. We conducted a prospective cohort study among 238,130 women in the Nurses' Health Studies (NHS, 1976-2012; NHSII, 1989-2013). Incident SLE was confirmed by American College of Rheumatology 1997 criteria and validated through medical record review. Body mass index (BMI, kg/m 2 ) was calculated at baseline and on biennial questionnaires. Cox proportional hazards models estimated HRs (95% CIs) for SLE by cumulative average BMI category {18.5 to <25 [normal (reference)], 25 to <30 (overweight), ≥30 (obese)}, adjusting for potential time-varying confounders. Models were performed separately in each cohort; results were meta-analyzed. Sensitivity analyses used simple time-varying BMI, a 4-year lag between exposure and SLE risk window to address potential reverse causation, and evaluated BMI at age 18 and weight change since age 18. A secondary analysis started follow-up in both cohorts at similar calendar years when the prevalence of obesity in the U.S. increased most dramatically [1988 (NHS)/1989 (NHSII)]. We identified 153 NHS incident SLE cases and 115 incident NHSII cases during 5,602,653 person-years of follow-up. At baseline, 8.4% of women in NHS and 11.8% in NHSII were obese. Mean age at enrollment was 42.5 (SD 7.2) years in NHS and 34.4 (SD 4.7) years in NHSII. Cumulative average obesity was significantly associated with SLE risk in NHSII [HR = 1.85 (1.17-2.91)], but not in NHS [HR = 1.11 (0.65-1.87)] compared to normal BMI. In the meta-analysis of both cohorts, obesity was not significantly associated with increased risk of SLE [HR = 1.46 (0.88-2.40)]. Simple time-varying BMI and lagging the exposure window by 4 years produced similar findings to the primary analysis. In NHSII, a 4.54 kg gain between age 18 and enrollment slightly increased SLE risk [HR = 1.09 (1.02-1.18)]. In the secondary analysis starting follow-up of both cohorts at similar calendar years, the point estimate for obesity in NHS was higher than the primary analysis [HR = 1.67 (0.81-3.45)]. We observed an 85% significantly increased risk of SLE among obese compared to normal BMI women in the more recent NHSII cohort, but no association was observed in the earlier NHS cohort. Secular trends in obesity may account for the differences between the two birth cohorts. Copyright © 2017 Elsevier Inc. All rights reserved.

Development of an Automated, Real Time Surveillance Tool for Predicting Readmissions at a Community Hospital

PubMed Central

Gildersleeve, R.; Cooper, P.

2013-01-01

Background The Centers for Medicare and Medicaid Services’ Readmissions Reduction Program adjusts payments to hospitals based on 30-day readmission rates for patients with acute myocardial infarction, heart failure, and pneumonia. This holds hospitals accountable for a complex phenomenon about which there is little evidence regarding effective interventions. Further study may benefit from a method for efficiently and inexpensively identifying patients at risk of readmission. Several models have been developed to assess this risk, many of which may not translate to a U.S. community hospital setting. Objective To develop a real-time, automated tool to stratify risk of 30-day readmission at a semirural community hospital. Methods A derivation cohort was created by extracting demographic and clinical variables from the data repository for adult discharges from calendar year 2010. Multivariate logistic regression identified variables that were significantly associated with 30-day hospital readmission. Those variables were incorporated into a formula to produce a Risk of Readmission Score (RRS). A validation cohort from 2011 assessed the predictive value of the RRS. A SQL stored procedure was created to calculate the RRS for any patient and publish its value, along with an estimate of readmission risk and other factors, to a secure intranet site. Results Eleven variables were significantly associated with readmission in the multivariate analysis of each cohort. The RRS had an area under the receiver operating characteristic curve (c-statistic) of 0.74 (95% CI 0.73-0.75) in the derivation cohort and 0.70 (95% CI 0.69-0.71) in the validation cohort. Conclusion Clinical and administrative data available in a typical community hospital database can be used to create a validated, predictive scoring system that automatically assigns a probability of 30-day readmission to hospitalized patients. This does not require manual data extraction or manipulation and uses commonly available systems. Additional study is needed to refine and confirm the findings. PMID:23874355

Prognostication of patients with clear cell renal cell carcinomas based on quantification of DNA methylation levels of CpG island methylator phenotype marker genes.

