Bladder cancer biomarker discovery using global metabolomic profiling of urine.

PubMed

Wittmann, Bryan M; Stirdivant, Steven M; Mitchell, Matthew W; Wulff, Jacob E; McDunn, Jonathan E; Li, Zhen; Dennis-Barrie, Aphrihl; Neri, Bruce P; Milburn, Michael V; Lotan, Yair; Wolfert, Robert L

2014-01-01

Bladder cancer (BCa) is a common malignancy worldwide and has a high probability of recurrence after initial diagnosis and treatment. As a result, recurrent surveillance, primarily involving repeated cystoscopies, is a critical component of post diagnosis patient management. Since cystoscopy is invasive, expensive and a possible deterrent to patient compliance with regular follow-up screening, new non-invasive technologies to aid in the detection of recurrent and/or primary bladder cancer are strongly needed. In this study, mass spectrometry based metabolomics was employed to identify biochemical signatures in human urine that differentiate bladder cancer from non-cancer controls. Over 1000 distinct compounds were measured including 587 named compounds of known chemical identity. Initial biomarker identification was conducted using a 332 subject sample set of retrospective urine samples (cohort 1), which included 66 BCa positive samples. A set of 25 candidate biomarkers was selected based on statistical significance, fold difference and metabolic pathway coverage. The 25 candidate biomarkers were tested against an independent urine sample set (cohort 2) using random forest analysis, with palmitoyl sphingomyelin, lactate, adenosine and succinate providing the strongest predictive power for differentiating cohort 2 cancer from non-cancer urines. Cohort 2 metabolite profiling revealed additional metabolites, including arachidonate, that were higher in cohort 2 cancer vs. non-cancer controls, but were below quantitation limits in the cohort 1 profiling. Metabolites related to lipid metabolism may be especially interesting biomarkers. The results suggest that urine metabolites may provide a much needed non-invasive adjunct diagnostic to cystoscopy for detection of bladder cancer and recurrent disease management.

Cesarean Outcomes in US Birth Centers and Collaborating Hospitals: A Cohort Comparison.

PubMed

Thornton, Patrick; McFarlin, Barbara L; Park, Chang; Rankin, Kristin; Schorn, Mavis; Finnegan, Lorna; Stapleton, Susan

2017-01-01

High rates of cesarean birth are a significant health care quality issue, and birth centers have shown potential to reduce rates of cesarean birth. Measuring this potential is complicated by lack of randomized trials and limited observational comparisons. Cesarean rates vary by provider type, setting, and clinical and nonclinical characteristics of women, but our understanding of these dynamics is incomplete. We sought to isolate labor setting from other risk factors in order to assess the effect of birth centers on the odds of cesarean birth. We generated low-risk cohorts admitted in labor to hospitals (n = 2527) and birth centers (n = 8776) using secondary data obtained from the American Association of Birth Centers (AABC). All women received prenatal care in the birth center and midwifery care in labor, but some chose hospital admission for labor. Analysis was intent to treat according to site of admission in spontaneous labor. We used propensity score adjustment and multivariable logistic regression to control for cohort differences and measured effect sizes associated with setting. There was a 37% (adjusted odds ratio [OR], 0.63; 95% confidence interval [CI], 0.50-0.79) to 38% (adjusted OR, 0.62; 95% CI, 0.49-0.79) decreased odds of cesarean in the birth center cohort and a remarkably low overall cesarean rate of less than 5% in both cohorts. These findings suggest that low rates of cesarean in birth centers are not attributable to labor setting alone. The entire birth center care model, including prenatal preparation and relationship-based midwifery care, should be studied, promoted, and implemented by policy makers interested in achieving appropriate cesarean rates in the United States. © 2016 by the American College of Nurse-Midwives.

PTGER4 gene variant rs76523431 is a candidate risk factor for radiological joint damage in rheumatoid arthritis patients: a genetic study of six cohorts.

PubMed

Rodriguez-Rodriguez, Luis; Ivorra-Cortes, Jose; Carmona, F David; Martín, Javier; Balsa, Alejandro; van Steenbergen, Hanna W; van der Helm-van Mil, Annette H M; González-Álvaro, Isidoro; Fernandez-Gutiérrez, Benjamín

2015-11-05

Prostaglandin E receptor 4 (PTGER4) is implicated in immune regulation and bone metabolism. The aim of this study was to analyze its role in radiological joint damage in rheumatoid arthritis (RA). Six independent cohorts of patients with RA of European or North American descent were included, comprising 1789 patients with 5083 sets of X-rays. The Hospital Clínico San Carlos Rheumatoid Arthritis, Princesa Early Arthritis Register Longitudinal study, and Hospital Universitario de La Paz early arthritis (Spain) cohorts were used as discovery cohorts, and the Leiden Early Arthritis Clinic (The Netherlands), Wichita (United States), and National Databank for Rheumatic Diseases (United States and Canada) cohorts as replication cohorts. First, the PTGER4 rs6896969 single-nucleotide polymorphism (SNP) was genotyped using TaqMan assays and available Illumina Immunochip data and studied in the discovery and replication cohorts. Second, the PTGER4 gene and adjacent regions were analyzed using Immunochip genotyping data in the discovery cohorts. On the basis of pooled p values, linkage disequilibrium structure of the region, and location in regions with transcriptional properties, SNPs were selected for replication. The results from discovery, replication, and overall cohorts were pooled using inverse-variance-weighted meta-analysis. Influence of the polymorphisms on the overall radiological damage (constant effect) and on damage progression over time (time-varying effect) was analyzed. The rs6896969 polymorphism showed a significant association with radiological damage in the constant effect pooled analysis of the discovery cohorts, although no significant association was observed in the replication cohorts or the overall pooled analysis. Regarding the analysis of the PTGER4 region, 976 variants were analyzed in the discovery cohorts. From the constant and time-varying effect analyses, 12 and 20 SNPs, respectively, were selected for replication. Only the rs76523431 variant showed a significant association with radiographic progression in the time-varying effect pooled analysis of the discovery, replication, and overall cohorts. The overall pooled effect size was 1.10 (95 % confidence interval 1.05-1.14, p = 2.10 × 10(-5)), meaning that radiographic yearly progression was 10 % greater for each copy of the minor allele. The PTGER4 gene is a candidate risk factor for radiological progression in RA.

Decision tree analysis in subarachnoid hemorrhage: prediction of outcome parameters during the course of aneurysmal subarachnoid hemorrhage using decision tree analysis.

PubMed

Hostettler, Isabel Charlotte; Muroi, Carl; Richter, Johannes Konstantin; Schmid, Josef; Neidert, Marian Christoph; Seule, Martin; Boss, Oliver; Pangalu, Athina; Germans, Menno Robbert; Keller, Emanuela

2018-01-19

OBJECTIVE The aim of this study was to create prediction models for outcome parameters by decision tree analysis based on clinical and laboratory data in patients with aneurysmal subarachnoid hemorrhage (aSAH). METHODS The database consisted of clinical and laboratory parameters of 548 patients with aSAH who were admitted to the Neurocritical Care Unit, University Hospital Zurich. To examine the model performance, the cohort was randomly divided into a derivation cohort (60% [n = 329]; training data set) and a validation cohort (40% [n = 219]; test data set). The classification and regression tree prediction algorithm was applied to predict death, functional outcome, and ventriculoperitoneal (VP) shunt dependency. Chi-square automatic interaction detection was applied to predict delayed cerebral infarction on days 1, 3, and 7. RESULTS The overall mortality was 18.4%. The accuracy of the decision tree models was good for survival on day 1 and favorable functional outcome at all time points, with a difference between the training and test data sets of < 5%. Prediction accuracy for survival on day 1 was 75.2%. The most important differentiating factor was the interleukin-6 (IL-6) level on day 1. Favorable functional outcome, defined as Glasgow Outcome Scale scores of 4 and 5, was observed in 68.6% of patients. Favorable functional outcome at all time points had a prediction accuracy of 71.1% in the training data set, with procalcitonin on day 1 being the most important differentiating factor at all time points. A total of 148 patients (27%) developed VP shunt dependency. The most important differentiating factor was hyperglycemia on admission. CONCLUSIONS The multiple variable analysis capability of decision trees enables exploration of dependent variables in the context of multiple changing influences over the course of an illness. The decision tree currently generated increases awareness of the early systemic stress response, which is seemingly pertinent for prognostication.

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.

Retrospective return on investment analysis of an electronic treatment adherence device piloted in the Northern Cape Province.

PubMed

Broomhead, Sean; Mars, Maurice

2012-01-01

The return on investment (ROI) for utilizing the SIMpill electronic treatment adherence solution as an adjunct to directly observed treatment short-course (DOTS) is assessed using data from a 2005 pilot of the SIMpill solution among new smear-positive tuberculosis (TB) patients in the Northern Cape Province. The value of this cost minimization analysis (CMA), for use by public health planners in low-resource settings as a precursor to more rigorous assessment, is discussed. The retrospective analysis compares the costs and health outcomes of the DOTS-SIMpill cohort with DOTS-only controls. Hypothetical 5-year cash flows are generated and discounted to estimate net present values (NPVs). Comparison between the DOTS-SIMpill pilot cohort and DOTS-only supported controls, for a hypothetical implementation of 1,000 devices, over 5 years, demonstrates positive ROI for the DOTS-SIMpill cohort based on improved health outcomes and reduced average cost per patient. The net stream is shown to be positive from the first year. Discounted NPV is ZAR 3,255,256 (US$ 493,221) for a cohort that would have started mid 2005 and ZAR 3,747,636 (US$ 487,339) starting mid 2010. This is an ROI of 23% over the 5-year period. The addition of electronic treatment adherence support technology can help to improve TB outcomes and lower average cost per patient by reducing treatment failure and the associated higher cost and burden on limited resources. CMA is an appropriate initial analysis for health planners to highlight options that may justify more sophisticated methods such as cost effectiveness analysis or full cost benefit analysis where a preferred option is immediately revealed. CMA is proposed as a tool for use by public health planners in low-resource settings to evaluate the ROI of treatment adherence technology postpilot and prior to implementation.

A comparison of Cox and logistic regression for use in genome-wide association studies of cohort and case-cohort design.

PubMed

Staley, James R; Jones, Edmund; Kaptoge, Stephen; Butterworth, Adam S; Sweeting, Michael J; Wood, Angela M; Howson, Joanna M M

2017-06-01

Logistic regression is often used instead of Cox regression to analyse genome-wide association studies (GWAS) of single-nucleotide polymorphisms (SNPs) and disease outcomes with cohort and case-cohort designs, as it is less computationally expensive. Although Cox and logistic regression models have been compared previously in cohort studies, this work does not completely cover the GWAS setting nor extend to the case-cohort study design. Here, we evaluated Cox and logistic regression applied to cohort and case-cohort genetic association studies using simulated data and genetic data from the EPIC-CVD study. In the cohort setting, there was a modest improvement in power to detect SNP-disease associations using Cox regression compared with logistic regression, which increased as the disease incidence increased. In contrast, logistic regression had more power than (Prentice weighted) Cox regression in the case-cohort setting. Logistic regression yielded inflated effect estimates (assuming the hazard ratio is the underlying measure of association) for both study designs, especially for SNPs with greater effect on disease. Given logistic regression is substantially more computationally efficient than Cox regression in both settings, we propose a two-step approach to GWAS in cohort and case-cohort studies. First to analyse all SNPs with logistic regression to identify associated variants below a pre-defined P-value threshold, and second to fit Cox regression (appropriately weighted in case-cohort studies) to those identified SNPs to ensure accurate estimation of association with disease.

Improving accuracy and power with transfer learning using a meta-analytic database.

PubMed

Schwartz, Yannick; Varoquaux, Gaël; Pallier, Christophe; Pinel, Philippe; Poline, Jean-Baptiste; Thirion, Bertrand

2012-01-01

Typical cohorts in brain imaging studies are not large enough for systematic testing of all the information contained in the images. To build testable working hypotheses, investigators thus rely on analysis of previous work, sometimes formalized in a so-called meta-analysis. In brain imaging, this approach underlies the specification of regions of interest (ROIs) that are usually selected on the basis of the coordinates of previously detected effects. In this paper, we propose to use a database of images, rather than coordinates, and frame the problem as transfer learning: learning a discriminant model on a reference task to apply it to a different but related new task. To facilitate statistical analysis of small cohorts, we use a sparse discriminant model that selects predictive voxels on the reference task and thus provides a principled procedure to define ROIs. The benefits of our approach are twofold. First it uses the reference database for prediction, i.e., to provide potential biomarkers in a clinical setting. Second it increases statistical power on the new task. We demonstrate on a set of 18 pairs of functional MRI experimental conditions that our approach gives good prediction. In addition, on a specific transfer situation involving different scanners at different locations, we show that voxel selection based on transfer learning leads to higher detection power on small cohorts.

Genetic variation in GPR133 is associated with height: genome wide association study in the self-contained population of Sorbs.

PubMed

Tönjes, Anke; Koriath, Moritz; Schleinitz, Dorit; Dietrich, Kerstin; Böttcher, Yvonne; Rayner, Nigel W; Almgren, Peter; Enigk, Beate; Richter, Olaf; Rohm, Silvio; Fischer-Rosinsky, Antje; Pfeiffer, Andreas; Hoffmann, Katrin; Krohn, Knut; Aust, Gabriela; Spranger, Joachim; Groop, Leif; Blüher, Matthias; Kovacs, Peter; Stumvoll, Michael

2009-12-01

Recently, associations of several common genetic variants with height have been reported in different populations. We attempted to identify further variants associated with adult height in a self-contained population (the Sorbs in Eastern Germany) as discovery set. We performed a genome wide association study (GWAS) (approximately 390,000 genetic polymorphisms, Affymetrix gene arrays) on adult height in 929 Sorbian individuals. Subsequently, the best SNPs (P < 0.001) were taken forward to a meta-analysis together with two independent cohorts [Diabetes Genetics Initiative, British 1958 Birth Cohort, (58BC, publicly available)]. Furthermore, we genotyped our best signal for replication in two additional German cohorts (Leipzig, n = 1044 and Berlin, n = 1728). In the primary Sorbian GWAS, we identified 5 loci with a P-value < 10(-5) and 455 SNPs with P-value < 0.001. In the meta-analysis on those 455 SNPs, only two variants in GPR133 (rs1569019 and rs1976930; in LD with each other) retained a P-value at or below 10(-6) and were associated with height in the three cohorts individually. Upon replication, the SNP rs1569019 showed significant effects on height in the Leipzig cohort (P = 0.004, beta = 1.166) and in 577 men of the Berlin cohort (P = 0.049, beta = 1.127) though not in women. The combined analysis of all five cohorts (n = 6,687) resulted in a P-value of 4.7 x 10(-8) (beta = 0.949). In conclusion, our GWAS suggests novel loci influencing height. In view of the robust replication in five different cohorts, we propose GPR133 to be a novel gene associated with adult height.

A Nasal Brush-based Classifier of Asthma Identified by Machine Learning Analysis of Nasal RNA Sequence Data.

PubMed

Pandey, Gaurav; Pandey, Om P; Rogers, Angela J; Ahsen, Mehmet E; Hoffman, Gabriel E; Raby, Benjamin A; Weiss, Scott T; Schadt, Eric E; Bunyavanich, Supinda

2018-06-11

Asthma is a common, under-diagnosed disease affecting all ages. We sought to identify a nasal brush-based classifier of mild/moderate asthma. 190 subjects with mild/moderate asthma and controls underwent nasal brushing and RNA sequencing of nasal samples. A machine learning-based pipeline identified an asthma classifier consisting of 90 genes interpreted via an L2-regularized logistic regression classification model. This classifier performed with strong predictive value and sensitivity across eight test sets, including (1) a test set of independent asthmatic and control subjects profiled by RNA sequencing (positive and negative predictive values of 1.00 and 0.96, respectively; AUC of 0.994), (2) two independent case-control cohorts of asthma profiled by microarray, and (3) five cohorts with other respiratory conditions (allergic rhinitis, upper respiratory infection, cystic fibrosis, smoking), where the classifier had a low to zero misclassification rate. Following validation in large, prospective cohorts, this classifier could be developed into a nasal biomarker of asthma.

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

Genomic copy number analysis of Chernobyl papillary thyroid carcinoma in the Ukrainian–American Cohort

PubMed Central

Selmansberger, Martin; Braselmann, Herbert; Hess, Julia; Bogdanova, Tetiana; Abend, Michael; Tronko, Mykola; Brenner, Alina; Zitzelsberger, Horst; Unger, Kristian

2015-01-01

One of the major consequences of the 1986 Chernobyl reactor accident was a dramatic increase in papillary thyroid carcinoma (PTC) incidence, predominantly in patients exposed to the radioiodine fallout at young age. The present study is the first on genomic copy number alterations (CNAs) of PTCs of the Ukrainian–American cohort (UkrAm) generated by array comparative genomic hybridization (aCGH). Unsupervised hierarchical clustering of CNA profiles revealed a significant enrichment of a subgroup of patients with female gender, long latency (>17 years) and negative lymph node status. Further, we identified single CNAs that were significantly associated with latency, gender, radiation dose and BRAF V600E mutation status. Multivariate analysis revealed no interactions but additive effects of parameters gender, latency and dose on CNAs. The previously identified radiation-associated gain of the chromosomal bands 7q11.22-11.23 was present in 29% of cases. Moreover, comparison of our radiation-associated PTC data set with the TCGA data set on sporadic PTCs revealed altered copy numbers of the tumor driver genes NF2 and CHEK2. Further, we integrated the CNA data with transcriptomic data that were available on a subset of the herein analyzed cohort and did not find statistically significant associations between the two molecular layers. However, applying hierarchical clustering on a ‘BRAF-like/RAS-like’ transcriptome signature split the cases into four groups, one of which containing all BRAF-positive cases validating the signature in an independent data set. PMID:26320103

Cost-effectiveness of vaccination against cervical cancer: a multi-regional analysis assessing the impact of vaccine characteristics and alternative vaccination scenarios.

PubMed

Suárez, Eugenio; Smith, Jennifer S; Bosch, F Xavier; Nieminen, Pekka; Chen, Chien-Jen; Torvinen, Saku; Demarteau, Nadia; Standaert, Baudouin

2008-09-15

Mathematical models provide valuable insights into the public health and economic impact of cervical cancer vaccination programmes. An in-depth economic analysis should explore the effects of different vaccine-related factors and vaccination scenarios (independent of screening practices) on health benefits and costs. In this analysis, a Markov cohort model was used to explore the impact of vaccine characteristics (e.g. cross-type protection and waning of immunity) and different vaccination scenarios (e.g. age at vaccination and multiple cohort strategies) on the cost-effectiveness results of cervical cancer vaccination programmes. The analysis was applied across different regions in the world (Chile, Finland, Ireland, Poland and Taiwan) to describe the influence of location-specific conditions. The results indicate that in all the different settings cervical cancer vaccination becomes more cost-effective with broader and sustained vaccine protection, with vaccination at younger ages, and with the inclusion of several cohorts. When other factors were varied, the cost-effectiveness of vaccination was most negatively impacted by increasing the discount rate applied to costs and health effects.

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.

Evaluation to Redesign a Prototype Officer Data Base for Interdisciplinary Research

DTIC Science & Technology

1992-01-01

accommodate cohort longitudinal research and econometric model testing . Recommendations regarding the adoption of the LOADB were presented. Utilization...commission data sets (Younkman, 1987), and the AIMS data set ( Ramsey & Younkman, 1989). An analysis of selected standardized tests for ROTC screening was...ARI Research Note 92-16 Evaluation to Redesign a Prototype il Officer Data Base for Interdisciplinary Research Dianne D. Younkman and Lori G. Ramsey

Genetic Analysis of Association Between Calcium Signaling and Hippocampal Activation, Memory Performance in the Young and Old, and Risk for Sporadic Alzheimer Disease.