PubMed

Tian, Ying; Arai, Eri; Gotoh, Masahiro; Komiyama, Motokiyo; Fujimoto, Hiroyuki; Kanai, Yae

2014-10-20

The CpG island methylator phenotype (CIMP) of clear cell renal cell carcinomas (ccRCCs) is characterized by accumulation of DNA methylation at CpG islands and poorer patient outcome. The aim of this study was to establish criteria for prognostication of patients with ccRCCs using the ccRCC-specific CIMP marker genes. DNA methylation levels at 299 CpG sites in the 14 CIMP marker genes were evaluated quantitatively in tissue specimens of 88 CIMP-negative and 14 CIMP-positive ccRCCs in a learning cohort using the MassARRAY system. An additional 100 ccRCCs were also analyzed as a validation cohort. Receiver operating characteristic curve analysis showed that area under the curve values for the 23 CpG units including the 32 CpG sites in the 7 CIMP-marker genes, i.e. FAM150A, ZNF540, ZNF671, ZNF154, PRAC, TRH and SLC13A5, for discrimination of CIMP-positive from CIMP-negative ccRCCs were larger than 0.95. Criteria combining the 23 CpG units discriminated CIMP-positive from CIMP-negative ccRCCs with 100% sensitivity and specificity in the learning cohort. Cancer-free and overall survival rates of patients with CIMP-positive ccRCCs diagnosed using the criteria combining the 23 CpG units in a validation cohort were significantly lower than those of patients with CIMP-negative ccRCCs (P = 1.41 × 10-5 and 2.43 × 10-13, respectively). Patients with CIMP-positive ccRCCs in the validation cohort had a higher likelihood of disease-related death (hazard ratio, 75.8; 95% confidence interval, 7.81 to 735; P = 1.89 × 10-4) than those with CIMP-negative ccRCCs. The established criteria are able to reproducibly diagnose CIMP-positive ccRCCs and may be useful for personalized medicine for patients with ccRCCs.

A Polymorphism within the Vitamin D Transporter Gene Predicts Outcome in Metastatic Colorectal Cancer Patients Treated with FOLFIRI/Bevacizumab or FOLFIRI/Cetuximab.

PubMed

Berger, Martin D; Stintzing, Sebastian; Heinemann, Volker; Cao, Shu; Yang, Dongyun; Sunakawa, Yu; Matsusaka, Satoshi; Ning, Yan; Okazaki, Satoshi; Miyamoto, Yuji; Suenaga, Mitsukuni; Schirripa, Marta; Hanna, Diana L; Soni, Shivani; Puccini, Alberto; Zhang, Wu; Cremolini, Chiara; Falcone, Alfredo; Loupakis, Fotios; Lenz, Heinz-Josef

2018-02-15

Purpose: Vitamin D exerts its inhibitory influence on colon cancer growth by inhibiting Wnt signaling and angiogenesis. We hypothesized that SNPs in genes involved in vitamin D transport, metabolism, and signaling are associated with outcome in metastatic colorectal cancer (mCRC) patients treated with first-line FOLFIRI and bevacizumab. Experimental Design: 522 mCRC patients enrolled in the FIRE-3 (discovery cohort) and TRIBE (validation set) trials treated with FOLFIRI/bevacizumab were included in this study. 278 patients receiving FOLFIRI and cetuximab (FIRE-3) served as a control cohort. Six SNPs in 6 genes ( GC, CYP24A1, CYP27B1, VDR, DKK1, CST5 ) were analyzed. Results: In the discovery cohort, AA carriers of the GC rs4588 SNP encoding for the vitamin D-binding protein, and treated with FOLFIRI/bevacizumab had a shorter overall survival (OS) than those harboring any C allele (15.9 vs. 25.1 months) in both univariable ( P = 0.001) and multivariable analyses ( P = 0.047). This association was confirmed in the validation cohort in multivariable analysis (OS 18.1 vs. 26.2 months, HR, 1.83; P = 0.037). Interestingly, AA carriers in the control set exhibited a longer OS (48.0 vs. 25.2 months, HR, 0.50; P = 0.021). This association was further confirmed in a second validation cohort comprising refractory mCRC patients treated with cetuximab ± irinotecan (PFS 8.7 vs. 3.7 months) in univariable ( P = 0.033) and multivariable analyses ( P = 0.046). Conclusions: GC rs4588 SNP might serve as a predictive marker in mCRC patients treated with FOLFIRI/bevacizumab or FOLFIRI/cetuximab. Whereas AA carriers derive a survival benefit with FOLFIRI/cetuximab, treatment with FOLFIRI/bevacizumab is associated with a worse outcome. Clin Cancer Res; 24(4); 784-93. ©2017 AACR . ©2017 American Association for Cancer Research.

Rapid Rule-Out of Acute Myocardial Injury Using a Single High-Sensitivity Cardiac Troponin I Measurement.

PubMed

Sandoval, Yader; Smith, Stephen W; Shah, Anoop S V; Anand, Atul; Chapman, Andrew R; Love, Sara A; Schulz, Karen; Cao, Jing; Mills, Nicholas L; Apple, Fred S

2017-01-01

Rapid rule-out strategies using high-sensitivity cardiac troponin assays are largely supported by studies performed outside the US in selected cohorts of patients with chest pain that are atypical of US practice, and focused exclusively on ruling out acute myocardial infarction (AMI), rather than acute myocardial injury, which is more common and associated with a poor prognosis. Prospective, observational study of consecutive patients presenting to emergency departments [derivation (n = 1647) and validation (n = 2198) cohorts], where high-sensitivity cardiac troponin I (hs-cTnI) was measured on clinical indication. The negative predictive value (NPV) and diagnostic sensitivity of an hs-cTnI concentration

Lessons Learned From Methodological Validation Research in E-Epidemiology.

PubMed

Kesse-Guyot, Emmanuelle; Assmann, Karen; Andreeva, Valentina; Castetbon, Katia; Méjean, Caroline; Touvier, Mathilde; Salanave, Benoît; Deschamps, Valérie; Péneau, Sandrine; Fezeu, Léopold; Julia, Chantal; Allès, Benjamin; Galan, Pilar; Hercberg, Serge

2016-10-18

Traditional epidemiological research methods exhibit limitations leading to high logistics, human, and financial burden. The continued development of innovative digital tools has the potential to overcome many of the existing methodological issues. Nonetheless, Web-based studies remain relatively uncommon, partly due to persistent concerns about validity and generalizability. The objective of this viewpoint is to summarize findings from methodological studies carried out in the NutriNet-Santé study, a French Web-based cohort study. On the basis of the previous findings from the NutriNet-Santé e-cohort (>150,000 participants are currently included), we synthesized e-epidemiological knowledge on sample representativeness, advantageous recruitment strategies, and data quality. Overall, the reported findings support the usefulness of Web-based studies in overcoming common methodological deficiencies in epidemiological research, in particular with regard to data quality (eg, the concordance for body mass index [BMI] classification was 93%), reduced social desirability bias, and access to a wide range of participant profiles, including the hard-to-reach subgroups such as young (12.30% [15,118/122,912], <25 years) and old people (6.60% [8112/122,912], ≥65 years), unemployed or homemaker (12.60% [15,487/122,912]), and low educated (38.50% [47,312/122,912]) people. However, some selection bias remained (78.00% (95,871/122,912) of the participants were women, and 61.50% (75,590/122,912) had postsecondary education), which is an inherent aspect of cohort study inclusion; other specific types of bias may also have occurred. Given the rapidly growing access to the Internet across social strata, the recruitment of participants with diverse socioeconomic profiles and health risk exposures was highly feasible. Continued efforts concerning the identification of specific biases in e-cohorts and the collection of comprehensive and valid data are still needed. This summary of methodological findings from the NutriNet-Santé cohort may help researchers in the development of the next generation of high-quality Web-based epidemiological studies.