PubMed

Heck, Angela; Fastenrath, Matthias; Coynel, David; Auschra, Bianca; Bickel, Horst; Freytag, Virginie; Gschwind, Leo; Hartmann, Francina; Jessen, Frank; Kaduszkiewicz, Hanna; Maier, Wolfgang; Milnik, Annette; Pentzek, Michael; Riedel-Heller, Steffi G; Spalek, Klara; Vogler, Christian; Wagner, Michael; Weyerer, Siegfried; Wolfsgruber, Steffen; de Quervain, Dominique J-F; Papassotiropoulos, Andreas

2015-10-01

Human episodic memory performance is linked to the function of specific brain regions, including the hippocampus; declines as a result of increasing age; and is markedly disturbed in Alzheimer disease (AD), an age-associated neurodegenerative disorder that primarily affects the hippocampus. Exploring the molecular underpinnings of human episodic memory is key to the understanding of hippocampus-dependent cognitive physiology and pathophysiology. To determine whether biologically defined groups of genes are enriched in episodic memory performance across age, memory encoding-related brain activity, and AD. In this multicenter collaborative study, which began in August 2008 and is ongoing, gene set enrichment analysis was done by using primary and meta-analysis data from 57 968 participants. The Swiss cohorts consisted of 3043 healthy young adults assessed for episodic memory performance. In a subgroup (n = 1119) of one of these cohorts, functional magnetic resonance imaging was used to identify gene set-dependent differences in brain activity related to episodic memory. The German Study on Aging, Cognition, and Dementia in Primary Care Patients cohort consisted of 763 elderly participants without dementia who were assessed for episodic memory performance. The International Genomics of Alzheimer's Project case-control sample consisted of 54 162 participants (17 008 patients with sporadic AD and 37 154 control participants). Analyses were conducted between January 2014 and June 2015. Gene set enrichment analysis in all samples was done using genome-wide single-nucleotide polymorphism data. Episodic memory performance in the Swiss cohort and German Study on Aging, Cognition, and Dementia in Primary Care Patients cohort was quantified by picture and verbal delayed free recall tasks. In the functional magnetic resonance imaging experiment, activation of the hippocampus during encoding of pictures served as the phenotype of interest. In the International Genomics of Alzheimer's Project sample, diagnosis of sporadic AD served as the phenotype of interest. In the discovery sample, we detected significant enrichment for genes constituting the calcium signaling pathway, especially those related to the elevation of cytosolic calcium (P = 2 × 10-4). This enrichment was replicated in 2 additional samples of healthy young individuals (P = .02 and .04, respectively) and a sample of healthy elderly participants (P = .004). Hippocampal activation (P = 4 × 10-4) and the risk for sporadic AD (P = .01) were also significantly enriched for genes related to the elevation of cytosolic calcium. By detecting consistent significant enrichment in independent cohorts of young and elderly participants, this study identified that calcium signaling plays a central role in hippocampus-dependent human memory processes in cognitive health and disease, contributing to the understanding and potential treatment of hippocampus-dependent cognitive pathology.

Global teaching and training initiatives for emerging cohort studies

PubMed Central

Paulus, Jessica K.; Santoyo-Vistrain, Rocío; Havelick, David; Cohen, Amy; Kalyesubula, Robert; Ajayi, Ikeoluwapo O.; Mattsson, Jens G.; Adami, Hans-Olov; Dalal, Shona

2015-01-01

A striking disparity exists across the globe, with essentially no large-scale longitudinal studies ongoing in regions that will be significantly affected by the oncoming non-communicable disease epidemic. The successful implementation of cohort studies in most low-resource research environments presents unique challenges that may be aided by coordinated training programs. Leaders of emerging cohort studies attending the First World Cohort Integration Workshop were surveyed about training priorities, unmet needs and potential cross-cohort solutions to these barriers through an electronic pre-workshop questionnaire and focus groups. Cohort studies representing India, Mexico, Nigeria, South Africa, Sweden, Tanzania and Uganda described similar training needs, including on-the-job training, data analysis software instruction, and database and bio-bank management. A lack of funding and protected time for training activities were commonly identified constraints. Proposed solutions include a collaborative cross-cohort teaching platform with web-based content and interactive teaching methods for a range of research personnel. An international network for research mentorship and idea exchange, and modifying the graduate thesis structure were also identified as key initiatives. Cross-cohort integrated educational initiatives will efficiently meet shared needs, catalyze the development of emerging cohorts, speed closure of the global disparity in cohort research, and may fortify scientific capacity development in low-resource settings. PMID:23856451

Analysis of Formant Frequencies in Patients with Oral or Oropharyngeal Cancers Treated by Glossectomy

ERIC Educational Resources Information Center

Kazi, Rehan; Prasad, Vyas M. N.; Kanagalingam, Jeeve; Georgalas, Christos; Venkitaraman, Ramachandran; Nutting, Christopher M.; Clarke, Peter; Rhys-Evans, Peter; Harrington, Kevin J.

2007-01-01

Aims: To compare voice quality as defined by formant analysis using a sustained vowel in patients who have undergone a partial glossectomy with a group of normal subjects. Methods & Procedures: The design consisted of a single centre, cross-sectional cohort study. The setting was an Adult Tertiary Referral Unit. A total of 26 patients (19…

Feasibility of a cohort study on health risks caused by occupational exposure to radiofrequency electromagnetic fields

PubMed Central

2009-01-01

Background The aim of this study was to examine the feasibility of performing a cohort study on health risks from occupational exposure to radiofrequency electromagnetic fields (RF-EMF) in Germany. Methods A set of criteria was developed to evaluate the feasibility of such a cohort study. The criteria aimed at conditions of exposure and exposure assessment (level, duration, preferably on an individual basis), the possibility to assemble a cohort and the feasibility of ascertaining various disease endpoints. Results Twenty occupational settings with workers potentially exposed to RF-EMF and, in addition, a cohort of amateur radio operators were considered. Based on expert ratings, literature reviews and our set of predefined criteria, three of the cohorts were identified as promising for further evaluation: the personnel (technicians) of medium/short wave broadcasting stations, amateur radio operators, and workers on dielectric heat sealers. After further analyses, the cohort of workers on dielectric heat sealers seems not to be feasible due to the small number of exposed workers available and to the difficulty of assessing exposure (exposure depends heavily on the respective working process and mixture of exposures, e.g. plastic vapours), although exposure was highest in this occupational setting. The advantage of the cohort of amateur radio operators was the large number of persons it includes, while the advantage of the cohort of personnel working at broadcasting stations was the quality of retrospective exposure assessment. However, in the cohort of amateur radio operators the exposure assessment was limited, and the cohort of technicians was hampered by the small number of persons working in this profession. Conclusion The majority of occupational groups exposed to RF-EMF are not practicable for setting up an occupational cohort study due to the small numbers of exposed subjects or due to exposure levels being only marginally higher than those of the general public. PMID:19480652

Breaking Cancer Bad News to Patients With Cancer: A Comprehensive Perspective of Patients, Their Relatives, and the Public—Example From a Middle Eastern Country

PubMed Central

Zekri, Jamal

2016-01-01

Purpose Empowering patients with cancer requires that they be continuously informed about their condition. In some Eastern cultures, this concept is often opposed by caregivers. We aim to compare the extent of disclosure desired by actual and presumed patients with cancer and their relatives in our practice. Methods Nine questions reflecting possible bad news communication to patients from diagnosis to the end of life were designed to investigate the extent of desired disclosure and were answered by 100 patients (cohort I) and 103 accompanying relatives (cohort II) in an outpatient setting. In addition, 103 public participants attending a family medicine clinic (cohort III) each answered the questions from the perspective of a presumed patient (cohort IIIA) and the perspective of a relative (cohort IIIB). The primary end point was affirmative response to six or more questions (AR ≥ 6), reflecting a preference to be informed of the majority (≥ 67%) of possible bad news. Results AR ≥ 6 was reported in 85% of cohort I and 52% of cohort II (χ2 P < .001). On multivariable analysis, AR ≥ 6 showed significant association with being a patient (in cohorts I and II) and having nonmetastatic disease (only in cohort I). In the public cohort, AR ≥ 6 was reported in 91% in cohort IIIA and 63% in cohort IIIB (χ2 P < .001). On multivariable analysis, AR ≥ 6 in cohort III was significantly associated with being a presumed patient and having at least a college education. Conclusion Patients desire disclosure of the majority of cancer-related bad news. This is in contrast to the views and requests of relatives. The public participants would also desire similar disclosure if they were to be diagnosed with cancer. PMID:28717713

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

The Role of Preference on Outcomes of People Receiving Evidence-Informed Community Wound Care in Their Home or in a Nurse-Clinic Setting: A Cohort Study (n = 230).

PubMed

Harrison, Margaret B; VanDenKerkhof, Elizabeth G; Hopman, Wilma M; Carley, Meg E

2014-09-19

This study followed a cohort of community-dwelling individuals receiving wound-care in a large urban-rural region. During a randomized control trial (RCT) evaluating outcomes of receiving care in a nurse-clinic or at home, many approached were willing to participate if they could choose their location of care. This provided a unique opportunity to enroll them as a "choice" cohort, following them in the same manner as the trial participants but allowing them to select their setting of care. The objective was to investigate the role of preference and location of care on care outcomes, including satisfaction with care, healing, health-related quality of life (HRQL), pain, and resource use. This is a secondary analysis of a prospective cohort of 126 individuals enrolled in an RCT to receive care at home or in a nurse-clinic (Allocated group), and an additional 104 who received care at home or in a nurse-clinic based on their preference (Choice group). Mobile individuals with a leg ulcer of venous or mixed venous etiology, referred for community leg ulcer care, were eligible. Specially-trained nurses provided care to both groups using an evidence-informed protocol. Baseline data included socio-demographic, circumstance-of-living and a detailed wound assessment. Mean age of the cohort was 68 years. Satisfaction, healing, recurrence, pain, HRQL, and resource utilization did not differ between groups. If available, individuals should have an option of care venue given almost half of those approached indicated a clear preference for clinic or home. With outcomes being similar, health care planners and decision-makers, as well as individuals and their families, can feel confident that the setting of care will not impact the outcomes. However, larger studies in other contexts are needed to explore the interaction between choice and setting.

Effects of cemented versus press-fit primary humeral stem fixation in the setting of revision shoulder arthroplasty.

PubMed

Salesky, Madeleine A; Grace, Trevor R; Feeley, Brian T; Ma, C Benjamin; Zhang, Alan L

2018-05-01

The influence of primary humeral stem fixation method (cemented or press fit) on intraoperative or postoperative outcomes in the setting of revision shoulder arthroplasty is unknown. A retrospective analysis of a prospectively collected cohort of revision shoulder arthroplasty patients from a single tertiary center was performed. Demographic variables, intraoperative data, and 90-day complication rates were compared between cemented and press-fit primary stem fixation cohorts. Follow-up radiographs were graded and compared using a modified Gruen system for humeral lucencies. Eighty-six primary shoulder replacements (34 hemiarthroplasties, 39 anatomic total shoulder arthroplasties, 13 reverse total shoulder arthroplasties) underwent revision arthroplasty with humeral stem removal between 2004 and 2017. Forty-five patients had cemented primary humeral fixation and 41 had press-fit fixation. The cemented cohort was older than the cementless cohort (66.6 vs. 61.4 years; P = .03) but otherwise demonstrated no difference in gender, body mass index, type of primary prosthesis (hemi, total, or reverse), or time between primary and revision operations. The cemented and cementless cohorts showed similar rates of humeral osteotomy (28.9% vs. 29.3%; P = .97), operative time (133.5  vs. 121.3 minutes; P = .16), and 90-day complication rates (13.3% vs. 9.8%; P = .61). Cemented vs. press-fit primary stems also had similar rates of humeral lucencies seen on follow-up radiographs after revision (77.1% vs. 60.6%; P = .14). Humeral stem fixation with or without cement during primary shoulder arthroplasty demonstrated similar operative time, need for intraoperative humeral osteotomy, and postoperative complication rates in the setting of revision arthroplasty. Copyright © 2017 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

A powerful and efficient set test for genetic markers that handles confounders

PubMed Central

Listgarten, Jennifer; Lippert, Christoph; Kang, Eun Yong; Xiang, Jing; Kadie, Carl M.; Heckerman, David

2013-01-01

Motivation: Approaches for testing sets of variants, such as a set of rare or common variants within a gene or pathway, for association with complex traits are important. In particular, set tests allow for aggregation of weak signal within a set, can capture interplay among variants and reduce the burden of multiple hypothesis testing. Until now, these approaches did not address confounding by family relatedness and population structure, a problem that is becoming more important as larger datasets are used to increase power. Results: We introduce a new approach for set tests that handles confounders. Our model is based on the linear mixed model and uses two random effects—one to capture the set association signal and one to capture confounders. We also introduce a computational speedup for two random-effects models that makes this approach feasible even for extremely large cohorts. Using this model with both the likelihood ratio test and score test, we find that the former yields more power while controlling type I error. Application of our approach to richly structured Genetic Analysis Workshop 14 data demonstrates that our method successfully corrects for population structure and family relatedness, whereas application of our method to a 15 000 individual Crohn’s disease case–control cohort demonstrates that it additionally recovers genes not recoverable by univariate analysis. Availability: A Python-based library implementing our approach is available at http://mscompbio.codeplex.com. Contact: jennl@microsoft.com or lippert@microsoft.com or heckerma@microsoft.com Supplementary information: Supplementary data are available at Bioinformatics online. PMID:23599503

Machine learning for neuroimaging with scikit-learn.

PubMed

Abraham, Alexandre; Pedregosa, Fabian; Eickenberg, Michael; Gervais, Philippe; Mueller, Andreas; Kossaifi, Jean; Gramfort, Alexandre; Thirion, Bertrand; Varoquaux, Gaël

2014-01-01

Statistical machine learning methods are increasingly used for neuroimaging data analysis. Their main virtue is their ability to model high-dimensional datasets, e.g., multivariate analysis of activation images or resting-state time series. Supervised learning is typically used in decoding or encoding settings to relate brain images to behavioral or clinical observations, while unsupervised learning can uncover hidden structures in sets of images (e.g., resting state functional MRI) or find sub-populations in large cohorts. By considering different functional neuroimaging applications, we illustrate how scikit-learn, a Python machine learning library, can be used to perform some key analysis steps. Scikit-learn contains a very large set of statistical learning algorithms, both supervised and unsupervised, and its application to neuroimaging data provides a versatile tool to study the brain.

Machine learning for neuroimaging with scikit-learn

PubMed Central

Abraham, Alexandre; Pedregosa, Fabian; Eickenberg, Michael; Gervais, Philippe; Mueller, Andreas; Kossaifi, Jean; Gramfort, Alexandre; Thirion, Bertrand; Varoquaux, Gaël

2014-01-01

Statistical machine learning methods are increasingly used for neuroimaging data analysis. Their main virtue is their ability to model high-dimensional datasets, e.g., multivariate analysis of activation images or resting-state time series. Supervised learning is typically used in decoding or encoding settings to relate brain images to behavioral or clinical observations, while unsupervised learning can uncover hidden structures in sets of images (e.g., resting state functional MRI) or find sub-populations in large cohorts. By considering different functional neuroimaging applications, we illustrate how scikit-learn, a Python machine learning library, can be used to perform some key analysis steps. Scikit-learn contains a very large set of statistical learning algorithms, both supervised and unsupervised, and its application to neuroimaging data provides a versatile tool to study the brain. PMID:24600388

Spatial gender-age-period-cohort analysis of pancreatic cancer mortality in Spain (1990–2013)

PubMed Central

Etxeberria, Jaione; Goicoa, Tomás; López-Abente, Gonzalo; Riebler, Andrea

2017-01-01

Recently, the interest in studying pancreatic cancer mortality has increased due to its high lethality. In this work a detailed analysis of pancreatic cancer mortality in Spanish provinces was performed using recent data. A set of multivariate spatial gender-age-period-cohort models was considered to look for potential candidates to analyze pancreatic cancer mortality rates. The selected model combines features of APC (age-period-cohort) models with disease mapping approaches. To ensure model identifiability sum-to-zero constraints were applied. A fully Bayesian approach based on integrated nested Laplace approximations (INLA) was considered for model fitting and inference. Sensitivity analyses were also conducted. In general, estimated average rates by age, cohort, and period are higher in males than in females. The higher differences according to age between males and females correspond to the age groups [65, 70), [70, 75), and [75, 80). Regarding the cohort, the greatest difference between men and women is observed for those born between the forties and the sixties. From there on, the younger the birth cohort is, the smaller the difference becomes. Some cohort differences are also identified by regions and age-groups. The spatial pattern indicates a North-South gradient of pancreatic cancer mortality in Spain, the provinces in the North being the ones with the highest effects on mortality during the studied period. Finally, the space-time evolution shows that the space pattern has changed little over time. PMID:28199327

A GWAS meta-analysis from 5 population-based cohorts implicates ion channel genes in the pathogenesis of irritable bowel syndrome.

PubMed

Bonfiglio, F; Henström, M; Nag, A; Hadizadeh, F; Zheng, T; Cenit, M C; Tigchelaar, E; Williams, F; Reznichenko, A; Ek, W E; Rivera, N V; Homuth, G; Aghdassi, A A; Kacprowski, T; Männikkö, M; Karhunen, V; Bujanda, L; Rafter, J; Wijmenga, C; Ronkainen, J; Hysi, P; Zhernakova, A; D'Amato, M

2018-04-19

Irritable bowel syndrome (IBS) shows genetic predisposition, however, large-scale, powered gene mapping studies are lacking. We sought to exploit existing genetic (genotype) and epidemiological (questionnaire) data from a series of population-based cohorts for IBS genome-wide association studies (GWAS) and their meta-analysis. Based on questionnaire data compatible with Rome III Criteria, we identified a total of 1335 IBS cases and 9768 asymptomatic individuals from 5 independent European genotyped cohorts. Individual GWAS were carried out with sex-adjusted logistic regression under an additive model, followed by meta-analysis using the inverse variance method. Functional annotation of significant results was obtained via a computational pipeline exploiting ontology and interaction networks, and tissue-specific and gene set enrichment analyses. Suggestive GWAS signals (P ≤ 5.0 × 10 -6 ) were detected for 7 genomic regions, harboring 64 gene candidates to affect IBS risk via functional or expression changes. Functional annotation of this gene set convincingly (best FDR-corrected P = 3.1 × 10 -10 ) highlighted regulation of ion channel activity as the most plausible pathway affecting IBS risk. Our results confirm the feasibility of population-based studies for gene-discovery efforts in IBS, identify risk genes and loci to be prioritized in independent follow-ups, and pinpoint ion channels as important players and potential therapeutic targets warranting further investigation. © 2018 John Wiley & Sons Ltd.

Methodological challenges in measuring vaccine effectiveness using population cohorts in low resource settings.

PubMed

King, C; Beard, J; Crampin, A C; Costello, A; Mwansambo, C; Cunliffe, N A; Heyderman, R S; French, N; Bar-Zeev, N

2015-09-11

Post-licensure real world evaluation of vaccine implementation is important for establishing evidence of vaccine effectiveness (VE) and programme impact, including indirect effects. Large cohort studies offer an important epidemiological approach for evaluating VE, but have inherent methodological challenges. Since March 2012, we have conducted an open prospective cohort study in two sites in rural Malawi to evaluate the post-introduction effectiveness of 13-valent pneumococcal conjugate vaccine (PCV13) against all-cause post-neonatal infant mortality and monovalent rotavirus vaccine (RV1) against diarrhoea-related post-neonatal infant mortality. Our study sites cover a population of 500,000, with a baseline post-neonatal infant mortality of 25 per 1000 live births. We conducted a methodological review of cohort studies for vaccine effectiveness in a developing country setting, applied to our study context. Based on published literature, we outline key considerations when defining the denominator (study population), exposure (vaccination status) and outcome ascertainment (mortality and cause of death) of such studies. We assess various definitions in these three domains, in terms of their impact on power, effect size and potential biases and their direction, using our cohort study for illustration. Based on this iterative process, we discuss the pros and cons of our final per-protocol analysis plan. Since no single set of definitions or analytical approach accounts for all possible biases, we propose sensitivity analyses to interrogate our assumptions and methodological decisions. In the poorest regions of the world where routine vital birth and death surveillance are frequently unavailable and the burden of disease and death is greatest We conclude that provided the balance between definitions and their overall assumed impact on estimated VE are acknowledged, such large scale real-world cohort studies can provide crucial information to policymakers by providing robust and compelling evidence of total benefits of newly introduced vaccines on reducing child mortality. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Methodological challenges in measuring vaccine effectiveness using population cohorts in low resource settings

PubMed Central

King, C.; Beard, J.; Crampin, A.C.; Costello, A.; Mwansambo, C.; Cunliffe, N.A.; Heyderman, R.S.; French, N.; Bar-Zeev, N.

2015-01-01

Post-licensure real world evaluation of vaccine implementation is important for establishing evidence of vaccine effectiveness (VE) and programme impact, including indirect effects. Large cohort studies offer an important epidemiological approach for evaluating VE, but have inherent methodological challenges. Since March 2012, we have conducted an open prospective cohort study in two sites in rural Malawi to evaluate the post-introduction effectiveness of 13-valent pneumococcal conjugate vaccine (PCV13) against all-cause post-neonatal infant mortality and monovalent rotavirus vaccine (RV1) against diarrhoea-related post-neonatal infant mortality. Our study sites cover a population of 500,000, with a baseline post-neonatal infant mortality of 25 per 1000 live births. We conducted a methodological review of cohort studies for vaccine effectiveness in a developing country setting, applied to our study context. Based on published literature, we outline key considerations when defining the denominator (study population), exposure (vaccination status) and outcome ascertainment (mortality and cause of death) of such studies. We assess various definitions in these three domains, in terms of their impact on power, effect size and potential biases and their direction, using our cohort study for illustration. Based on this iterative process, we discuss the pros and cons of our final per-protocol analysis plan. Since no single set of definitions or analytical approach accounts for all possible biases, we propose sensitivity analyses to interrogate our assumptions and methodological decisions. In the poorest regions of the world where routine vital birth and death surveillance are frequently unavailable and the burden of disease and death is greatest We conclude that provided the balance between definitions and their overall assumed impact on estimated VE are acknowledged, such large scale real-world cohort studies can provide crucial information to policymakers by providing robust and compelling evidence of total benefits of newly introduced vaccines on reducing child mortality. PMID:26235370

Esophagus cancer and radiation exposure due to nuclear test fallout: an analysis based on the data of the Semipalatinsk historical cohort, 1960-1999.

PubMed

Bauer, S; Gusev, B I; Pivina, L M; Apsalikov, K N; Grosche, B

2006-01-01

This paper describes the Semipalatinsk historical cohort study and, in particular, examines the association between combined external and internal radiation exposure and esophagus cancer. Esophagus cancer is the most frequent single cancer site in the cause of death follow-up for the Semipalatinsk cohort. Set up in the 1960s, this historical cohort included 10 exposed settlements in the vicinity of the Semipalatinsk nuclear test site in East Kazakhstan as well as 6 comparison settlements in a low exposure area of the same region. The external and internal radiation doses to the population of the settlements under study were mainly due to local fallout from atmospheric nuclear testing (1949-1962). The database includes dosimetry and health information for 19.545 inhabitants of exposed and comparison villages in the Semipalatinsk region, comprising a total of 582.750 person-years of follow-up between 1960 and 1999. Cumulative effective dose estimates in this cohort range from 20 mSv to -4 Sv, with a mean dose of 634 mSv in the exposed group. Relative risks were calculated in terms of rate ratios, using a Poisson regression model for grouped person-time data. Esophagus cancer was found substantially elevated, with a statistically significant increase of the relative risk with dose and an ERR/Sv of 2.37 (1.45; 3.28) for the total cohort. If the data set was restricted to the exposed group only, the ERR/Sv was found considerably lower (0.18 (-0.16; 0.52)), whereas the dose-response remained significant only in women. Overall, our results based on the Semipalatinsk historical cohort indicate an association between fallout exposure and the risk of esophagus cancer that should be further investigated.

Plasma Nervonic Acid Is a Potential Biomarker for Major Depressive Disorder: A Pilot Study.

PubMed

Kageyama, Yuki; Kasahara, Takaoki; Nakamura, Takemichi; Hattori, Kotaro; Deguchi, Yasuhiko; Tani, Munehide; Kuroda, Kenji; Yoshida, Sumiko; Goto, Yu-Ichi; Inoue, Koki; Kato, Tadafumi

2018-03-01

Diagnostic biomarkers of major depressive disorder, bipolar disorder, and schizophrenia are urgently needed, because none are currently available. We performed a comprehensive metabolome analysis of plasma samples from drug-free patients with major depressive disorder (n=9), bipolar disorder (n=6), schizophrenia (n=17), and matched healthy controls (n=19) (cohort 1) using liquid chromatography time-of-flight mass spectrometry. A significant effect of diagnosis was found for 2 metabolites: nervonic acid and cortisone, with nervonic acid being the most significantly altered. The reproducibility of the results and effects of psychotropic medication on nervonic acid were verified in cohort 2, an independent sample set of medicated patients [major depressive disorder (n=45), bipolar disorder (n=71), schizophrenia (n=115)], and controls (n=90) using gas chromatography time-of-flight mass spectrometry. The increased levels of nervonic acid in patients with major depressive disorder compared with controls and patients with bipolar disorder in cohort 1 were replicated in the independent sample set (cohort 2). In cohort 2, plasma nervonic acid levels were also increased in the patients with major depressive disorder compared with the patients with schizophrenia. In cohort 2, nervonic acid levels were increased in the depressive state in patients with major depressive disorder compared with the levels in the remission state in patients with major depressive disorder and the depressive state in patients with bipolar disorder. These results suggested that plasma nervonic acid is a good candidate biomarker for the depressive state of major depressive disorder. © The Author 2017. Published by Oxford University Press on behalf of CINP.

Cohort monitoring of persons with hypertension: an illustrated example from a primary healthcare clinic for Palestine refugees in Jordan.

PubMed

Khader, Ali; Farajallah, Loai; Shahin, Yousef; Hababeh, Majed; Abu-Zayed, Ishtaiwi; Kochi, Arata; Harries, Anthony D; Zachariah, Rony; Kapur, Anil; Venter, Wendy; Seita, Akihiro

2012-09-01

Recording and reporting systems borrowed from the DOTS framework for tuberculosis control can be used to record, monitor and report on chronic disease. In a primary healthcare clinic run by UNRWA in Amman, Jordan, serving Palestine refugees with hypertension, we set out to illustrate the method of cohort reporting for persons with hypertension by presenting on quarterly and cumulative case finding, cumulative and 12-month analysis of cohort outcomes and to assess how these data may inform and improve the quality of hypertension care services. This was a descriptive study using routine programme data collected through E-Health. There were 97 newly registered patients with hypertension in quarter 1, 2012, and a total of 4130 patients with hypertension ever registered since E-Health started in October 2009. By 31 March 2012, 3119 (76%) of 4130 patients were retained in care, 878 (21%) had failed to present to a healthcare worker in the last 3 months and the remainder had died, transferred out or were lost to follow-up. Cumulative and 12-month cohort outcome analysis indicated deficiencies in several components of clinical performance related to blood pressure measurements and fasting blood glucose tests to screen simultaneously for diabetes. Between 8% and 15% of patients with HT had serious complications such as cardiovascular disease and stroke. Cohort analysis is a valuable tool for the monitoring and management of non-communicable chronic diseases such as HT. © 2012 Blackwell Publishing Ltd.

Lung Reference Set A Application: LaszloTakacs - Biosystems (2010) — EDRN Public Portal

Cancer.gov

We would like to access the NCI lung cancer Combined Pre-Validation Reference Set A in order to further validate a lung cancer diagnostic test candidate. Our test is based on a panel of antibodies which have been tested on 4 different cohorts (see below, paragraph “Preliminary Data and Methods”). This Reference Set A, whose clinical setting is “Diagnosis of lung cancer”, will be used to validate the panel of monoclonal antibodies which have been demonstrated by extensive data analysis to provide the best discrimination between controls and Lung Cancer patient plasma samples, sensitivity and specificity values from ROC analyses are superior than 85 %.

Healthcare utilization and costs in persons with insomnia in a managed care population.

PubMed

Anderson, Louise H; Whitebird, Robin R; Schultz, Jennifer; McEvoy, Charlene E; Kreitzer, Mary Jo; Gross, Cynthia R

2014-05-01

To better understand the direct costs of insomnia. Our study aimed to compare healthcare costs and utilization of patients diagnosed with insomnia who received care in a managed care organization with a set of matched controls. Our observational, retrospective cohort study compared 7647 adults with an insomnia diagnosis with an equally sized matched cohort of health plan members without an insomnia diagnosis between 2003 and 2006. We also compared a subset of patients diagnosed with and treated for insomnia with those diagnosed with insomnia but not treated. A large Midwestern health plan with more than 600,000 members. Multivariate analysis was used to estimate the association between insomnia diagnosis and costs, controlling for covariates, in the baseline and follow-up periods. Although we cannot conclude a causal relationship between insomnia and healthcare costs, our analysis found that insomnia diagnosis was associated with 26% higher costs in the baseline and 46% in the 12 months after diagnosis. When comorbidities were recognized, the insomnia cohort had 80% higher costs, on average, than the matched control cohort. These outcomes suggest the need to look beyond the direct cost of insomnia to how its interaction with comorbid conditions drives healthcare cost and utilization.

Multiple imputation of missing data in nested case-control and case-cohort studies.

PubMed

Keogh, Ruth H; Seaman, Shaun R; Bartlett, Jonathan W; Wood, Angela M

2018-06-05

The nested case-control and case-cohort designs are two main approaches for carrying out a substudy within a prospective cohort. This article adapts multiple imputation (MI) methods for handling missing covariates in full-cohort studies for nested case-control and case-cohort studies. We consider data missing by design and data missing by chance. MI analyses that make use of full-cohort data and MI analyses based on substudy data only are described, alongside an intermediate approach in which the imputation uses full-cohort data but the analysis uses only the substudy. We describe adaptations to two imputation methods: the approximate method (MI-approx) of White and Royston () and the "substantive model compatible" (MI-SMC) method of Bartlett et al. (). We also apply the "MI matched set" approach of Seaman and Keogh () to nested case-control studies, which does not require any full-cohort information. The methods are investigated using simulation studies and all perform well when their assumptions hold. Substantial gains in efficiency can be made by imputing data missing by design using the full-cohort approach or by imputing data missing by chance in analyses using the substudy only. The intermediate approach brings greater gains in efficiency relative to the substudy approach and is more robust to imputation model misspecification than the full-cohort approach. The methods are illustrated using the ARIC Study cohort. Supplementary Materials provide R and Stata code. © 2018, The International Biometric Society.

Clinical significance of cerebral microbleeds on MRI: A comprehensive meta-analysis of risk of intracerebral hemorrhage, ischemic stroke, mortality, and dementia in cohort studies (v1).

PubMed

Charidimou, Andreas; Shams, Sara; Romero, Jose R; Ding, Jie; Veltkamp, Roland; Horstmann, Solveig; Eiriksdottir, Gudny; van Buchem, Mark A; Gudnason, Vilmundur; Himali, Jayandra J; Gurol, M Edip; Viswanathan, Anand; Imaizumi, Toshio; Vernooij, Meike W; Seshadri, Sudha; Greenberg, Steven M; Benavente, Oscar R; Launer, Lenore J; Shoamanesh, Ashkan

2018-01-01

Background Cerebral microbleeds can confer a high risk of intracerebral hemorrhage, ischemic stroke, death and dementia, but estimated risks remain imprecise and often conflicting. We investigated the association between cerebral microbleeds presence and these outcomes in a large meta-analysis of all published cohorts including: ischemic stroke/TIA, memory clinic, "high risk" elderly populations, and healthy individuals in population-based studies. Methods Cohorts (with > 100 participants) that assessed cerebral microbleeds presence on MRI, with subsequent follow-up (≥3 months) were identified. The association between cerebral microbleeds and each of the outcomes (ischemic stroke, intracerebral hemorrhage, death, and dementia) was quantified using random effects models of (a) unadjusted crude odds ratios and (b) covariate-adjusted hazard rations. Results We identified 31 cohorts ( n = 20,368): 19 ischemic stroke/TIA ( n = 7672), 4 memory clinic ( n = 1957), 3 high risk elderly ( n = 1458) and 5 population-based cohorts ( n = 11,722). Cerebral microbleeds were associated with an increased risk of ischemic stroke (OR: 2.14; 95% CI: 1.58-2.89 and adj-HR: 2.09; 95% CI: 1.71-2.57), but the relative increase in future intracerebral hemorrhage risk was greater (OR: 4.65; 95% CI: 2.68-8.08 and adj-HR: 3.93; 95% CI: 2.71-5.69). Cerebral microbleeds were an independent predictor of all-cause mortality (adj-HR: 1.36; 95% CI: 1.24-1.48). In three population-based studies, cerebral microbleeds were independently associated with incident dementia (adj-HR: 1.35; 95% CI: 1.00-1.82). Results were overall consistent in analyses stratified by different populations, but with different degrees of heterogeneity. Conclusions Our meta-analysis shows that cerebral microbleeds predict an increased risk of stroke, death, and dementia and provides up-to-date effect sizes across different clinical settings. These pooled estimates can inform clinical decisions and trials, further supporting cerebral microbleeds role as biomarkers of underlying subclinical brain pathology in research and clinical settings.

Assessing the order of magnitude of outcomes in single-arm cohorts through systematic comparison with corresponding cohorts: An example from the AMOS study

PubMed Central

Hamre, Harald J; Glockmann, Anja; Tröger, Wilfried; Kienle, Gunver S; Kiene, Helmut

2008-01-01

Background When a therapy has been evaluated in the first clinical study, the outcome is often compared descriptively to outcomes in corresponding cohorts receiving other treatments. Such comparisons are often limited to selected studies, and often mix different outcomes and follow-up periods. Here we give an example of a systematic comparison to all cohorts with identical outcomes and follow-up periods. Methods The therapy to be compared (anthroposophic medicine, a complementary therapy system) had been evaluated in one single-arm cohort study: the Anthroposophic Medicine Outcomes Study (AMOS). The five largest AMOS diagnosis groups (A-cohorts: asthma, depression, low back pain, migraine, neck pain) were compared to all retrievable corresponding cohorts (C-cohorts) receiving other therapies with identical outcomes (SF-36 scales or summary measures) and identical follow-up periods (3, 6 or 12 months). Between-group differences (pre-post difference in an A-cohort minus pre-post difference in the respective C-cohort) were divided with the standard deviation (SD) of the baseline score of the A-cohort. Results A-cohorts (5 cohorts with 392 patients) were similar to C-cohorts (84 cohorts with 16,167 patients) regarding age, disease duration, baseline affection and follow-up rates. A-cohorts had ≥ 0.50 SD larger improvements than C-cohorts in 13.5% (70/517) of comparisons; improvements of the same order of magnitude (small or minimal differences: -0.49 to 0.49 SD) were found in 80.1% of comparisons; and C-cohorts had ≥ 0.50 SD larger improvements than A-cohorts in 6.4% of comparisons. Analyses stratified by diagnosis had similar results. Sensitivity analyses, restricting the comparisons to C-cohorts with similar study design (observational studies), setting (primary care) or interventions (drugs, physical therapies, mixed), or restricting comparisons to SF-36 scales with small baseline differences between A- and C-cohorts (-0.49 to 0.49 SD) also had similar results. Conclusion In this descriptive analysis, anthroposophic therapy was associated with SF-36 improvements largely of the same order of magnitude as improvements following other treatments. Although these non-concurrent comparisons cannot assess comparative effectiveness, they suggest that improvements in health status following anthroposophic therapy can be clinically meaningful. The analysis also demonstrates the value of a systematic approach when comparing a therapy cohort to corresponding therapy cohorts. PMID:18366683

In Which Ways and to What Extent Do English and Shanghai Students Understand Linear Function?

ERIC Educational Resources Information Center

Wang, Yuqian; Barmby, Patrick; Bolden, David

2017-01-01

This study investigates how students in England and Shanghai understand linear function. Understanding is defined theoretically in terms of five hierarchical levels: Dependent Relationship; Connecting Representations; Property Noticing; Object Analysis; and Inventising. A pilot study instrument presented a set of problems to both cohorts, showing…

Whole-Exome Sequencing in Familial Parkinson Disease

PubMed Central

Farlow, Janice L.; Robak, Laurie A.; Hetrick, Kurt; Bowling, Kevin; Boerwinkle, Eric; Coban-Akdemir, Zeynep H.; Gambin, Tomasz; Gibbs, Richard A.; Gu, Shen; Jain, Preti; Jankovic, Joseph; Jhangiani, Shalini; Kaw, Kaveeta; Lai, Dongbing; Lin, Hai; Ling, Hua; Liu, Yunlong; Lupski, James R.; Muzny, Donna; Porter, Paula; Pugh, Elizabeth; White, Janson; Doheny, Kimberly; Myers, Richard M.; Shulman, Joshua M.; Foroud, Tatiana

2016-01-01

IMPORTANCE Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors. OBJECTIVE To identify genetic variants contributing to disease risk in familial PD. DESIGN, SETTING, AND PARTICIPANTS A 2-stage study design that included a discovery cohort of families with PD and a replication cohort of familial probands was used. In the discovery cohort, rare exonic variants that segregated in multiple affected individuals in a family and were predicted to be conserved or damaging were retained. Genes with retained variants were prioritized if expressed in the brain and located within PD-relevant pathways. Genes in which prioritized variants were observed in at least 4 families were selected as candidate genes for replication in the replication cohort. The setting was among individuals with familial PD enrolled from academic movement disorder specialty clinics across the United States. All participants had a family history of PD. MAIN OUTCOMES AND MEASURES Identification of genes containing rare, likely deleterious, genetic variants in individuals with familial PD using a 2-stage exome sequencing study design. RESULTS The 93 individuals from 32 families in the discovery cohort (49.5% [46 of 93] female) had a mean (SD) age at onset of 61.8 (10.0) years. The 49 individuals with familial PD in the replication cohort (32.6% [16 of 49] female) had a mean (SD) age at onset of 50.1 (15.7) years. Discovery cohort recruitment dates were 1999 to 2009, and replication cohort recruitment dates were 2003 to 2014. Data analysis dates were 2011 to 2015. Three genes containing a total of 13 rare and potentially damaging variants were prioritized in the discovery cohort. Two of these genes (TNK2 and TNR) also had rare variants that were predicted to be damaging in the replication cohort. All 9 variants identified in the 2 replicated genes in 12 families across the discovery and replication cohorts were confirmed via Sanger sequencing. CONCLUSIONS AND RELEVANCE TNK2 and TNR harbored rare, likely deleterious, variants in individuals having familial PD, with similar findings in an independent cohort. To our knowledge, these genes have not been previously associated with PD, although they have been linked to critical neuronal functions. Further studies are required to confirm a potential role for these genes in the pathogenesis of PD. PMID:26595808

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.

Expression of PAM50 Genes in Lung Cancer: Evidence that Interactions between Hormone Receptors and HER2/HER3 Contribute to Poor Outcome.