Reduced serum club cell protein as a pulmonary damage marker for chronic fine particulate matter exposure in Chinese population.

PubMed

Wang, Yanhua; Duan, Huawei; Meng, Tao; Shen, Meili; Ji, Qianpeng; Xing, Jie; Wang, Qingrong; Wang, Ting; Niu, Yong; Yu, Tao; Liu, Zhong; Jia, Hongbing; Zhan, Yuliang; Chen, Wen; Zhang, Zhihu; Su, Wenge; Dai, Yufei; Zhang, Xuchun; Zheng, Yuxin

2018-03-01

Exposure to fine particulate matter (PM 2.5 ) pollution is associated with increased morbidity and mortality from respiratory diseases. However, few population-based studies have been conducted to assess the alterations in circulating pulmonary proteins due to long-term PM 2.5 exposure. We designed a two-stage study. In the first stage (training set), we assessed the associations between PM 2.5 exposure and levels of pulmonary damage markers (CC16, SP-A and SP-D) and lung function in a coke oven emission (COE) cohort with 558 coke plant workers and 210 controls. In the second stage (validation set), significant initial findings were validated by an independent diesel engine exhaust (DEE) cohort with 50 DEE exposed workers and 50 controls. Serum CC16 levels decreased in a dose response manner in association with both external and internal PM 2.5 exposures in the two cohorts. In the training set, serum CC16 levels decreased with increasing duration of occupational PM 2.5 exposure history. An interquartile range (IQR) (122.0μg/m 3 ) increase in PM 2.5 was associated with a 5.76% decrease in serum CC16 levels, whereas an IQR (1.06μmol/mol creatinine) increase in urinary 1-hydroxypyrene (1-OHP) concentration was associated with a 5.36% decrease in serum CC16 levels in the COE cohort. In the validation set, the concentration of serum CC16 in the PM 2.5 exposed group was 22.42% lower than that of the controls and an IQR (1.24μmol/mol creatinine) increase in urinary 1-OHP concentration was associated with a 12.24% decrease in serum CC16 levels in the DEE cohort. Serum CC16 levels may be a sensitive marker for pulmonary damage in populations with high PM 2.5 exposure. Copyright © 2017 Elsevier Ltd. All rights reserved.

PD-L1 promoter methylation is a prognostic biomarker for biochemical recurrence-free survival in prostate cancer patients following radical prostatectomy.

PubMed

Gevensleben, Heidrun; Holmes, Emily Eva; Goltz, Diane; Dietrich, Jörn; Sailer, Verena; Ellinger, Jörg; Dietrich, Dimo; Kristiansen, Glen

2016-11-29

The rapid development of programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors has generated an urgent need for biomarkers assisting the selection of patients eligible for therapy. The use of PD-L1 immunohistochemistry, which has been suggested as a predictive biomarker, however, is confounded by multiple unresolved issues. The aim of this study therefore was to quantify PD-L1 DNA methylation (mPD-L1) in prostate tissue samples and to evaluate its potential as a biomarker in prostate cancer (PCa). In the training cohort, normal tissue showed significantly lower levels of mPD-L1 compared to tumor tissue. High mPD-L1 in PCa was associated with biochemical recurrence (BCR) in univariate Cox proportional hazards (hazard ratio (HR)=2.60 [95%CI: 1.50-4.51], p=0.001) and Kaplan-Meier analyses (p<0.001). These results were corroborated in an independent validation cohort in univariate Cox (HR=1.24 [95%CI: 1.08-1.43], p=0.002) and Kaplan-Meier analyses (p=0.029). Although mPD-L1 and PD-L1 protein expression did not correlate in the validation cohort, both parameters added significant prognostic information in bivariate Cox analysis (HR=1.22 [95%CI: 1.05-1.42], p=0.008 for mPD-L1 and HR=2.58 [95%CI: 1.43-4.63], p=0.002 for PD-L1 protein expression). mPD-L1 was analyzed in a training cohort from The Cancer Genome Atlas (n=498) and was subsequently measured in an independent validation cohort (n=299) by quantitative methylation-specific real-time PCR. All patients had undergone radical prostatectomy. mPD-L1 is a promising biomarker for the risk stratification of PCa patients and might offer additional relevant prognostic information to the implemented clinical parameters, particularly in the setting of immune checkpoint inhibition.