PubMed

Siegfried, Jill M; Lin, Yan; Diergaarde, Brenda; Lin, Hui-Min; Dacic, Sanja; Pennathur, Arjun; Weissfeld, Joel L; Romkes, Marjorie; Nukui, Tomoko; Stabile, Laura P

2015-11-01

Non-small cell lung cancers (NSCLCs) frequently express estrogen receptor (ER) β, and estrogen signaling is active in many lung tumors. We investigated the ability of genes contained in the prediction analysis of microarray 50 (PAM50) breast cancer risk predictor gene signature to provide prognostic information in NSCLC. Supervised principal component analysis of mRNA expression data was used to evaluate the ability of the PAM50 panel to provide prognostic information in a stage I NSCLC cohort, in an all-stage NSCLC cohort, and in The Cancer Genome Atlas data. Immunohistochemistry was used to determine status of ERβ and other proteins in lung tumor tissue. Associations with prognosis were observed in the stage I cohort. Cross-validation identified seven genes that, when analyzed together, consistently showed survival associations. In pathway analysis, the seven-gene panel described one network containing the ER and progesterone receptor, as well as human epidermal growth factor receptor (HER)2/HER3 and neuregulin-1. NSCLC cases also showed a significant association between ERβ and HER2 protein expression. Cases positive for HER2 expression were more likely to express HER3, and ERβ-positive cases were less likely to be both HER2 and HER3 negative. Prognostic ability of genes in the PAM50 panel was verified in an ERβ-positive cohort representing all NSCLC stages. In The Cancer Genome Atlas data sets, the PAM50 gene set was prognostic in both adenocarcinoma and squamous cell carcinoma, whereas the seven-gene panel was prognostic only in squamous cell carcinoma. Genes in the PAM50 panel, including those linking ER and HER2, identify lung cancer patients at risk for poor outcome, especially among ERβ-positive cases and squamous cell carcinoma. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Retrospective cohort study of the performance of the Pinnacle metal on metal (MoM) total hip replacement: a single-centre investigation in combination with the findings of a national retrieval centre

PubMed Central

Langton, David John; Sidaginamale, Raghavendra Prasad; Avery, Peter; Waller, Sue; Tank, Ghanshyabhai; Lord, James; Joyce, Thomas; Cooke, Nick; Logishetty, Raj; Nargol, Antoni Viraf Francis

2016-01-01

Objectives To determine risk factors for revision in patients implanted with a commonly used metal on metal (MoM) hip replacement. Design Retrospective cohort study in combination with a prospective national retrieval study (Northern Retrieval Registry (NRR)). Setting Combined orthopaedic unit in combination with the NRR. Participants All patients implanted with a DePuy Pinnacle MoM hip prostheses by the 2 senior authors were invited to attend for a review which included clinical examination, blood metal ion measurements, radiographs and targeted imaging. Explanted components underwent wear analysis using validated methodology and these results were compared with those obtained from the NRR. Results 489 MoM Pinnacle hips were implanted into 434 patients (243 females and 191 males). Of these, 352 patients attended the MoM recall clinics. 64 patients had died during the study period. For the purposes of survival analysis, non-attendees were assumed to have well-functioning prostheses. The mean follow-up of the cohort as a whole was 89 months. 71 hips were revised. Prosthetic survival for the whole cohort was 83.6% (79.9–87.3) at 9 years. The majority of explanted devices exhibited signs of taper junction failure. Risk factors for revision were bilateral MoM prostheses, smaller Pinnacle liners, and implantation in 2006 and later years. A significant number of devices were found to be manufactured out of their specifications. This was confirmed with analysis of the wider data set from the NRR. Conclusions This device was found to have an unacceptably high revision rate. Bilateral prostheses, those implanted into female patients and devices implanted in later years were found to be at greater risk. A significant number of explanted components were found to be manufactured with bearing diameters outside of the manufacturer's stated tolerances. Our findings highlight the clinical importance of hitherto unrecognised variations in device production. PMID:27130159

A Comparison of Live Classroom Instruction and Internet-Based Lessons for a Preparatory Training Course Delivered to 4th Year Pharmacy Students

NASA Astrophysics Data System (ADS)

Nuffer, Wesley; Duke, Jodi

2013-08-01

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 prepared by receiving only live classroom instruction. All students in the four cohorts were given a survey to evaluate the training sessions, and results were analyzed using the analysis of variance statistical test (ANOVA). Preceptors at the sites who interacted with students in all four cohorts were surveyed to evaluate which students appeared more prepared; these data were compared using paired t tests. Final assessment data for students in all four cohorts were analyzed using ANOVA. There were statistical differences between the two live training groups, with the second group finding the training to be more beneficial for preparing them, feeling the training length was appropriate and preferring the live modality for delivery. The two internet training cohorts were similar except for perceptions regarding the length of the online training. Comparing responses from those students who received live training with those receiving internet instruction demonstrated a statistical difference with the live groups rating the trainings as more helpful in preparing them for the clinics, rating the training as necessary, and rating their confidence higher in seeing patients. Preceptors rated the live training statistically higher than online training in preparing students. There was no difference between groups on their final site assessments. Live classroom training appears to be superior to the recorded internet training in preparing pharmacy students to oversee a diabetes management program in community settings.

Pathway-based discovery of genetic interactions in breast cancer

PubMed Central

Xu, Zack Z.; Boone, Charles; Lange, Carol A.

2017-01-01

Breast cancer is the second largest cause of cancer death among U.S. women and the leading cause of cancer death among women worldwide. Genome-wide association studies (GWAS) have identified several genetic variants associated with susceptibility to breast cancer, but these still explain less than half of the estimated genetic contribution to the disease. Combinations of variants (i.e. genetic interactions) may play an important role in breast cancer susceptibility. However, due to a lack of statistical power, the current tests for genetic interactions from GWAS data mainly leverage prior knowledge to focus on small sets of genes or SNPs that are known to have an association with breast cancer. Thus, many genetic interactions, particularly among novel variants, remain understudied. Reverse-genetic interaction screens in model organisms have shown that genetic interactions frequently cluster into highly structured motifs, where members of the same pathway share similar patterns of genetic interactions. Based on this key observation, we recently developed a method called BridGE to search for such structured motifs in genetic networks derived from GWAS studies and identify pathway-level genetic interactions in human populations. We applied BridGE to six independent breast cancer cohorts and identified significant pathway-level interactions in five cohorts. Joint analysis across all five cohorts revealed a high confidence consensus set of genetic interactions with support in multiple cohorts. The discovered interactions implicated the glutathione conjugation, vitamin D receptor, purine metabolism, mitotic prometaphase, and steroid hormone biosynthesis pathways as major modifiers of breast cancer risk. Notably, while many of the pathways identified by BridGE show clear relevance to breast cancer, variants in these pathways had not been previously discovered by traditional single variant association tests, or single pathway enrichment analysis that does not consider SNP-SNP interactions. PMID:28957314

Developing and validating a predictive model for stroke progression.

PubMed

Craig, L E; Wu, O; Gilmour, H; Barber, M; Langhorne, P

2011-01-01

Progression is believed to be a common and important complication in acute stroke, and has been associated with increased mortality and morbidity. Reliable identification of predictors of early neurological deterioration could potentially benefit routine clinical care. The aim of this study was to identify predictors of early stroke progression using two independent patient cohorts. Two patient cohorts were used for this study - the first cohort formed the training data set, which included consecutive patients admitted to an urban teaching hospital between 2000 and 2002, and the second cohort formed the test data set, which included patients admitted to the same hospital between 2003 and 2004. A standard definition of stroke progression was used. The first cohort (n = 863) was used to develop the model. Variables that were statistically significant (p < 0.1) on univariate analysis were included in the multivariate model. Logistic regression was the technique employed using backward stepwise regression to drop the least significant variables (p > 0.1) in turn. The second cohort (n = 216) was used to test the performance of the model. The performance of the predictive model was assessed in terms of both calibration and discrimination. Multiple imputation methods were used for dealing with the missing values. Variables shown to be significant predictors of stroke progression were conscious level, history of coronary heart disease, presence of hyperosmolarity, CT lesion, living alone on admission, Oxfordshire Community Stroke Project classification, presence of pyrexia and smoking status. The model appears to have reasonable discriminative properties [the median receiver-operating characteristic curve value was 0.72 (range 0.72-0.73)] and to fit well with the observed data, which is indicated by the high goodness-of-fit p value [the median p value from the Hosmer-Lemeshow test was 0.90 (range 0.50-0.92)]. The predictive model developed in this study contains variables that can be easily collected in practice therefore increasing its usability in clinical practice. Using this analysis approach, the discrimination and calibration of the predictive model appear sufficiently high to provide accurate predictions. This study also offers some discussion around the validation of predictive models for wider use in clinical practice.

Methodologic considerations in the design and analysis of nested case-control studies: association between cytokines and postoperative delirium.

PubMed

Ngo, Long H; Inouye, Sharon K; Jones, Richard N; Travison, Thomas G; Libermann, Towia A; Dillon, Simon T; Kuchel, George A; Vasunilashorn, Sarinnapha M; Alsop, David C; Marcantonio, Edward R

2017-06-06

The nested case-control study (NCC) design within a prospective cohort study is used when outcome data are available for all subjects, but the exposure of interest has not been collected, and is difficult or prohibitively expensive to obtain for all subjects. A NCC analysis with good matching procedures yields estimates that are as efficient and unbiased as estimates from the full cohort study. We present methodological considerations in a matched NCC design and analysis, which include the choice of match algorithms, analysis methods to evaluate the association of exposures of interest with outcomes, and consideration of overmatching. Matched, NCC design within a longitudinal observational prospective cohort study in the setting of two academic hospitals. Study participants are patients aged over 70 years who underwent scheduled major non-cardiac surgery. The primary outcome was postoperative delirium from in-hospital interviews and medical record review. The main exposure was IL-6 concentration (pg/ml) from blood sampled at three time points before delirium occurred. We used nonparametric signed ranked test to test for the median of the paired differences. We used conditional logistic regression to model the risk of IL-6 on delirium incidence. Simulation was used to generate a sample of cohort data on which unconditional multivariable logistic regression was used, and the results were compared to those of the conditional logistic regression. Partial R-square was used to assess the level of overmatching. We found that the optimal match algorithm yielded more matched pairs than the greedy algorithm. The choice of analytic strategy-whether to consider measured cytokine levels as the predictor or outcome-- yielded inferences that have different clinical interpretations but similar levels of statistical significance. Estimation results from NCC design using conditional logistic regression, and from simulated cohort design using unconditional logistic regression, were similar. We found minimal evidence for overmatching. Using a matched NCC approach introduces methodological challenges into the study design and data analysis. Nonetheless, with careful selection of the match algorithm, match factors, and analysis methods, this design is cost effective and, for our study, yields estimates that are similar to those from a prospective cohort study design.

METHODOLOGICAL ISSUES IN THE USE OF GENERALIZED ADDITIVE MODELS FOR THE ANALYSIS OF PARTICULATE MATTER; CONFERENCE PROCEEDINGS FOR 9TH INT'L. INHALATION SYMPOSIUM ON EFFECTS OF AIR CONTAMINANTS ON THE RESPIRATORY TRACT - INTERPRETATIONS FROM MOLECULES TO META ANALYSIS

EPA Science Inventory

Open cohort ("time-series") studies of the adverse health effects of short-term exposures to ambient particulate matter and gaseous co-pollutants have been essential in the standard setting process. Last year, a number of serious issues were raised concerning the fitting of Gener...

Vitamin B6 Intake and the Risk of Colorectal Cancer: A Meta-Analysis of Prospective Cohort Studies.

PubMed

Jia, Kai; Wang, Rong; Tian, Jingfeng

2017-07-01

We performed this meta-analysis to estimate the association between vitamin B 6 intake and colorectal cancer risk. Prospective cohort studies on vitamin B 6 intake and colorectal cancer risk were identified by searching databases from the period of 1960 to 2016. Results from individual studies were synthetically combined using Stata 13.0 software. A total of 10 prospective cohort studies including 13 data sets were included in our meta-analysis, containing 7,817 cases and 784,550 subjects. The combined relative risks (RR) of colorectal cancer for the highest vitamin B 6 intake compared with the lowest vitamin B 6 intake was 0.88 [95% confidence intervals (CIs): 0.77-1.02]. Dose-response meta-analysis based on five eligible studies showed that for each additional 3 and 5 mg of vitamin B 6 intake, the risk would decrease by 11% (RR: 0.89, 95%CI: 0.81-0.98) and 17% (RR: 0.83, 95%CI: 0.71-0.97), respectively. Little evidence of publication bias was found. This meta-analysis provides evidence of a nonsignificant decrease in colorectal cancer risk associated with the high level of vitamin B 6 intake, but the risk in dose-response analysis is significant. However, the latter finding is based on a limited number of studies, which should be interpreted with caution.

Inference and quantification of peptidoforms in large sample cohorts by SWATH-MS

PubMed Central

Röst, Hannes L; Ludwig, Christina; Buil, Alfonso; Bensimon, Ariel; Soste, Martin; Spector, Tim D; Dermitzakis, Emmanouil T; Collins, Ben C; Malmström, Lars; Aebersold, Ruedi

2017-01-01

The consistent detection and quantification of protein post-translational modifications (PTMs) across sample cohorts is an essential prerequisite for the functional analysis of biological processes. Data-independent acquisition (DIA), a bottom-up mass spectrometry based proteomic strategy, exemplified by SWATH-MS, provides complete precursor and fragment ion information of a sample and thus, in principle, the information to identify peptidoforms, the modified variants of a peptide. However, due to the convoluted structure of DIA data sets the confident and systematic identification and quantification of peptidoforms has remained challenging. Here we present IPF (Inference of PeptidoForms), a fully automated algorithm that uses spectral libraries to query, validate and quantify peptidoforms in DIA data sets. The method was developed on data acquired by SWATH-MS and benchmarked using a synthetic phosphopeptide reference data set and phosphopeptide-enriched samples. The data indicate that IPF reduced false site-localization by more than 7-fold in comparison to previous approaches, while recovering 85.4% of the true signals. IPF was applied to detect and quantify peptidoforms carrying ten different types of PTMs in DIA data acquired from more than 200 samples of undepleted blood plasma of a human twin cohort. The data approportioned, for the first time, the contribution of heritable, environmental and longitudinal effects on the observed quantitative variability of specific modifications in blood plasma of a human population. PMID:28604659

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

Wang, Xusheng; Pandey, Ashutosh K.; Mulligan, Megan K.

Phenome-wide association is a novel reverse genetic strategy to analyze genome-to-phenome relations in human clinical cohorts. Here we test this approach using a large murine population segregating for ~5 million sequence variants, and we compare our results to those extracted from a matched analysis of gene variants in a large human cohort. For the mouse cohort, we amassed a deep and broad open-access phenome consisting of ~4,500 metabolic, physiological, pharmacological and behavioural traits, and more than 90 independent expression quantitative trait locus (QTL), transcriptome, proteome, metagenome and metabolome data sets-by far the largest coherent phenome for any experimental cohort (www.genenetwork.org).more » Here, we tested downstream effects of subsets of variants and discovered several novel associations, including a missense mutation in fumarate hydratase that controls variation in the mitochondrial unfolded protein response in both mouse and Caenorhabditis elegans, and missense mutations in Col6a5 that underlies variation in bone mineral density in both mouse and human.« less

Joint mouse–human phenome-wide association to test gene function and disease risk

DOE PAGES

Wang, Xusheng; Pandey, Ashutosh K.; Mulligan, Megan K.; ...

2016-02-02

Phenome-wide association is a novel reverse genetic strategy to analyze genome-to-phenome relations in human clinical cohorts. Here we test this approach using a large murine population segregating for ~5 million sequence variants, and we compare our results to those extracted from a matched analysis of gene variants in a large human cohort. For the mouse cohort, we amassed a deep and broad open-access phenome consisting of ~4,500 metabolic, physiological, pharmacological and behavioural traits, and more than 90 independent expression quantitative trait locus (QTL), transcriptome, proteome, metagenome and metabolome data sets-by far the largest coherent phenome for any experimental cohort (www.genenetwork.org).more » Here, we tested downstream effects of subsets of variants and discovered several novel associations, including a missense mutation in fumarate hydratase that controls variation in the mitochondrial unfolded protein response in both mouse and Caenorhabditis elegans, and missense mutations in Col6a5 that underlies variation in bone mineral density in both mouse and human.« less

Selecting, Adapting, and Implementing Evidence-based Interventions in Rural Settings: An Analysis of 70 Community Examples.

PubMed

Smith, Tina Anderson; Adimu, Tanisa Foxworth; Martinez, Amanda Phillips; Minyard, Karen

2016-01-01

This paper explores how communities translate evidence-based and promising health practices to rural contexts. A descriptive, qualitative analysis was conducted using data from 70 grantees funded by the Federal Office of Rural Health Policy to implement evidence-based health practices in rural settings. Findings were organized using The Interactive Systems Framework for Dissemination and Implementation. Grantees broadly interpreted evidence-based and promising practices, resulting in the implementation of a patchwork of health-related interventions that fell along a spectrum of evidentiary rigor. The cohort faced common challenges translating recognized practices into rural community settings and reported making deliberate modifications to original models as a result. Opportunities for building a more robust rural health evidence base include investments to incentivize evidence-based programming in rural settings; rural-specific research and theory-building; translation of existing evidence using a rural lens; technical assistance to support rural innovation; and prioritization of evaluation locally.

Patterns and Correlates of Substance Use among Affluent, Suburban High School Students

ERIC Educational Resources Information Center

McMahon, Thomas J.; Luthar, Suniya S.

2006-01-01

Despite ongoing concern about substance use during adolescence, very little is known about alcohol and drug use among teens living in affluent social settings. In this longitudinal study, cluster analysis was used to characterize patterns of substance use and change in other dimensions of psychosocial adjustment within a cohort of 292 high school…

Running in Place: Low-Income Students and the Dynamics of Higher Education Stratification

ERIC Educational Resources Information Center

Bastedo, Michael N.; Jaquette, Ozan

2011-01-01

The increasing concentration of wealthy students at highly selective colleges is widely perceived, but few analyses examine the underlying dynamics of higher education stratification over time. To examine these dynamics, the authors build an analysis data set of four cohorts from 1972 to 2004. They find that low-income students have made…

Doctor communication quality and Friends' attitudes influence complementary medicine use in inflammatory bowel disease.

PubMed

Mountifield, Réme; Andrews, Jane M; Mikocka-Walus, Antonina; Bampton, Peter

2015-03-28

To examine the frequency of regular complementary and alternative therapy (CAM) use in three Australian cohorts of contrasting care setting and geography, and identify independent attitudinal and psychological predictors of CAM use across all cohorts. A cross sectional questionnaire was administered to inflammatory bowel disease (IBD) patients in 3 separate cohorts which differed by geographical region and care setting. Demographics and frequency of regular CAM use were assessed, along with attitudes towards IBD medication and psychological parameters such as anxiety, depression, personality traits and quality of life (QOL), and compared across cohorts. Independent attitudinal and psychological predictors of CAM use were determined using binary logistic regression analysis. In 473 respondents (mean age 50.3 years, 60.2% female) regular CAM use was reported by 45.4%, and did not vary between cohorts. Only 54.1% of users disclosed CAM use to their doctor. Independent predictors of CAM use which confirm those reported previously were: covert conventional medication dose reduction (P < 0.001), seeking psychological treatment (P < 0.001), adverse effects of conventional medication (P = 0.043), and higher QOL (P < 0.001). Newly identified predictors were CAM use by family or friends (P < 0.001), dissatisfaction with patient-doctor communication (P < 0.001), and lower depression scores (P < 0.001). In addition to previously identified predictors of CAM use, these data show that physician attention to communication and the patient-doctor relationship is important as these factors influence CAM use. Patient reluctance to discuss CAM with physicians may promote greater reliance on social contacts to influence CAM decisions.

Increased prevalence of sex chromosome aneuploidies in specific language impairment and dyslexia

PubMed Central

Simpson, Nuala H; Addis, Laura; Brandler, William M; Slonims, Vicky; Clark, Ann; Watson, Jocelynne; Scerri, Thomas S; Hennessy, Elizabeth R; Bolton, Patrick F; Conti-Ramsden, Gina; Fairfax, Benjamin P; Knight, Julian C; Stein, John; Talcott, Joel B; O'Hare, Anne; Baird, Gillian; Paracchini, Silvia; Fisher, Simon E; Newbury, Dianne F; Consortium, SLI

2014-01-01

Aim Sex chromosome aneuploidies increase the risk of spoken or written language disorders but individuals with specific language impairment (SLI) or dyslexia do not routinely undergo cytogenetic analysis. We assess the frequency of sex chromosome aneuploidies in individuals with language impairment or dyslexia. Method Genome-wide single nucleotide polymorphism genotyping was performed in three sample sets: a clinical cohort of individuals with speech and language deficits (87 probands: 61 males, 26 females; age range 4 to 23 years), a replication cohort of individuals with SLI, from both clinical and epidemiological samples (209 probands: 139 males, 70 females; age range 4 to 17 years), and a set of individuals with dyslexia (314 probands: 224 males, 90 females; age range 7 to 18 years). Results In the clinical language-impaired cohort, three abnormal karyotypic results were identified in probands (proband yield 3.4%). In the SLI replication cohort, six abnormalities were identified providing a consistent proband yield (2.9%). In the sample of individuals with dyslexia, two sex chromosome aneuploidies were found giving a lower proband yield of 0.6%. In total, two XYY, four XXY (Klinefelter syndrome), three XXX, one XO (Turner syndrome), and one unresolved karyotype were identified. Interpretation The frequency of sex chromosome aneuploidies within each of the three cohorts was increased over the expected population frequency (approximately 0.25%) suggesting that genetic testing may prove worthwhile for individuals with language and literacy problems and normal non-verbal IQ. Early detection of these aneuploidies can provide information and direct the appropriate management for individuals. PMID:24117048

Doctor communication quality and Friends' attitudes influence complementary medicine use in inflammatory bowel disease

PubMed Central

Mountifield, Réme; Andrews, Jane M; Mikocka-Walus, Antonina; Bampton, Peter

2015-01-01

AIM: To examine the frequency of regular complementary and alternative therapy (CAM) use in three Australian cohorts of contrasting care setting and geography, and identify independent attitudinal and psychological predictors of CAM use across all cohorts. METHODS: A cross sectional questionnaire was administered to inflammatory bowel disease (IBD) patients in 3 separate cohorts which differed by geographical region and care setting. Demographics and frequency of regular CAM use were assessed, along with attitudes towards IBD medication and psychological parameters such as anxiety, depression, personality traits and quality of life (QOL), and compared across cohorts. Independent attitudinal and psychological predictors of CAM use were determined using binary logistic regression analysis. RESULTS: In 473 respondents (mean age 50.3 years, 60.2% female) regular CAM use was reported by 45.4%, and did not vary between cohorts. Only 54.1% of users disclosed CAM use to their doctor. Independent predictors of CAM use which confirm those reported previously were: covert conventional medication dose reduction (P < 0.001), seeking psychological treatment (P < 0.001), adverse effects of conventional medication (P = 0.043), and higher QOL (P < 0.001). Newly identified predictors were CAM use by family or friends (P < 0.001), dissatisfaction with patient-doctor communication (P < 0.001), and lower depression scores (P < 0.001). CONCLUSION: In addition to previously identified predictors of CAM use, these data show that physician attention to communication and the patient-doctor relationship is important as these factors influence CAM use. Patient reluctance to discuss CAM with physicians may promote greater reliance on social contacts to influence CAM decisions. PMID:25834335

Mother's education and the risk of preterm and small for gestational age birth: a DRIVERS meta-analysis of 12 European cohorts.

PubMed

Ruiz, Milagros; Goldblatt, Peter; Morrison, Joana; Kukla, Lubomír; Švancara, Jan; Riitta-Järvelin, Marjo; Taanila, Anja; Saurel-Cubizolles, Marie-Josèphe; Lioret, Sandrine; Bakoula, Chryssa; Veltsista, Alexandra; Porta, Daniela; Forastiere, Francesco; van Eijsden, Manon; Vrijkotte, Tanja G M; Eggesbø, Merete; White, Richard A; Barros, Henrique; Correia, Sofia; Vrijheid, Martine; Torrent, Maties; Rebagliato, Marisa; Larrañaga, Isabel; Ludvigsson, Johnny; Olsen Faresjö, Åshild; Hryhorczuk, Daniel; Antipkin, Youriy; Marmot, Michael; Pikhart, Hynek

2015-09-01

A healthy start to life is a major priority in efforts to reduce health inequalities across Europe, with important implications for the health of future generations. There is limited combined evidence on inequalities in health among newborns across a range of European countries. Prospective cohort data of 75 296 newborns from 12 European countries were used. Maternal education, preterm and small for gestational age births were determined at baseline along with covariate data. Regression models were estimated within each cohort and meta-analyses were conducted to compare and measure heterogeneity between cohorts. Mother's education was linked to an appreciable risk of preterm and small for gestational age (SGA) births across 12 European countries. The excess risk of preterm births associated with low maternal education was 1.48 (1.29 to 1.69) and 1.84 (0.99 to 2.69) in relative and absolute terms (Relative/Slope Index of Inequality, RII/SII) for all cohorts combined. Similar effects were found for SGA births, but absolute inequalities were greater, with an SII score of 3.64 (1.74 to 5.54). Inequalities at birth were strong in the Netherlands, the UK, Sweden and Spain and marginal in other countries studied. This study highlights the value of comparative cohort analysis to better understand the relationship between maternal education and markers of fetal growth in different settings across Europe. 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.

Association analysis of nine candidate gene polymorphisms in Indian patients with type 2 diabetic retinopathy.

PubMed

Balasubbu, Suganthalakshmi; Sundaresan, Periasamy; Rajendran, Anand; Ramasamy, Kim; Govindarajan, Gowthaman; Perumalsamy, Namperumalsamy; Hejtmancik, J Fielding

2010-11-10

Diabetic retinopathy (DR) is classically defined as a microvasculopathy that primarily affects the small blood vessels of the inner retina as a complication of diabetes mellitus (DM).It is a multifactorial disease with a strong genetic component. The aim of this study is to investigate the association of a set of nine candidate genes with the development of diabetic retinopathy in a South Indian cohort who have type 2 diabetes mellitus (T2DM). Seven candidate genes (RAGE, PEDF, AKR1B1, EPO, HTRA1, ICAM and HFE) were chosen based on reported association with DR in the literature. Two more, CFH and ARMS2, were chosen based on their roles in biological pathways previously implicated in DR. Fourteen single nucleotide polymorphisms (SNPs) and one dinucleotide repeat polymorphism, previously reported to show association with DR or other related diseases, were genotyped in 345 DR and 356 diabetic patients without retinopathy (DNR). The genes which showed positive association in this screening set were tested further in additional sets of 100 DR and 90 DNR additional patients from the Aravind Eye Hospital. Those which showed association in the secondary screen were subjected to a combined analysis with the 100 DR and 100 DNR subjects previously recruited and genotyped through the Sankara Nethralaya Hospital, India. Genotypes were evaluated using a combination of direct sequencing, TaqMan SNP genotyping, RFLP analysis, and SNaPshot PCR assays. Chi-square and Fisher exact tests were used to analyze the genotype and allele frequencies. Among the nine loci (15 polymorphisms) screened, SNP rs2070600 (G82S) in the RAGE gene, showed significant association with DR (allelic P = 0.016, dominant model P = 0.012), compared to DNR. SNP rs2070600 further showed significant association with DR in the confirmation cohort (P = 0.035, dominant model P = 0.032). Combining the two cohorts gave an allelic P < 0.003 and dominant P = 0.0013). Combined analysis with the Sankara Nethralaya cohort gave an allelic P = 0.0003 and dominant P = 0.00011 with an OR = 0.49 (0.34 - 0.70) for the minor allele. In HTRA1, rs11200638 (G>A), showed marginal significance with DR (P = 0.055) while rs10490924 in LOC387715 gave a P = 0.07. No statistical significance was observed for SNPs in the other 7 genes studied. This study confirms significant association of one polymorphism only (rs2070600 in RAGE) with DR in an Indian population which had T2DM.

Multiple Score Comparison: a network meta-analysis approach to comparison and external validation of prognostic scores.

PubMed

Haile, Sarah R; Guerra, Beniamino; Soriano, Joan B; Puhan, Milo A

2017-12-21

Prediction models and prognostic scores have been increasingly popular in both clinical practice and clinical research settings, for example to aid in risk-based decision making or control for confounding. In many medical fields, a large number of prognostic scores are available, but practitioners may find it difficult to choose between them due to lack of external validation as well as lack of comparisons between them. Borrowing methodology from network meta-analysis, we describe an approach to Multiple Score Comparison meta-analysis (MSC) which permits concurrent external validation and comparisons of prognostic scores using individual patient data (IPD) arising from a large-scale international collaboration. We describe the challenges in adapting network meta-analysis to the MSC setting, for instance the need to explicitly include correlations between the scores on a cohort level, and how to deal with many multi-score studies. We propose first using IPD to make cohort-level aggregate discrimination or calibration scores, comparing all to a common comparator. Then, standard network meta-analysis techniques can be applied, taking care to consider correlation structures in cohorts with multiple scores. Transitivity, consistency and heterogeneity are also examined. We provide a clinical application, comparing prognostic scores for 3-year mortality in patients with chronic obstructive pulmonary disease using data from a large-scale collaborative initiative. We focus on the discriminative properties of the prognostic scores. Our results show clear differences in performance, with ADO and eBODE showing higher discrimination with respect to mortality than other considered scores. The assumptions of transitivity and local and global consistency were not violated. Heterogeneity was small. We applied a network meta-analytic methodology to externally validate and concurrently compare the prognostic properties of clinical scores. Our large-scale external validation indicates that the scores with the best discriminative properties to predict 3 year mortality in patients with COPD are ADO and eBODE.

South Asians and coronary disease: is there discordance between effects on incidence and prognosis?

PubMed Central

Zaman, M Justin S; Philipson, Pete; Chen, Ruoling; Farag, Ahmed; Shipley, Martin; Marmot, Michael G; Timmis, Adam D; Hemingway, Harry

2013-01-01

Objective To determine whether the effect of South Asian ethnicity differs between studies of incidence and prognosis of coronary disease. Design Systematic literature review and meta-analysis, and cohort analysis from a national acute coronary syndrome (ACS) registry linked to mortality (National Institute of Cardiovascular Outcomes Research/Myocardial Infarction National Audit Project). Setting International for the review, and England and Wales for the cohort analysis. Patients The numbers of South Asians included in the meta-analysis were 111 555 (incidence) and 14 531 (prognosis) of whom 8251 were from the ACS cohort. Main outcome measures Incidence studies: non-fatal myocardial infarction or fatal coronary heart disease; prognostic studies: mortality; HRs for 1-year all-cause death in ACS cohort. Results South Asians had higher incidence of coronary disease compared with white subjects (HR 1.35 95% CI 1.30 to 1.40) based on meta-analysis of nine studies. Among 10 studies on prognosis, South Asians had better prognosis compared with white subjects (HR 0.78 95% CI 0.74 to 0.82). In the ACS cohort, the impact of diabetes (42.4% of South Asians, 16.9% of white subjects) on 1-year mortality was stronger in South Asians than white subjects (age-adjusted HR 1.83 95% CI 1.59 to 2.11 vs 1.53 95% CI 1.49 to 1.57). However, prognosis was better in South Asians even among diabetics, older people and those living in areas of the highest social deprivation. Conclusions South Asian ethnicity is associated with higher incidence of coronary disease, but lower mortality once coronary disease is manifest. The dissociation between effects on incidence and prognosis suggests that public health initiatives to reduce inequalities in mortality between South Asian and white populations should focus on primary prevention. This is a CALIBER study with ClinicalTrials.gov Identifier: NCT01163513. PMID:23406688

Aspirin exposure reveals novel genes associated with platelet function and cardiovascular events.

PubMed

Voora, Deepak; Cyr, Derek; Lucas, Joseph; Chi, Jen-Tsan; Dungan, Jennifer; McCaffrey, Timothy A; Katz, Richard; Newby, L Kristin; Kraus, William E; Becker, Richard C; Ortel, Thomas L; Ginsburg, Geoffrey S

2013-10-01

The aim of this study was to develop ribonucleic acid (RNA) profiles that could serve as novel biomarkers for the response to aspirin. Aspirin reduces death and myocardial infarction (MI), suggesting that aspirin interacts with biological pathways that may underlie these events. Aspirin was administered, followed by whole-blood RNA microarray profiling, in a discovery cohort of healthy volunteers (HV1) (n = 50) and 2 validation cohorts of healthy volunteers (HV2) (n = 53) and outpatient cardiology patients (OPC) (n = 25). Platelet function was assessed using the platelet function score (PFS) in HV1 and HV2 and the VerifyNow Aspirin Test (Accumetrics, Inc., San Diego, California) in OPC. Bayesian sparse factor analysis identified sets of coexpressed transcripts, which were examined for associations with PFS in HV1 and validated in HV2 and OPC. Proteomic analysis confirmed the association of validated transcripts in platelet proteins. Validated gene sets were tested for association with death or MI in 2 patient cohorts (n = 587 total) from RNA samples collected at cardiac catheterization. A set of 60 coexpressed genes named the "aspirin response signature" (ARS) was associated with PFS in HV1 (r = -0.31, p = 0.03), HV2 (r = -0.34, Bonferroni p = 0.03), and OPC (p = 0.046). Corresponding proteins for the 17 ARS genes were identified in the platelet proteome, of which 6 were associated with PFS. The ARS was associated with death or MI in both patient cohorts (odds ratio: 1.2 [p = 0.01]; hazard ratio: 1.5 [p = 0.001]), independent of cardiovascular risk factors. Compared with traditional risk factors, reclassification (net reclassification index = 31% to 37%, p ≤ 0.0002) was improved by including the ARS or 1 of its genes, ITGA2B. RNA profiles of platelet-specific genes are novel biomarkers for identifying patients who do not respond adequately to aspirin and who are at risk for death or MI. Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Defining Multiple Chronic Conditions for Quality Measurement.

PubMed

Drye, Elizabeth E; Altaf, Faseeha K; Lipska, Kasia J; Spatz, Erica S; Montague, Julia A; Bao, Haikun; Parzynski, Craig S; Ross, Joseph S; Bernheim, Susannah M; Krumholz, Harlan M; Lin, Zhenqiu

2018-02-01

Patients with multiple chronic conditions (MCCs) are a critical but undefined group for quality measurement. We present a generally applicable systematic approach to defining an MCC cohort of Medicare fee-for-service beneficiaries that we developed for a national quality measure, risk-standardized rates of unplanned admissions for Accountable Care Organizations. To define the MCC cohort we: (1) identified potential chronic conditions; (2) set criteria for cohort conditions based on MCC framework and measure concept; (3) applied the criteria informed by empirical analysis, experts, and the public; (4) described "broader" and "narrower" cohorts; and (5) selected final cohort with stakeholder input. Subjects were patients with chronic conditions. Participants included 21.8 million Medicare fee-for-service beneficiaries in 2012 aged 65 years and above with ≥1 of 27 Medicare Chronic Condition Warehouse condition(s). In total, 10 chronic conditions were identified based on our criteria; 8 of these 10 were associated with notably increased admission risk when co-occurring. A broader cohort (2+ of the 8 conditions) included 4.9 million beneficiaries (23% of total cohort) with an admission rate of 70 per 100 person-years. It captured 53% of total admissions. The narrower cohort (3+ conditions) had 2.2 million beneficiaries (10%) with 100 admissions per 100 person-years and captured 32% of admissions. Most stakeholders viewed the broader cohort as best aligned with the measure concept. By systematically narrowing chronic conditions to those most relevant to the outcome and incorporating stakeholder input, we defined an MCC admission measure cohort supported by stakeholders. This approach can be used as a model for other MCC outcome measures.

Diagnosis of autosomal dominant polycystic kidney disease using efficient PKD1 and PKD2 targeted next-generation sequencing.

PubMed

Trujillano, Daniel; Bullich, Gemma; Ossowski, Stephan; Ballarín, José; Torra, Roser; Estivill, Xavier; Ars, Elisabet

2014-09-01

Molecular diagnostics of autosomal dominant polycystic kidney disease (ADPKD) relies on mutation screening of PKD1 and PKD2, which is complicated by extensive allelic heterogeneity and the presence of six highly homologous sequences of PKD1. To date, specific sequencing of PKD1 requires laborious long-range amplifications. The high cost and long turnaround time of PKD1 and PKD2 mutation analysis using conventional techniques limits its widespread application in clinical settings. We performed targeted next-generation sequencing (NGS) of PKD1 and PKD2. Pooled barcoded DNA patient libraries were enriched by in-solution hybridization with PKD1 and PKD2 capture probes. Bioinformatics analysis was performed using an in-house developed pipeline. We validated the assay in a cohort of 36 patients with previously known PKD1 and PKD2 mutations and five control individuals. Then, we used the same assay and bioinformatics analysis in a discovery cohort of 12 uncharacterized patients. We detected 35 out of 36 known definitely, highly likely, and likely pathogenic mutations in the validation cohort, including two large deletions. In the discovery cohort, we detected 11 different pathogenic mutations in 10 out of 12 patients. This study demonstrates that laborious long-range PCRs of the repeated PKD1 region can be avoided by in-solution enrichment of PKD1 and PKD2 and NGS. This strategy significantly reduces the cost and time for simultaneous PKD1 and PKD2 sequence analysis, facilitating routine genetic diagnostics of ADPKD.

Comparing the cohort design and the nested case–control design in the presence of both time-invariant and time-dependent treatment and competing risks: bias and precision

PubMed Central

Austin, Peter C; Anderson, Geoffrey M; Cigsar, Candemir; Gruneir, Andrea

2012-01-01

Purpose Observational studies using electronic administrative healthcare databases are often used to estimate the effects of treatments and exposures. Traditionally, a cohort design has been used to estimate these effects, but increasingly, studies are using a nested case–control (NCC) design. The relative statistical efficiency of these two designs has not been examined in detail. Methods We used Monte Carlo simulations to compare these two designs in terms of the bias and precision of effect estimates. We examined three different settings: (A) treatment occurred at baseline, and there was a single outcome of interest; (B) treatment was time varying, and there was a single outcome; and C treatment occurred at baseline, and there was a secondary event that competed with the primary event of interest. Comparisons were made of percentage bias, length of 95% confidence interval, and mean squared error (MSE) as a combined measure of bias and precision. Results In Setting A, bias was similar between designs, but the cohort design was more precise and had a lower MSE in all scenarios. In Settings B and C, the cohort design was more precise and had a lower MSE in all scenarios. In both Settings B and C, the NCC design tended to result in estimates with greater bias compared with the cohort design. Conclusions We conclude that in a range of settings and scenarios, the cohort design is superior in terms of precision and MSE. Copyright © 2012 John Wiley & Sons, Ltd. PMID:22653805

Sardasht-Iran cohort study of chemical warfare victims: design and methods.

PubMed

Ghazanfari, Tooba; Faghihzadeh, Soghrat; Aragizadeh, Hassan; Soroush, Mohammad-Reza; Yaraee, Roya; Mohammad Hassan, Zuhair; Foroutan, Abbas; Vaez-Mahdavi, Mohammad-Reza; Javadi, Mohammad-Ali; Moaiedmohseni, Sakine; Azizi, Fereidoun; Panahi, Yunes; Mostafaie, Ali; Ghasemi, Hassan; Shams, Jalaleddin; Pourfarzam, Shahryar; Jalali-Nadoushan, Mohammad-Reza; Fallahi, Faramarz; Ebtekar, Massoumeh; Davoudi, Seyyed-Masoud; Ghazanfari, Zeinab; Ardestani, Sussan K; Shariat-Panahi, Shamsa; Moin, Athar; Rezaei, Abbas; Kariminia, Amina; Ajdary, Soheila; Mahmoudi, Mahmoud; Roshan, Rasoul; Ghaderi, Sulayman; Babai, Mahmoud; Naghizadeh, Mohammad-Mehdi; Ghanei, Mohammad-Mostafa

2009-01-01

Insights into long-term clinical consequences of sulfur mustard have emerged from some investigations but less is known about the basic and molecular mechanisms of these complications. Sardasht-Iran Cohort Study is a comprehensive historical cohort study on Sardasht chemical victims' population which was designed to find out the long-term complications of sulfur mustard exposure and the basic mechanisms underlying clinical manifestations. This paper describes the design and methodology of Sardasht-Iran Cohort Study. In Sardasht-Iran Cohort Study, 500 individuals including 372 subjects from Sardasht, as the exposed group, and 128 subjects from Rabat, as the unexposed age-matched control group were evaluated. The exposed group was divided into two groups based on the severity of clinical complications at the time of exposure. Different samples including blood, sputum, saliva, tear, urine, and semen were collected for immunologic, hematologic, biochemical, and other laboratory analysis. Data were gathered from medical records, clinical examinations, laboratory tests, and questionnaires for psychological and lifestyle situations. The important distinctions setting this study apart from the previous ones are discussed. The Sardasht-Iran Cohort Study provides important information on various aspects of long-term consequences of sulfur mustard exposure. This database will provide a better position to suggest guidelines for the diagnosis, treatment, and prevention of delayed complications in the patients exposed to sulfur mustard.

Urgent and Elective Robotic Single-Site Cholecystectomy: Analysis and Learning Curve of 150 Consecutive Cases.

PubMed

Kubat, Eric; Hansen, Nathan; Nguyen, Huy; Wren, Sherry M; Eisenberg, Dan

2016-03-01

The use of robotic single-site cholecystectomy has increased exponentially. There are few reports describing the safety, efficacy, and operative learning curve of robotic single-site cholecystectomy either in the community setting or with nonelective surgery. We performed a retrospective review of a prospective database of our initial experience with robotic single-site cholecystectomy. Demographics and perioperative outcomes were evaluated for both urgent and elective cholecystectomy. Cumulative sum analysis was performed to determine the surgeon's learning curve. One hundred fifty patients underwent robotic single-site cholecystectomy. Seventy-four (49.3%) patients underwent urgent robotic single-site cholecystectomy, and 76 (50.7%) underwent elective robotic single-site cholecystectomy. Mean total operative time for robotic single-site cholecystectomy was 83.3 ± 2.7 minutes. Mean operative time for the urgent cohort was significantly longer than for the elective cohort (95.0 ± 4.4 versus 71.9 ± 2.6 minutes; P < .001). There was one conversion in the urgent cohort and none in the elective cohort. There was one bile duct injury (0.7%) in the urgent cohort. Perioperative complications occurred in 8.7% of patients, and most consisted of superficial surgical-site infections. There were no incisional hernias detected. The surgeon's learning curve, inclusive of urgent and elective cases, was 48 operations. Robotic single-site cholecystectomy can be performed safely and effectively in both elective and urgent cholecystectomy with a reasonable learning curve and acceptable perioperative outcomes.