Analysis of subarachnoid hemorrhage using the Nationwide Inpatient Sample: the NIS-SAH Severity Score and Outcome Measure.

PubMed

Washington, Chad W; Derdeyn, Colin P; Dacey, Ralph G; Dhar, Rajat; Zipfel, Gregory J

2014-08-01

Studies using the Nationwide Inpatient Sample (NIS), a large ICD-9-based (International Classification of Diseases, Ninth Revision) administrative database, to analyze aneurysmal subarachnoid hemorrhage (SAH) have been limited by an inability to control for SAH severity and the use of unverified outcome measures. To address these limitations, the authors developed and validated a surrogate marker for SAH severity, the NIS-SAH Severity Score (NIS-SSS; akin to Hunt and Hess [HH] grade), and a dichotomous measure of SAH outcome, the NIS-SAH Outcome Measure (NIS-SOM; akin to modified Rankin Scale [mRS] score). Three separate and distinct patient cohorts were used to define and then validate the NIS-SSS and NIS-SOM. A cohort (n = 148,958, the "model population") derived from the 1998-2009 NIS was used for developing the NIS-SSS and NIS-SOM models. Diagnoses most likely reflective of SAH severity were entered into a regression model predicting poor outcome; model coefficients of significant factors were used to generate the NIS-SSS. Nationwide Inpatient Sample codes most likely to reflect a poor outcome (for example, discharge disposition, tracheostomy) were used to create the NIS-SOM. Data from 716 patients with SAH (the "validation population") treated at the authors' institution were used to validate the NIS-SSS and NIS-SOM against HH grade and mRS score, respectively. Lastly, 147,395 patients (the "assessment population") from the 1998-2009 NIS, independent of the model population, were used to assess performance of the NIS-SSS in predicting outcome. The ability of the NIS-SSS to predict outcome was compared with other common measures of disease severity (All Patient Refined Diagnosis Related Group [APR-DRG], All Payer Severity-adjusted DRG [APS-DRG], and DRG). RESULTS The NIS-SSS significantly correlated with HH grade, and there was no statistical difference between the abilities of the NIS-SSS and HH grade to predict mRS-based outcomes. As compared with the APR-DRG, APSDRG, and DRG, the NIS-SSS was more accurate in predicting SAH outcome (area under the curve [AUC] = 0.69, 0.71, 0.71, and 0.79, respectively). A strong correlation between NIS-SOM and mRS was found, with an agreement and kappa statistic of 85% and 0.63, respectively, when poor outcome was defined by an mRS score > 2 and 95% and 0.84 when poor outcome was defined by an mRS score > 3. Data in this study indicate that in the analysis of NIS data sets, the NIS-SSS is a valid measure of SAH severity that outperforms previous measures of disease severity and that the NIS-SOM is a valid measure of SAH outcome. It is critically important that outcomes research in SAH using administrative data sets incorporate the NIS-SSS and NIS-SOM to adjust for neurology-specific disease severity.

Emotional stress and traffic accidents: the impact of separation and divorce.