Characteristics and Trends of Attrition from the United States Naval Academy

DTIC Science & Technology

2006-06-01

dissatisfaction, they are having a more difficult time fitting in and finding large social circles that fully support their development . 3. Stage 3 The...degree of MASTER OF SCIENCE IN LEADERSHIP AND HUMAN RESOURCE DEVELOPMENT from the NAVAL POSTGRADUATE SCHOOL June 2006 Author: James W. Bishop Approved...21 B. STAGE 1: COHORT ANALYSES...............................................................21 C. STAGE 2: DATA SET ANALYSIS

A Time Hazard Analysis of Student Persistence: A US University Undergraduate Mathematics Major Experience

ERIC Educational Resources Information Center

Bahi, Saïd; Higgins, Devin; Staley, Patrick

2015-01-01

Individual level data for the entire cohort of undergraduate mathematics students of a relatively small US public university was used to estimate the risk that a student will switch major to another one before degree completion. The data set covers the period from 1999 to 2006. Survival tables and logistic models were estimated and used to discuss…

Naturally Occurring Human Urinary Peptides for Use in Diagnosis of Chronic Kidney Disease*

PubMed Central

Good, David M.; Zürbig, Petra; Argilés, Àngel; Bauer, Hartwig W.; Behrens, Georg; Coon, Joshua J.; Dakna, Mohammed; Decramer, Stéphane; Delles, Christian; Dominiczak, Anna F.; Ehrich, Jochen H. H.; Eitner, Frank; Fliser, Danilo; Frommberger, Moritz; Ganser, Arnold; Girolami, Mark A.; Golovko, Igor; Gwinner, Wilfried; Haubitz, Marion; Herget-Rosenthal, Stefan; Jankowski, Joachim; Jahn, Holger; Jerums, George; Julian, Bruce A.; Kellmann, Markus; Kliem, Volker; Kolch, Walter; Krolewski, Andrzej S.; Luppi, Mario; Massy, Ziad; Melter, Michael; Neusüss, Christian; Novak, Jan; Peter, Karlheinz; Rossing, Kasper; Rupprecht, Harald; Schanstra, Joost P.; Schiffer, Eric; Stolzenburg, Jens-Uwe; Tarnow, Lise; Theodorescu, Dan; Thongboonkerd, Visith; Vanholder, Raymond; Weissinger, Eva M.; Mischak, Harald; Schmitt-Kopplin, Philippe

2010-01-01

Because of its availability, ease of collection, and correlation with physiology and pathology, urine is an attractive source for clinical proteomics/peptidomics. However, the lack of comparable data sets from large cohorts has greatly hindered the development of clinical proteomics. Here, we report the establishment of a reproducible, high resolution method for peptidome analysis of naturally occurring human urinary peptides and proteins, ranging from 800 to 17,000 Da, using samples from 3,600 individuals analyzed by capillary electrophoresis coupled to MS. All processed data were deposited in an Structured Query Language (SQL) database. This database currently contains 5,010 relevant unique urinary peptides that serve as a pool of potential classifiers for diagnosis and monitoring of various diseases. As an example, by using this source of information, we were able to define urinary peptide biomarkers for chronic kidney diseases, allowing diagnosis of these diseases with high accuracy. Application of the chronic kidney disease-specific biomarker set to an independent test cohort in the subsequent replication phase resulted in 85.5% sensitivity and 100% specificity. These results indicate the potential usefulness of capillary electrophoresis coupled to MS for clinical applications in the analysis of naturally occurring urinary peptides. PMID:20616184

Azacitidine for Front-Line Therapy of Patients with AML: Reproducible Efficacy Established by Direct Comparison of International Phase 3 Trial Data with Registry Data from the Austrian Azacitidine Registry of the AGMT Study Group

PubMed Central

Pleyer, Lisa; Döhner, Hartmut; Dombret, Hervé; Seymour, John F.; Schuh, Andre C.; Beach, CL; Swern, Arlene S.; Burgstaller, Sonja; Stauder, Reinhard; Girschikofsky, Michael; Sill, Heinz; Schlick, Konstantin; Thaler, Josef; Halter, Britta; Machherndl Spandl, Sigrid; Zebisch, Armin; Pichler, Angelika; Pfeilstöcker, Michael; Autzinger, Eva M.; Lang, Alois; Geissler, Klaus; Voskova, Daniela; Sperr, Wolfgang R.; Hojas, Sabine; Rogulj, Inga M.; Andel, Johannes; Greil, Richard

2017-01-01

We recently published a clinically-meaningful improvement in median overall survival (OS) for patients with acute myeloid leukaemia (AML), >30% bone marrow (BM) blasts and white blood cell (WBC) count ≤15 G/L, treated with front-line azacitidine versus conventional care regimens within a phase 3 clinical trial (AZA-AML-001; NCT01074047; registered: February 2010). As results obtained in clinical trials are facing increased pressure to be confirmed by real-world data, we aimed to test whether data obtained in the AZA-AML-001 trial accurately represent observations made in routine clinical practice by analysing additional AML patients treated with azacitidine front-line within the Austrian Azacitidine Registry (AAR; NCT01595295; registered: May 2012) and directly comparing patient-level data of both cohorts. We assessed the efficacy of front-line azacitidine in a total of 407 patients with newly-diagnosed AML. Firstly, we compared data from AML patients with WBC ≤ 15 G/L and >30% BM blasts included within the AZA-AML-001 trial treated with azacitidine (“AML-001” cohort; n = 214) with AAR patients meeting the same inclusion criteria (“AAR (001-like)” cohort; n = 95). The current analysis thus represents a new sub-analysis of the AML-001 trial, which is directly compared with a new sub-analysis of the AAR. Baseline characteristics, azacitidine application, response rates and OS were comparable between all patient cohorts within the trial or registry setting. Median OS was 9.9 versus 10.8 months (p = 0.616) for “AML-001” versus “AAR (001-like)” cohorts, respectively. Secondly, we pooled data from both cohorts (n = 309) and assessed the outcome. Median OS of the pooled cohorts was 10.3 (95% confidence interval: 8.7, 12.6) months, and the one-year survival rate was 45.8%. Thirdly, we compared data from AAR patients meeting AZA-AML-001 trial inclusion criteria (n = 95) versus all AAR patients with World Health Organization (WHO)-defined AML (“AAR (WHO-AML)” cohort; n = 193). Within the registry population, median OS for AAR patients meeting trial inclusion criteria versus all WHO-AML patients was 10.8 versus 11.8 months (p = 0.599), respectively. We thus tested and confirmed the efficacy of azacitidine as a front-line agent in patients with AML, >30% BM blasts and WBC ≤ 15 G/L in a routine clinical practice setting. We further show that the efficacy of azacitidine does not appear to be limited to AML patients who meet stringent clinical trial inclusion criteria, but instead appears efficacious as front-line treatment in all patients with WHO-AML. PMID:28212292

Marginal Structural Models for Case-Cohort Study Designs to Estimate the Association of Antiretroviral Therapy Initiation With Incident AIDS or Death

PubMed Central

Cole, Stephen R.; Hudgens, Michael G.; Tien, Phyllis C.; Anastos, Kathryn; Kingsley, Lawrence; Chmiel, Joan S.; Jacobson, Lisa P.

2012-01-01

To estimate the association of antiretroviral therapy initiation with incident acquired immunodeficiency syndrome (AIDS) or death while accounting for time-varying confounding in a cost-efficient manner, the authors combined a case-cohort study design with inverse probability-weighted estimation of a marginal structural Cox proportional hazards model. A total of 950 adults who were positive for human immunodeficiency virus type 1 were followed in 2 US cohort studies between 1995 and 2007. In the full cohort, 211 AIDS cases or deaths occurred during 4,456 person-years. In an illustrative 20% random subcohort of 190 participants, 41 AIDS cases or deaths occurred during 861 person-years. Accounting for measured confounders and determinants of dropout by inverse probability weighting, the full cohort hazard ratio was 0.41 (95% confidence interval: 0.26, 0.65) and the case-cohort hazard ratio was 0.47 (95% confidence interval: 0.26, 0.83). Standard multivariable-adjusted hazard ratios were closer to the null, regardless of study design. The precision lost with the case-cohort design was modest given the cost savings. Results from Monte Carlo simulations demonstrated that the proposed approach yields approximately unbiased estimates of the hazard ratio with appropriate confidence interval coverage. Marginal structural model analysis of case-cohort study designs provides a cost-efficient design coupled with an accurate analytic method for research settings in which there is time-varying confounding. PMID:22302074

Early Environment and Neurobehavioral Development Predict Adult Temperament Clusters

PubMed Central

Congdon, Eliza; Service, Susan; Wessman, Jaana; Seppänen, Jouni K.; Schönauer, Stefan; Miettunen, Jouko; Turunen, Hannu; Koiranen, Markku; Joukamaa, Matti; Järvelin, Marjo-Riitta; Veijola, Juha; Mannila, Heikki; Paunio, Tiina; Freimer, Nelson B.

2012-01-01

Background Investigation of the environmental influences on human behavioral phenotypes is important for our understanding of the causation of psychiatric disorders. However, there are complexities associated with the assessment of environmental influences on behavior. Methods/Principal Findings We conducted a series of analyses using a prospective, longitudinal study of a nationally representative birth cohort from Finland (the Northern Finland 1966 Birth Cohort). Participants included a total of 3,761 male and female cohort members who were living in Finland at the age of 16 years and who had complete temperament scores. Our initial analyses (Wessman et al., in press) provide evidence in support of four stable and robust temperament clusters. Using these temperament clusters, as well as independent temperament dimensions for comparison, we conducted a data-driven analysis to assess the influence of a broad set of life course measures, assessed pre-natally, in infancy, and during adolescence, on adult temperament. Results Measures of early environment, neurobehavioral development, and adolescent behavior significantly predict adult temperament, classified by both cluster membership and temperament dimensions. Specifically, our results suggest that a relatively consistent set of life course measures are associated with adult temperament profiles, including maternal education, characteristics of the family’s location and residence, adolescent academic performance, and adolescent smoking. Conclusions Our finding that a consistent set of life course measures predict temperament clusters indicate that these clusters represent distinct developmental temperament trajectories and that information about a subset of life course measures has implications for adult health outcomes. PMID:22815688

European Prevention of Alzheimer's Dementia Registry: Recruitment and prescreening approach for a longitudinal cohort and prevention trials.

PubMed

Vermunt, Lisa; Veal, Colin D; Ter Meulen, Lea; Chrysostomou, Charalambos; van der Flier, Wiesje; Frisoni, Giovanni B; Guessous, Idris; Kivipelto, Miia; Marizzoni, Moira; Martinez-Lage, Pablo; Molinuevo, José Luis; Porteous, David; Ritchie, Karen; Scheltens, Philip; Ousset, Pierre-Jean; Ritchie, Craig W; Luscan, Gerald; Brookes, Anthony J; Visser, Pieter Jelle

2018-06-01

It is a challenge to find participants for Alzheimer's disease (AD) prevention trials within a short period of time. The European Prevention of Alzheimer's Dementia Registry (EPAD) aims to facilitate recruitment by preselecting subjects from ongoing cohort studies. This article introduces this novel approach. A virtual registry, with access to risk factors and biomarkers for AD through minimal data sets of ongoing cohort studies, was set up. To date, ten cohorts have been included in the EPAD. Around 2500 participants have been selected, using variables associated with the risk for AD. Of these, 15% were already recruited in the EPAD longitudinal cohort study, which serves as a trial readiness cohort. This study demonstrates that a virtual registry can be used for the preselection of participants for AD studies. Copyright © 2018 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Genome-wide association study identifies SNPs in the MHC class II loci that are associated with self-reported history of whooping cough

PubMed Central

McMahon, George; Ring, Susan M.; Davey-Smith, George; Timpson, Nicholas J.

2015-01-01

Whooping cough is currently seeing resurgence in countries despite high vaccine coverage. There is considerable variation in subject-specific response to infection and vaccine efficacy, but little is known about the role of human genetics. We carried out a case–control genome-wide association study of adult or parent-reported history of whooping cough in two cohorts from the UK: the ALSPAC cohort and the 1958 British Birth Cohort (815/758 cases and 6341/4308 controls, respectively). We also imputed HLA alleles using dense SNP data in the MHC region and carried out gene-based and gene-set tests of association and estimated the amount of additive genetic variation explained by common SNPs. We observed a novel association at SNPs in the MHC class II region in both cohorts [lead SNP rs9271768 after meta-analysis, odds ratio [95% confidence intervals (CIs)] 1.47 (1.35, 1.6), P-value 1.21E − 18]. Multiple strong associations were also observed at alleles at the HLA class II loci. The majority of these associations were explained by the lead SNP rs9271768. Gene-based and gene-set tests and estimates of explainable common genetic variation could not establish the presence of additional associations in our sample. Genetic variation at the MHC class II region plays a role in susceptibility to whooping cough. These findings provide additional perspective on mechanisms of whooping cough infection and vaccine efficacy. PMID:26231221

Increased prevalence of sex chromosome aneuploidies in specific language impairment and dyslexia.

PubMed

Simpson, Nuala H; Addis, Laura; Brandler, William M; Slonims, Vicky; Clark, Ann; Watson, Jocelynne; Scerri, Thomas S; Hennessy, Elizabeth R; Bolton, Patrick F; Conti-Ramsden, Gina; Fairfax, Benjamin P; Knight, Julian C; Stein, John; Talcott, Joel B; O'Hare, Anne; Baird, Gillian; Paracchini, Silvia; Fisher, Simon E; Newbury, Dianne F

2014-04-01

Sex chromosome aneuploidies increase the risk of spoken or written language disorders but individuals with specific language impairment (SLI) or dyslexia do not routinely undergo cytogenetic analysis. We assess the frequency of sex chromosome aneuploidies in individuals with language impairment or dyslexia. Genome-wide single nucleotide polymorphism genotyping was performed in three sample sets: a clinical cohort of individuals with speech and language deficits (87 probands: 61 males, 26 females; age range 4 to 23 years), a replication cohort of individuals with SLI, from both clinical and epidemiological samples (209 probands: 139 males, 70 females; age range 4 to 17 years), and a set of individuals with dyslexia (314 probands: 224 males, 90 females; age range 7 to 18 years). In the clinical language-impaired cohort, three abnormal karyotypic results were identified in probands (proband yield 3.4%). In the SLI replication cohort, six abnormalities were identified providing a consistent proband yield (2.9%). In the sample of individuals with dyslexia, two sex chromosome aneuploidies were found giving a lower proband yield of 0.6%. In total, two XYY, four XXY (Klinefelter syndrome), three XXX, one XO (Turner syndrome), and one unresolved karyotype were identified. The frequency of sex chromosome aneuploidies within each of the three cohorts was increased over the expected population frequency (approximately 0.25%) suggesting that genetic testing may prove worthwhile for individuals with language and literacy problems and normal non-verbal IQ. Early detection of these aneuploidies can provide information and direct the appropriate management for individuals. © 2013 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.

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

Identification and Construction of Combinatory Cancer Hallmark-Based Gene Signature Sets to Predict Recurrence and Chemotherapy Benefit in Stage II Colorectal Cancer.

PubMed

Gao, Shanwu; Tibiche, Chabane; Zou, Jinfeng; Zaman, Naif; Trifiro, Mark; O'Connor-McCourt, Maureen; Wang, Edwin

2016-01-01

Decisions regarding adjuvant therapy in patients with stage II colorectal cancer (CRC) have been among the most challenging and controversial in oncology over the past 20 years. To develop robust combinatory cancer hallmark-based gene signature sets (CSS sets) that more accurately predict prognosis and identify a subset of patients with stage II CRC who could gain survival benefits from adjuvant chemotherapy. Thirteen retrospective studies of patients with stage II CRC who had clinical follow-up and adjuvant chemotherapy were analyzed. Respective totals of 162 and 843 patients from 2 and 11 independent cohorts were used as the discovery and validation cohorts, respectively. A total of 1005 patients with stage II CRC were included in the 13 cohorts. Among them, 84 of 416 patients in 3 independent cohorts received fluorouracil-based adjuvant chemotherapy. Identification of CSS sets to predict relapse-free survival and identify a subset of patients with stage II CRC who could gain substantial survival benefits from fluorouracil-based adjuvant chemotherapy. Eight cancer hallmark-based gene signatures (30 genes each) were identified and used to construct CSS sets for determining prognosis. The CSS sets were validated in 11 independent cohorts of 767 patients with stage II CRC who did not receive adjuvant chemotherapy. The CSS sets accurately stratified patients into low-, intermediate-, and high-risk groups. Five-year relapse-free survival rates were 94%, 78%, and 45%, respectively, representing 60%, 28%, and 12% of patients with stage II disease. The 416 patients with CSS set-defined high-risk stage II CRC who received fluorouracil-based adjuvant chemotherapy showed a substantial gain in survival benefits from the treatment (ie, recurrence reduced by 30%-40% in 5 years). The CSS sets substantially outperformed other prognostic predictors of stage 2 CRC. They are more accurate and robust for prognostic predictions and facilitate the identification of patients with stage II disease who could gain survival benefit from fluorouracil-based adjuvant chemotherapy.

Impact of Month of Birth on the Risk of Development of Autoimmune Addison's Disease

PubMed Central

Fichna, Marta; Mitchell, Anna L.; Napier, Catherine M.; Gan, Earn; Ruchała, Marek; Santibanez-Koref, Mauro; Pearce, Simon H.

2016-01-01

Context: The pathogenesis of autoimmune Addison's disease (AAD) is thought to be due to interplay of genetic, immune, and environmental factors. A month-of-birth effect, with increased risk for those born in autumn/winter months, has been described in autoimmune conditions such as type 1 diabetes and autoimmune thyroid disease. Objective: Month-of-birth effect was investigated in 2 independent cohorts of AAD subjects. Design, Setting, and Patients: The monthly distribution of birth in AAD patients was compared with that of the general population using the cosinor test. A total of 415 AAD subjects from the United Kingdom cohort were compared with 8 180 180 United Kingdom births, and 231 AAD subjects from the Polish cohort were compared with 2 421 384 Polish births. Main Outcome Measures: Association between month of birth and the susceptibility to AAD. Results: In the entire cohort of AAD subjects, month-of-birth distribution analysis showed significant periodicity with peak of births in December and trough in May (P = .028). Analysis of the odds ratio distribution based on month of birth in 2 cohorts of patients with AAD versus the general population revealed a December peak and May trough, and January peak and July trough, in the United Kingdom and Polish cohorts, respectively. Conclusion: For the first time, we demonstrate that month of birth exerts an effect on the risk of developing AAD, with excess risk in individuals born in winter months and a protective effect when born in the summer. Exposure to seasonal viral infections in the perinatal period, coupled with vitamin D deficiency, could lead to dysregulation of innate immunity affecting the risk of developing AAD. PMID:27575942

Examining mortality risk and rate of ageing among Polish Olympic athletes: a survival follow-up from 1924 to 2012

PubMed Central

Lin, Yuhui; Gajewski, Antoni; Poznańska, Anna

2016-01-01

Objectives Population-based studies have shown that an active lifestyle reduces mortality risk. Therefore, it has been a longstanding belief that individuals who engage in frequent exercise will experience a slower rate of ageing. It is uncertain whether this widely-accepted assumption holds for intense wear-and-tear. Here, using the 88 years survival follow-up data of Polish Olympic athletes, we report for the first time on whether frequent exercise alters the rate of ageing. Design Longitudinal survival data of male elite Polish athletes who participated in the Olympic Games from year 1924 to 2010 were used. Deaths occurring before the end of World War II were excluded for reliable estimates. Setting and participants Recruited male elite athletes N=1273 were preassigned to two categorical birth cohorts—Cohort I 1890–1919; Cohort II 1920–1959—and a parametric frailty survival analysis was conducted. An event-history analysis was also conducted to adjust for medical improvements from year 1920 onwards: Cohort II. Results Our findings suggest (1) in Cohort I, for every threefold reduction in mortality risk, the rate of ageing decelerates by 1%; (2) socioeconomic transitions and interventions contribute to a reduction in mortality risk of 29% for the general population and 50% for Olympic athletes; (3) an optimum benefit gained for reducing the rate of ageing from competitive sports (Cohort I 0.086 (95% CI 0.047 to 0.157) and Cohort II 0.085 (95% CI 0.050 to 0.144)). Conclusions This study further suggests that intensive physical training during youth should be considered as a factor to improve ageing and mortality risk parameters. PMID:27091824

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

Developing and Validating a Predictive Model for Stroke Progression

PubMed Central

Craig, L.E.; Wu, O.; Gilmour, H.; Barber, M.; Langhorne, P.