PubMed

Lagarde, Emmanuel; Chastang, Jean-François; Gueguen, Alice; Coeuret-Pellicer, Mireille; Chiron, Mireille; Lafont, Sylviane

2004-11-01

Personal responses to stressful life events are suspected of increasing the risk of serious traffic accidents. We analyzed data from a French cohort study (the GAZEL cohort), including a retrospective driving behavior questionnaire, from 13,915 participants (10,542 men age 52-62 years and 3373 women age 47-62 years in 2001). Follow-up data covered 1993-2000. Hazard ratios for serious accidents (n = 713) were computed by Cox's proportional hazard regression with time-dependent covariates. Separate analyses were also performed to consider only at-fault accidents. Marital separation or divorce was associated with an increased risk of a serious accident (all serious accidents: hazard ratio 2.9, 95% confidence interval = 1.7-5.0; at-fault accidents: 4.4, 2.3-8.3). The impact of separation and divorce did not differ according to alcohol consumption levels. Other life events associated with increased risk of serious accident were a child leaving home (all accidents: 1.2, 0.97-1.6; at-fault accidents: 1.5, 1.1-2.1), an important purchase (all accidents: 1.4, 1.1-1.7; at-fault accidents: 1.6, 1.2-2.1), and hospitalization of the partner (all accidents: 1.4, 1.1-2.0). This study suggests that recent separation and divorce are associated with an increase in serious traffic accidents.

Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS).

PubMed

Ely, E Wesley; Truman, Brenda; Shintani, Ayumi; Thomason, Jason W W; Wheeler, Arthur P; Gordon, Sharon; Francis, Joseph; Speroff, Theodore; Gautam, Shiva; Margolin, Richard; Sessler, Curtis N; Dittus, Robert S; Bernard, Gordon R

2003-06-11

Goal-directed delivery of sedative and analgesic medications is recommended as standard care in intensive care units (ICUs) because of the impact these medications have on ventilator weaning and ICU length of stay, but few of the available sedation scales have been appropriately tested for reliability and validity. To test the reliability and validity of the Richmond Agitation-Sedation Scale (RASS). Prospective cohort study. Adult medical and coronary ICUs of a university-based medical center. Thirty-eight medical ICU patients enrolled for reliability testing (46% receiving mechanical ventilation) from July 21, 1999, to September 7, 1999, and an independent cohort of 275 patients receiving mechanical ventilation were enrolled for validity testing from February 1, 2000, to May 3, 2001. Interrater reliability of the RASS, Glasgow Coma Scale (GCS), and Ramsay Scale (RS); validity of the RASS correlated with reference standard ratings, assessments of content of consciousness, GCS scores, doses of sedatives and analgesics, and bispectral electroencephalography. In 290-paired observations by nurses, results of both the RASS and RS demonstrated excellent interrater reliability (weighted kappa, 0.91 and 0.94, respectively), which were both superior to the GCS (weighted kappa, 0.64; P<.001 for both comparisons). Criterion validity was tested in 411-paired observations in the first 96 patients of the validation cohort, in whom the RASS showed significant differences between levels of consciousness (P<.001 for all) and correctly identified fluctuations within patients over time (P<.001). In addition, 5 methods were used to test the construct validity of the RASS, including correlation with an attention screening examination (r = 0.78, P<.001), GCS scores (r = 0.91, P<.001), quantity of different psychoactive medication dosages 8 hours prior to assessment (eg, lorazepam: r = - 0.31, P<.001), successful extubation (P =.07), and bispectral electroencephalography (r = 0.63, P<.001). Face validity was demonstrated via a survey of 26 critical care nurses, which the results showed that 92% agreed or strongly agreed with the RASS scoring scheme, and 81% agreed or strongly agreed that the instrument provided a consensus for goal-directed delivery of medications. The RASS demonstrated excellent interrater reliability and criterion, construct, and face validity. This is the first sedation scale to be validated for its ability to detect changes in sedation status over consecutive days of ICU care, against constructs of level of consciousness and delirium, and correlated with the administered dose of sedative and analgesic medications.

The Validity of Interpersonal Skills Assessment via Situational Judgment Tests for Predicting Academic Success and Job Performance

ERIC Educational Resources Information Center

Lievens, Filip; Sackett, Paul R.

2012-01-01

This study provides conceptual and empirical arguments why an assessment of applicants' procedural knowledge about interpersonal behavior via a video-based situational judgment test might be valid for academic and postacademic success criteria. Four cohorts of medical students (N = 723) were followed from admission to employment. Procedural…