2011-01-01

Background Progression is believed to be a common and important complication in acute stroke, and has been associated with increased mortality and morbidity. Reliable identification of predictors of early neurological deterioration could potentially benefit routine clinical care. The aim of this study was to identify predictors of early stroke progression using two independent patient cohorts. Methods Two patient cohorts were used for this study – the first cohort formed the training data set, which included consecutive patients admitted to an urban teaching hospital between 2000 and 2002, and the second cohort formed the test data set, which included patients admitted to the same hospital between 2003 and 2004. A standard definition of stroke progression was used. The first cohort (n = 863) was used to develop the model. Variables that were statistically significant (p < 0.1) on univariate analysis were included in the multivariate model. Logistic regression was the technique employed using backward stepwise regression to drop the least significant variables (p > 0.1) in turn. The second cohort (n = 216) was used to test the performance of the model. The performance of the predictive model was assessed in terms of both calibration and discrimination. Multiple imputation methods were used for dealing with the missing values. Results Variables shown to be significant predictors of stroke progression were conscious level, history of coronary heart disease, presence of hyperosmolarity, CT lesion, living alone on admission, Oxfordshire Community Stroke Project classification, presence of pyrexia and smoking status. The model appears to have reasonable discriminative properties [the median receiver-operating characteristic curve value was 0.72 (range 0.72–0.73)] and to fit well with the observed data, which is indicated by the high goodness-of-fit p value [the median p value from the Hosmer-Lemeshow test was 0.90 (range 0.50–0.92)]. Conclusion The predictive model developed in this study contains variables that can be easily collected in practice therefore increasing its usability in clinical practice. Using this analysis approach, the discrimination and calibration of the predictive model appear sufficiently high to provide accurate predictions. This study also offers some discussion around the validation of predictive models for wider use in clinical practice. PMID:22566988

Prediction of cancer specific survival after radical nephroureterectomy for upper tract urothelial carcinoma: development of an optimized postoperative nomogram using decision curve analysis.

PubMed

Rouprêt, Morgan; Hupertan, Vincent; Seisen, Thomas; Colin, Pierre; Xylinas, Evanguelos; Yates, David R; Fajkovic, Harun; Lotan, Yair; Raman, Jay D; Zigeuner, Richard; Remzi, Mesut; Bolenz, Christian; Novara, Giacomo; Kassouf, Wassim; Ouzzane, Adil; Rozet, François; Cussenot, Olivier; Martinez-Salamanca, Juan I; Fritsche, Hans-Martin; Walton, Thomas J; Wood, Christopher G; Bensalah, Karim; Karakiewicz, Pierre I; Montorsi, Francesco; Margulis, Vitaly; Shariat, Shahrokh F

2013-05-01

We conceived and proposed a unique and optimized nomogram to predict cancer specific survival after radical nephroureterectomy in patients with upper tract urothelial carcinoma by merging the 2 largest multicenter data sets reported in this population. The international and the French national collaborative groups on upper tract urothelial carcinoma pooled data on 3,387 patients treated with radical nephroureterectomy for whom full data for nomogram development were available. The merged study population was randomly split into the development cohort (2,371) and the external validation cohort (1,016). Cox regressions were used for univariable and multivariable analyses, and to build different models. The ultimate reduced nomogram was assessed using Harrell's concordance index (c-index) and decision curve analysis. Of the 2,371 patients in the nomogram development cohort 510 (21.5%) died of upper tract urothelial carcinoma during followup. The actuarial cancer specific survival probability at 5 years was 73.7% (95% CI 71.9-75.6). Decision curve analysis revealed that the use of the best model was associated with benefit gains relative to the prediction of cancer specific survival. The optimized nomogram included only 5 variables associated with cancer specific survival on multivariable analysis, those of age (p = 0.001), T stage (p <0.001), N stage (p = 0.001), architecture (p = 0.02) and lymphovascular invasion (p = 0.001). The discriminative accuracy of the nomogram was 0.8 (95% CI 0.77-0.86). Using standard pathological features obtained from the largest data set of upper tract urothelial carcinomas worldwide, we devised and validated an accurate and ultimate nomogram, superior to any single clinical variable, for predicting cancer specific survival after radical nephroureterectomy. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Maternal Health Risk Assessment and Behavioral Intervention in the NICU Setting Following Very Low Birth Weight Delivery.

PubMed

Dunlop, Anne L; Logue, Kristi; Thorne, Castalia

2016-11-01

Objectives To investigate whether maternal health risk assessment and behavioral intervention in the neonatal intensive care unit (NICU) improves women's health care seeking and health behaviors following the birth of a very low birth weight (VLBW) infant. Methods Using a quasi-experimental non-equivalent control group pretest/posttest design, 80 women who had given birth to a VLBW infant that was admitted to the NICU were enrolled into one of two cohorts: 40 into a 'Minimal Intervention' cohort, who received a single session risk assessment and health education pamphlets, and 40 into an 'Enhanced Intervention' cohort, who received five counseling sessions targeting identified risks. The proportion of women with specific health care seeking and health behaviors in the two cohorts were compared at baseline and 3- and 9-months post-intervention. Results Women in the Enhanced Intervention cohort were more likely to attend the postpartum visit (73 % vs. 48 %; p = 0.04), ingest folic acid daily (65 % vs. 19 %, p < 0.001), and correctly and consistently use a method of contraception (82 % vs. 63 %, p = 0.03) over the 9-month follow-up period. In multivariate analysis, the between-cohort differences in daily folic acid use (aOR = 3.45, 95 % CI 1.61-7.40) and correct and consistent use of a method of contraception (aOR = 1.46, 95 % CI 1.05-2.06) remained statistically significant at 9-months and the reduction in risk of unintended pregnancy nearly achieved statistical significance (aOR = 0.62, 95 % CI 0.12-1.0). Conclusions for Practice This study provides support for the implementation of maternal risk assessment and behavioral intervention in the NICU setting to promote women's positive health care seeking and health behaviors.

Driving Pressure and Hospital Mortality in Patients Without ARDS: A Cohort Study.

PubMed

Schmidt, Marcello F S; Amaral, Andre C K B; Fan, Eddy; Rubenfeld, Gordon D

2018-01-01

Driving pressure (ΔP) is associated with mortality in patients with ARDS and with pulmonary complications in patients undergoing general anesthesia. Whether ΔP is associated with outcomes of patients without ARDS who undergo ventilation in the ICU is unknown. Our objective was to determine the independent association between ΔP and outcomes in mechanically ventilated patients without ARDS on day 1 of mechanical ventilation. This was a retrospective analysis of a cohort of 622 mechanically ventilated adult patients without ARDS on day 1 of mechanical ventilation from five ICUs in a tertiary center in the United States. The primary outcome was hospital mortality. The presence of ARDS was determined using the minimum daily Pao 2 to Fio 2 (PF) ratio and an automated text search of chest radiography reports. The data set was validated by first testing the model in 543 patients with ARDS. In patients without ARDS on day 1 of mechanical ventilation, ΔP was not independently associated with hospital mortality (OR, 1.01; 95% CI, 0.97-1.05). The results of the primary analysis were confirmed in a series of preplanned sensitivity analyses. In this cohort of patients without ARDS on day 1 of mechanical ventilation and within the limits of ventilatory settings normally used by clinicians, ΔP was not associated with hospital mortality. This study also confirms the association between ΔP and mortality in patients with ARDS not enrolled in a trial and in hypoxemic patients without ARDS. Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

The "DGPPN-Cohort": A national collaboration initiative by the German Association for Psychiatry and Psychotherapy (DGPPN) for establishing a large-scale cohort of psychiatric patients.

PubMed

Anderson-Schmidt, Heike; Adler, Lothar; Aly, Chadiga; Anghelescu, Ion-George; Bauer, Michael; Baumgärtner, Jessica; Becker, Joachim; Bianco, Roswitha; Becker, Thomas; Bitter, Cosima; Bönsch, Dominikus; Buckow, Karoline; Budde, Monika; Bührig, Martin; Deckert, Jürgen; Demiroglu, Sara Y; Dietrich, Detlef; Dümpelmann, Michael; Engelhardt, Uta; Fallgatter, Andreas J; Feldhaus, Daniel; Figge, Christian; Folkerts, Here; Franz, Michael; Gade, Katrin; Gaebel, Wolfgang; Grabe, Hans-Jörgen; Gruber, Oliver; Gullatz, Verena; Gusky, Linda; Heilbronner, Urs; Helbing, Krister; Hegerl, Ulrich; Heinz, Andreas; Hensch, Tilman; Hiemke, Christoph; Jäger, Markus; Jahn-Brodmann, Anke; Juckel, Georg; Kandulski, Franz; Kaschka, Wolfgang P; Kircher, Tilo; Koller, Manfred; Konrad, Carsten; Kornhuber, Johannes; Krause, Marina; Krug, Axel; Lee, Mahsa; Leweke, Markus; Lieb, Klaus; Mammes, Mechthild; Meyer-Lindenberg, Andreas; Mühlbacher, Moritz; Müller, Matthias J; Nieratschker, Vanessa; Nierste, Barbara; Ohle, Jacqueline; Pfennig, Andrea; Pieper, Marlenna; Quade, Matthias; Reich-Erkelenz, Daniela; Reif, Andreas; Reitt, Markus; Reininghaus, Bernd; Reininghaus, Eva Z; Riemenschneider, Matthias; Rienhoff, Otto; Roser, Patrik; Rujescu, Dan; Schennach, Rebecca; Scherk, Harald; Schmauss, Max; Schneider, Frank; Schosser, Alexandra; Schott, Björn H; Schwab, Sybille G; Schwanke, Jens; Skrowny, Daniela; Spitzer, Carsten; Stierl, Sebastian; Stöckel, Judith; Stübner, Susanne; Thiel, Andreas; Volz, Hans-Peter; von Hagen, Martin; Walter, Henrik; Witt, Stephanie H; Wobrock, Thomas; Zielasek, Jürgen; Zimmermann, Jörg; Zitzelsberger, Antje; Maier, Wolfgang; Falkai, Peter G; Rietschel, Marcella; Schulze, Thomas G

2013-12-01

The German Association for Psychiatry and Psychotherapy (DGPPN) has committed itself to establish a prospective national cohort of patients with major psychiatric disorders, the so-called DGPPN-Cohort. This project will enable the scientific exploitation of high-quality data and biomaterial from psychiatric patients for research. It will be set up using harmonised data sets and procedures for sample generation and guided by transparent rules for data access and data sharing regarding the central research database. While the main focus lies on biological research, it will be open to all kinds of scientific investigations, including epidemiological, clinical or health-service research.

Maternal Malaria and Malnutrition (M3) initiative, a pooled birth cohort of 13 pregnancy studies in Africa and the Western Pacific.

PubMed

Unger, Holger W; Cates, Jordan E; Gutman, Julie; Briand, Valerie; Fievet, Nadine; Valea, Innocent; Tinto, Halidou; d'Alessandro, Umberto; Landis, Sarah H; Adu-Afarwuah, Seth; Dewey, Kathryn G; Ter Kuile, Feiko; Dellicour, Stephanie; Ouma, Peter; Slutsker, Laurence; Terlouw, Dianne J; Kariuki, Simon; Ayisi, John; Nahlen, Bernard; Desai, Meghna; Madanitsa, Mwayi; Kalilani-Phiri, Linda; Ashorn, Per; Maleta, Kenneth; Mueller, Ivo; Stanisic, Danielle; Schmiegelow, Christentze; Lusingu, John; Westreich, Daniel; van Eijk, Anna Maria; Meshnick, Steven; Rogerson, Stephen

2016-12-21

The Maternal Malaria and Malnutrition (M3) initiative has pooled together 13 studies with the hope of improving understanding of malaria-nutrition interactions during pregnancy and to foster collaboration between nutritionists and malariologists. Data were pooled on 14 635 singleton, live birth pregnancies from women who had participated in 1 of 13 pregnancy studies. The 13 studies cover 8 countries in Africa and Papua New Guinea in the Western Pacific conducted from 1996 to 2015. Data are available at the time of antenatal enrolment of women into their respective parent study and at delivery. The data set comprises essential data such as malaria infection status, anthropometric assessments of maternal nutritional status, presence of anaemia and birth weight, as well as additional variables such gestational age at delivery for a subset of women. Participating studies are described in detail with regard to setting and primary outcome measures, and summarised data are available from each contributing cohort. This pooled birth cohort is the largest pregnancy data set to date to permit a more definite evaluation of the impact of plausible interactions between poor nutritional status and malaria infection in pregnant women on fetal growth and gestational length. Given the current comparative lack of large pregnancy cohorts in malaria-endemic settings, compilation of suitable pregnancy cohorts is likely to provide adequate statistical power to assess malaria-nutrition interactions, and could point towards settings where such interactions are most relevant. The M3 cohort may thus help to identify pregnant women at high risk of adverse outcomes who may benefit from tailored intensive antenatal care including nutritional supplements and alternative or intensified malaria prevention regimens, and the settings in which these interventions would be most effective. 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/.

Maternal Malaria and Malnutrition (M3) initiative, a pooled birth cohort of 13 pregnancy studies in Africa and the Western Pacific

PubMed Central

Unger, Holger W; Gutman, Julie; Briand, Valerie; Fievet, Nadine; Valea, Innocent; Tinto, Halidou; d'Alessandro, Umberto; Landis, Sarah H; Adu-Afarwuah, Seth; Dewey, Kathryn G; Ter Kuile, Feiko; Dellicour, Stephanie; Ouma, Peter; Slutsker, Laurence; Terlouw, Dianne J; Kariuki, Simon; Ayisi, John; Nahlen, Bernard; Desai, Meghna; Madanitsa, Mwayi; Kalilani-Phiri, Linda; Ashorn, Per; Maleta, Kenneth; Mueller, Ivo; Stanisic, Danielle; Schmiegelow, Christentze; Lusingu, John; Westreich, Daniel; van Eijk, Anna Maria; Meshnick, Steven; Rogerson, Stephen

2016-01-01

Purpose The Maternal Malaria and Malnutrition (M3) initiative has pooled together 13 studies with the hope of improving understanding of malaria–nutrition interactions during pregnancy and to foster collaboration between nutritionists and malariologists. Participants Data were pooled on 14 635 singleton, live birth pregnancies from women who had participated in 1 of 13 pregnancy studies. The 13 studies cover 8 countries in Africa and Papua New Guinea in the Western Pacific conducted from 1996 to 2015. Findings to date Data are available at the time of antenatal enrolment of women into their respective parent study and at delivery. The data set comprises essential data such as malaria infection status, anthropometric assessments of maternal nutritional status, presence of anaemia and birth weight, as well as additional variables such gestational age at delivery for a subset of women. Participating studies are described in detail with regard to setting and primary outcome measures, and summarised data are available from each contributing cohort. Future plans This pooled birth cohort is the largest pregnancy data set to date to permit a more definite evaluation of the impact of plausible interactions between poor nutritional status and malaria infection in pregnant women on fetal growth and gestational length. Given the current comparative lack of large pregnancy cohorts in malaria-endemic settings, compilation of suitable pregnancy cohorts is likely to provide adequate statistical power to assess malaria–nutrition interactions, and could point towards settings where such interactions are most relevant. The M3 cohort may thus help to identify pregnant women at high risk of adverse outcomes who may benefit from tailored intensive antenatal care including nutritional supplements and alternative or intensified malaria prevention regimens, and the settings in which these interventions would be most effective. PMID:28003287

Historical cohort study of US man-made vitreous fiber production workers: VIII. Exposure-specific job analysis.

PubMed

Quinn, M M; Smith, T J; Youk, A O; Marsh, G M; Stone, R A; Buchanich, J M; Gula, M J

2001-09-01

All jobs held by a cohort of US man-made vitreous fiber production workers were analyzed for airborne fiber exposure. This exposure-specific job analysis was part of an exposure assessment for an epidemiologic study of mortality patterns, with particular focus on respiratory cancer, among 35,145 workers employed in 10 fiberglass and five rock or slag wool plants. The exposure assessment was conducted from the start-up date of each plant (1917 to 1946) to 1990. For the job analysis, 15,465 crude department names and 47,693 crude job titles were grouped into 1668 unique department and job pairs (UDJobs), which represented a job title linked to a specific department within each plant. Every UDJob was evaluated according to a set of job elements related to airborne fiber exposure. The distribution of the cohort person-years by UDJob and the job-exposure elements was then evaluated. The results show the main departments and jobs that employed the workers for each plant. The distribution of person-years varies across the job-exposure elements. The same job title was used in different departments within and across plants. When job titles not linked to departments were evaluated, the values of the job-exposure elements varied considerably across all plants and within plant. (1) exposure misclassification could occur if job title alone were used for the exposure assessment; (2) the job-exposure elements analysis provides an efficient way to identify major job determinants of exposure without relying on the more detailed, resource-intensive task-based approach; and (3) the evaluation of the cohort person-years by UDJobs and job-exposure elements is an effective way to identify which plants, departments, and jobs have sufficient information for making precise risk estimates in the broader epidemiologic study.

PolyPhred analysis software for mutation detection from fluorescence-based sequence data.

PubMed

Montgomery, Kate T; Iartchouck, Oleg; Li, Li; Loomis, Stephanie; Obourn, Vanessa; Kucherlapati, Raju

2008-10-01

The ability to search for genetic variants that may be related to human disease is one of the most exciting consequences of the availability of the sequence of the human genome. Large cohorts of individuals exhibiting certain phenotypes can be studied and candidate genes resequenced. However, the challenge of analyzing sequence data from many individuals with accuracy, speed, and economy is great. This unit describes one set of software tools: Phred, Phrap, PolyPhred, and Consed. Coverage includes the advantages and disadvantages of these analysis tools, details for obtaining and using the software, and the results one may expect. The software is being continually updated to permit further automation of mutation analysis. Currently, however, at least some manual review is required if one wishes to identify 100% of the variants in a sample set.

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

Cadmium exposure and risk of lung cancer: a meta-analysis of cohort and case-control studies among general and occupational populations.

PubMed

Chen, Cheng; Xun, Pengcheng; Nishijo, Muneko; He, Ka

2016-09-01

The association between cadmium exposure and risk of lung cancer is still unclear. We quantitatively reviewed the observational studies that investigated the association between cadmium exposure and lung cancer risk in both general and occupational populations published through April 2015. The final data set is comprised of three cohort studies in the general population totaling 22,551 participants (354 events) with a mean follow-up of 15 years, five occupational cohort studies including 4205 individuals (180 events) with an average follow-up of 31 years, and three occupational case-control studies including 4740 cases and 6268 controls. Comparing the highest to the lowest category of cadmium exposure, the weighted relative risk and 95% confidence interval of lung cancer in the general population was 1.42 (95% CI (0.91, 2.23)); the weighted risk estimates (95% CIs) of lung cancer in three occupational cohort studies and three case-control studies were 0.68 (95% CI (0.33, 1.41)) and 1.61 (95% CI (0.94, 2.75)), respectively. No linear association was found. When comparing participants exposed to cadmium with non-exposed based on available data, the association became statistically significant. According to findings from this meta-analysis, the possibility that cadmium exposure may increase risk of lung cancer cannot be completely ruled out in either general or occupational population.

Efficacy and tolerability of vildagliptin-based versus comparative dual therapy in type 2 diabetes : Results of the Austrian subpopulation of the EDGE study.

PubMed

Brath, Helmut; Bialek, Christoph; Gingl, Ewald; Resl, Michael; Prager, Rudolf; Ratzinger, Michaela

2015-04-01

The aim of this post hoc analysis of data from the Austrian subpopulation of the EDGE study was the evaluation of the effectiveness and tolerability of vildagliptin as an add-on to an existing oral antidiabetic (OAD) monotherapy versus a combination therapy with two OADs without vildagliptin in patients with inadequately controlled type 2 diabetes. In Austria, 422 patients were included. In the framework of regular visits (at baseline, about once per quarter, and at the study end, after 12 months), adverse events (AEs), courses, and changes of therapy were recorded. In addition to the primary end point defined in the primary study, i.e., a reduction of HbA1c by > 0.3 % without hypoglycemia, weight gain ≥ 5 %, peripheral edema, or discontinuation due to gastrointestinal events, the most clinically relevant secondary end point, i.e., HbA1c reduction < 7 % without hypoglycemia or ≥ 3 % increase in body weight after 12 months was used for the analysis of the Austrian data. The initial HbA1c of all enrolled patients was 8.3 ± 1.4 %. The mean reduction of HbA1c was - 1.1 % in the vildagliptin cohort and - 1.0 % in the comparator cohort. In the vildagliptin cohort, 56.4 % of patients, and in the comparator cohort, 45.9 % of patients, reached the primary end point (odds ratio: 1.53, p = 0.04). In the vildagliptin cohort, 18.7 % of patients, and in the comparator cohort, 16.9 % of patients, reached the secondary end point (odds ratio: 1.13, p = 0.68). The incidence of hypoglycemic events (two in each cohort), AEs (approximately 15 % in each cohort), and serious AEs (approximately 2 % in each cohort) was comparable between the two groups. In a "real-life" setting, the effectiveness of vildagliptin as second-line treatment is superior to comparator OADs with regard to a reduction in HbA1c of greater than 0.3 % from baseline without well-recognized side effects in patients with inadequately controlled type 2 diabetes (mean baseline HbA1c: 8.5 % (vildagliptin cohort) vs. 8.1 % (comparator cohort)).

Treatment of Patients With Hepatitis C Virus Infection With Ledipasvir-Sofosbuvir in the Liver Transplant Setting.

PubMed

Abaalkhail, Faisal; Elsiesy, Hussein; Elbeshbeshy, Hany; Shawkat, Mohamed; Yousif, Sarra; Ullah, Waheed; Alabbad, Saleh; Al-Jedai, Ahmed; Ajlan, Aziza; Broering, Dieter; Saab, Sammy; Al Sebayel, Mohammed; Al-Hamoudi, Waleed

2017-11-01

Hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma and the leading indication for liver transplantation. In the Middle East, genotype 4 HCV infection is the most common genotype. However, limited data exists on the treatment of genotype-4 in the liver transplant setting. We evaluated the safety and efficacy of ledipasvir (LDV)-sofosbuvir (SOF) in treating HCV genotype-4 infected patients with cirrhosis or postliver transplantation. This prospective, single-arm, observational study includes cohort of patients with cirrhosis before liver transplantation (cohort A) and a cohort of postliver transplantation patients (cohort B). Patients received LDV/SOF (90-400 mg) once daily for 12 to 24 weeks with or without ribavirin (RBV). Patients with creatinine clearance below 30 were excluded. A total of 111 patients (61 cirrhotic; 50 postliver transplants) with HCV genotype 4 were treated in King Faisal Specialist Hospital and Research Center; 55% cohort A and 44% cohort B received RBV. Sustained virological response sustain virological response (SVR)12 was 91.8% and 86% of cohorts A and B, respectively. There were no treatment-related mortality or serious adverse effects. RBV dose reduction occurred in 25% without any treatment discontinuation. SVR12 rates in cohort A were significantly higher in patients with a viral load below 800 000 (100% vs 83.9%, P value = 0.022). Viral load did not impact SVR rates in cohort B. The use of RBV did not increase SVR12 and was associated with anemia. LDV/SOF without RBV is an effective and safe treatment option for patients with HCV genotype 4 infection in preliver and postliver transplant settings.

Expression profiles analysis of long non-coding RNAs identified novel lncRNA biomarkers with predictive value in outcome of cutaneous melanoma.

PubMed

Ma, Xu; He, Zhijuan; Li, Ling; Yang, Daping; Liu, Guofeng

2017-09-29

Recent advancements in cancer biology have identified a large number of lncRNAs that are dysregulated expression in the development and tumorigenesis of cancers, highlighting the importance of lncRNAs as a key player for human cancers. However, the prognostic value of lncRNAs still remains unclear and needs to be further investigated. In the present study, we aim to assess the prognostic value of lncRNAs in cutaneous melanoma by integrated lncRNA expression profiles from TCGA database and matched clinical information from a large cohort of patients with cutaneous melanoma. We finally identified a set of six lncRNAs that are significantly associated with survival of patients with cutaneous melanoma. A linear combination of six lncRNAs ( LINC01260, HCP5, PIGBOS1, RP11-247L20.4, CTA-292E10.6 and CTB-113P19.5 ) was constructed as a six-lncRNA signature which classified patients of training cohort into the high-risk group and low-risk group with significantly different survival time. The prognostic value of the six-lncRNA signature was validated in both the validation cohort and entire TCGA cohort. Moreover, the six-lncRNA signature is independent of known clinic-pathological factors by multivariate Cox regression analysis and demonstrated good performance for predicting three- and five-year overall survival by time-dependent receiver operating characteristic (ROC) analysis. Our study provides novel insights into the molecular heterogeneity of cutaneous melanoma and also shows potentially important implications of lncRNAs for prognosis and therapy for cutaneous melanoma.

Cost Implications for Subsequent Perinatal Outcomes After IVF Stratified by Number of Embryos Transferred: A Five Year Analysis of Vermont Data.

PubMed

Carpinello, Olivia J; Casson, Peter R; Kuo, Chia-Ling; Raj, Renju S; Sills, E Scott; Jones, Christopher A

2016-06-01

In states in the USA without in vitro fertilzation coverage (IVF) insurance coverage, more embryos are transferred per cycle leading to higher risks of multi-fetal pregnancies and adverse pregnancy outcomes. To determine frequency and cost of selected adverse perinatal complications based on number of embryos transferred during IVF, and calculate incremental cost per IVF live birth. Medical records of patients who conceived with IVF (n = 116) and delivered at >20 weeks gestational age between 2007 and 2011 were evaluated. Gestational age at delivery, low birth weight (LBW) term births, and delivery mode were tabulated. Healthcare costs per cohort, extrapolated costs assuming 100 patients per cohort, and incremental costs per infant delivered were calculated. The highest prematurity and cesarean section rates were recorded after double embryo transfers (DET), while the lowest rates were found in single embryo transfers (SET). Premature singleton deliveries increased directly with number of transferred embryos [6.3 % (SET), 9.1 % (DET) and 10.0 % for ≥3 embryos transferred]. This trend was also noted for rate of cesarean delivery [26.7 % (SET), 36.6 % (DET), and 47.1 % for ≥3 embryos transferred]. The proportion of LBW infants among deliveries after DET and for ≥3 embryos transferred was 3.9 and 9.1 %, respectively. Extrapolated costs per cohort were US$718,616, US$1,713,470 and US$1,227,396 for SET, DET, and ≥3 embryos transferred, respectively. Attempting to improve IVF pregnancy rates by permitting multiple embryo transfers results in sharply increased rates of multiple gestation and preterm delivery. This practice yields a greater frequency of adverse perinatal outcomes and substantially increased healthcare spending. Better efforts to encourage SET are necessary to normalize healthcare expenditures considering the frequency of very high cost sequela associated with IVF where multiple embryo transfers occur.

Embedded Experiences, Critical Conversations: Learning about Teaching in a Professional Development School Cohort Setting

ERIC Educational Resources Information Center

Schuchart, Daphne

2012-01-01

Using qualitative research techniques, the researcher explored preservice teacher learning among traditional college-age students engaged in a semester-long early field experience in an urban elementary school within a Literacy Education Professional Development School (LEPrDS) cohort setting. The purpose of this study was two-fold: (a) to explore…

A Case Study of Group Processes and Student Evaluation of Teaching

ERIC Educational Resources Information Center

Mortenson, Kristian G.; Sathe, Richard S.

2017-01-01

This paper documents a case study undertaken to understand the effect of group processes on student evaluation of teaching (SET). The study used interviews to investigate the experiences of students in a cohort model Master of Science in Accountancy degree program and how those experiences influenced SET. The cohort served as an extreme example in…

Independent Predictors of Prognosis Based on Oral Cavity Squamous Cell Carcinoma Surgical Margins.

PubMed

Buchakjian, Marisa R; Ginader, Timothy; Tasche, Kendall K; Pagedar, Nitin A; Smith, Brian J; Sperry, Steven M

2018-05-01

Objective To conduct a multivariate analysis of a large cohort of oral cavity squamous cell carcinoma (OCSCC) cases for independent predictors of local recurrence (LR) and overall survival (OS), with emphasis on the relationship between (1) prognosis and (2) main specimen permanent margins and intraoperative tumor bed frozen margins. Study Design Retrospective cohort study. Setting Tertiary academic head and neck cancer program. Subjects and Methods This study included 426 patients treated with OCSCC resection between 2005 and 2014 at University of Iowa Hospitals and Clinics. Patients underwent excision of OCSCC with intraoperative tumor bed frozen margin sampling and main specimen permanent margin assessment. Multivariate analysis of the data set to predict LR and OS was performed. Results Independent predictors of LR included nodal involvement, histologic grade, and main specimen permanent margin status. Specifically, the presence of a positive margin (odds ratio, 6.21; 95% CI, 3.3-11.9) or <1-mm/carcinoma in situ margin (odds ratio, 2.41; 95% CI, 1.19-4.87) on the main specimen was an independent predictor of LR, whereas intraoperative tumor bed margins were not predictive of LR on multivariate analysis. Similarly, independent predictors of OS on multivariate analysis included nodal involvement, extracapsular extension, and a positive main specimen margin. Tumor bed margins did not independently predict OS. Conclusion The main specimen margin is a strong independent predictor of LR and OS on multivariate analysis. Intraoperative tumor bed frozen margins do not independently predict prognosis. We conclude that emphasis should be placed on evaluating the main specimen margins when estimating prognosis after OCSCC resection.

Exploring generational cohort work satisfaction in hospital nurses.

PubMed

Gordon, Pamela Ann

2017-07-03

Purpose Although extensive research exists regarding job satisfaction, many previous studies used a more restrictive, quantitative methodology. The purpose of this qualitative study is to capture the perceptions of hospital nurses within generational cohorts regarding their work satisfaction. Design/methodology/approach A preliminary qualitative, phenomenological study design explored hospital nurses' work satisfaction within generational cohorts - Baby Boomers (1946-1964), Generation X (1965-1980) and Millennials (1981-2000). A South Florida hospital provided the venue for the research. In all, 15 full-time staff nurses, segmented into generational cohorts, participated in personal interviews to determine themes related to seven established factors of work satisfaction: pay, autonomy, task requirements, administration, doctor-nurse relationship, interaction and professional status. Findings An analysis of the transcribed interviews confirmed the importance of the seven factors of job satisfaction. Similarities and differences between the generational cohorts related to a combination of stages of life and generational attributes. Practical implications The results of any qualitative research relate only to the specific venue studied and are not generalizable. However, the information gleaned from this study is transferable and other organizations are encouraged to conduct their own research and compare the results. Originality/value This study is unique, as the seven factors from an extensively used and highly respected quantitative research instrument were applied as the basis for this qualitative inquiry into generational cohort job satisfaction in a hospital setting.

Weight Gain Reduction Among 2-Year College Students: The CHOICES RCT

PubMed Central

Lytle, Leslie A.; Laska, Melissa N.; Linde, Jennifer A.; Moe, Stacey G.; Nanney, Marilyn S.; Hannan, Peter J.; Erickson, Darin J.

2016-01-01

Introduction The young adult years have been recognized as an influential period for excess weight gain. Non-traditional students and those attending 2-year community colleges are at particularly high risk for a range of adverse weight-related outcomes. Design Choosing Healthy Options in College Environments and Settings was an RCT with students randomly assigned into a control or intervention condition after baseline assessment. The study was designed to evaluate if a 24-month weight gain prevention intervention reduces the expected increase in BMI and overweight prevalence in young adults attending 2-year colleges. Two cohorts were recruited, corresponding to the fall and spring semesters. Data collection occurred at four time points for each cohort, with baseline occurring in fall 2011 for Cohort 1 and spring 2012 for Cohort 2. The 24-month follow-up occurred in fall 2013 for Cohort 1 and spring 2014 for Cohort 2. Data analysis occurred in 2015–2016. Setting/participants This research was conducted with 441 students from three community colleges in Minnesota. Intervention The 24-month intervention began with a 1-credit college course on healthy weight behaviors. A social networking and social support website was introduced as part of the course and participation encouraged for the duration of the trial. Main outcome measures Changes in BMI, weight, body fat percentage, waist circumference, and weight status were assessed. Results Retention of the cohorts at 24 months was 83.4%. There was not a statistically significant difference in BMI between conditions at the end of the trial. However, there was a statically significant difference in the prevalence of overweight/obesity between treatment conditions at 24 months. Also, participants randomized to the intervention who were overweight or obese at baseline were more than three times as likely to transition to a healthy weight by the end of the trial as compared with control students. Conclusions The intervention was not successful in achieving BMI differences between treatment groups. However, an 8% reduction in the prevalence of overweight and obesity over time may have population-level significance. PMID:27939237

GFR at Initiation of Dialysis and Mortality in CKD: A Meta-analysis

PubMed Central

Susantitaphong, Paweena; Altamimi, Sarah; Ashkar, Motaz; Balk, Ethan M.; Stel, Vianda S.; Wright, Seth; Jaber, Bertrand L.

2012-01-01

Background The proportion of patients with advanced chronic kidney disease (CKD) initiating dialysis at higher glomerular filtration rate (GFR) has increased over the past decade. Recent data suggest that higher GFR may be associated with increased mortality. Study Design A meta-analysis of cohort studies and trials. Setting & Population Patients with advanced CKD. Selection Criteria for Studies We performed a systematic literature search in MEDLINE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, American Society of Nephrology abstracts, and bibliographies of retrieved articles to identify studies reporting on GFR at dialysis initiation and mortality. Predictor estimated or calculated GFR at dialysis initiation. Outcome Pooled adjusted hazard ratio (HR) of continuous GFR for all-cause mortality. Results Sixteen cohort studies and one randomized controlled trial were identified (n=1,081,116). By meta-analysis, restricted to the 15 cohorts (n=1,079,917), higher GFR at dialysis initiation was associated with a higher pooled adjusted HR for all-cause mortality (1.04; 95% CI, 1.03–1.05; P<0.001). However, there was significant heterogeneity (I2=97%; P<0.001). The association persisted among the 9 cohorts that adjusted analytically for nutritional covariates (HR 1.03; 95% CI 1.02, 1.04; P<0.001; residual I2=97%). The highest mortality risk was observed in hemodialysis cohorts (HR 1.05; 95% CI 1.02, 1.08; P<0.001) whereas there was no association between GFR and mortality in peritoneal dialysis cohorts (HR 1.04; 95% CI 0.99, 1.08, P=0.11; residual I2=98%). Finally, higher GFR was associated with a lower mortality risk in cohorts that calculated GFR (HR 0.80; 95% CI 0.71, 0.91; P=0.003), contrasting with a higher mortality risk in cohorts that estimated GFR (HR 1.04; 95% CI 1.03, 1.05; P<0.001; residual I2=97%). Limitations Paucity of randomized controlled trials; different methods for determining GFR; and substantial heterogeneity. Conclusions Higher estimated rather than calculated GFR at dialysis initiation is associated with a higher mortality risk among patients with advanced CKD, independent of nutritional status. Although there was substantial heterogeneity of effect size estimates across studies, this observation requires further study. PMID:22465328

Heterogeneity in outcomes of treated HIV-positive patients in Europe and North America: relation with patient and cohort characteristics.

PubMed

May, Margaret T; Hogg, Robert S; Justice, Amy C; Shepherd, Bryan E; Costagliola, Dominique; Ledergerber, Bruno; Thiébaut, Rodolphe; Gill, M John; Kirk, Ole; van Sighem, Ard; Saag, Michael S; Navarro, Gemma; Sobrino-Vegas, Paz; Lampe, Fiona; Ingle, Suzanne; Guest, Jodie L; Crane, Heidi M; D'Arminio Monforte, Antonella; Vehreschild, Jörg J; Sterne, Jonathan A C

2012-12-01

HIV cohort collaborations, which pool data from diverse patient cohorts, have provided key insights into outcomes of antiretroviral therapy (ART). However, the extent of, and reasons for, between-cohort heterogeneity in rates of AIDS and mortality are unclear. We obtained data on adult HIV-positive patients who started ART from 1998 without a previous AIDS diagnosis from 17 cohorts in North America and Europe. Patients were followed up from 1 month to 2 years after starting ART. We examined between-cohort heterogeneity in crude and adjusted (age, sex, HIV transmission risk, year, CD4 count and HIV-1 RNA at start of ART) rates of AIDS and mortality using random-effects meta-analysis and meta-regression. During 61 520 person-years, 754/38 706 (1.9%) patients died and 1890 (4.9%) progressed to AIDS. Between-cohort variance in mortality rates was reduced from 0.84 to 0.24 (0.73 to 0.28 for AIDS rates) after adjustment for patient characteristics. Adjusted mortality rates were inversely associated with cohorts' estimated completeness of death ascertainment [excellent: 96-100%, good: 90-95%, average: 75-89%; mortality rate ratio 0.66 (95% confidence interval 0.46-0.94) per category]. Mortality rate ratios comparing Europe with North America were 0.42 (0.31-0.57) before and 0.47 (0.30-0.73) after adjusting for completeness of ascertainment. Heterogeneity between settings in outcomes of HIV treatment has implications for collaborative analyses, policy and clinical care. Estimated mortality rates may require adjustment for completeness of ascertainment. Higher mortality rate in North American, compared with European, cohorts was not fully explained by completeness of ascertainment and may be because of the inclusion of more socially marginalized patients with higher mortality risk.

Retention of the rural allied health workforce in New South Wales: a comparison of public and private practitioners.

PubMed

Keane, Sheila; Lincoln, Michelle; Rolfe, Margaret; Smith, Tony

2013-01-27

Policy initiatives to improve retention of the rural health workforce have relied primarily on evidence for rural doctors, most of whom practice under a private business model. Much of the literature for rural allied health (AH) workforce focuses on the public sector. The AH professions are diverse, with mixed public, private or combined practice settings. This study explores sector differences in factors affecting retention of rural AH professionals. This study compared respondents from the 2008 Rural Allied Health Workforce (RAHW) survey recruiting all AH professionals in rural New South Wales. Comparisons between public (n = 833) and private (n = 756) groups were undertaken using Chi square analysis to measure association for demographics, job satisfaction and intention to leave. The final section of the RAHW survey comprised 33 questions relating to retention. A factor analysis was conducted for each cohort. Factor reliability was assessed and retained factors were included in a binary logistic regression analysis for each cohort predicting intention to leave. Six factors were identified: professional isolation, participation in community, clinical demand, taking time away from work, resources and 'specialist generalist' work. Factors differed slightly between groups. A seventh factor (management) was present only in the public cohort. Gender was not a significant predictor of intention to leave. Age group was the strongest predictor of intention to leave with younger and older groups being significantly more likely to leave than middle aged.In univariate logistic analysis (after adjusting for age group), the ability to get away from work did not predict intention to leave in either group. In multivariate analysis, high clinical demand predicted intention to leave in both the public (OR = 1.40, 95% CI = 1.08, 1.83) and private (OR = 1.61, 95% CI = 1.15, 2.25) cohorts. Professional isolation (OR = 1.39. 95% CI = 1.11, 1.75) and Participation in community (OR = 1.57, 95% CI = 1.13, 2.19) also contributed to the model in the public cohort. This paper demonstrates differences between those working in public versus private sectors and suggests that effectiveness of policy initiatives may be improved through better targeting.

Quantitative Analysis of {sup 18}F-Fluorodeoxyglucose Positron Emission Tomography Identifies Novel Prognostic Imaging Biomarkers in Locally Advanced Pancreatic Cancer Patients Treated With Stereotactic Body Radiation Therapy

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

Cui, Yi; Global Institution for Collaborative Research and Education, Hokkaido University, Sapporo; Song, Jie

Purpose: To identify prognostic biomarkers in pancreatic cancer using high-throughput quantitative image analysis. Methods and Materials: In this institutional review board–approved study, we retrospectively analyzed images and outcomes for 139 locally advanced pancreatic cancer patients treated with stereotactic body radiation therapy (SBRT). The overall population was split into a training cohort (n=90) and a validation cohort (n=49) according to the time of treatment. We extracted quantitative imaging characteristics from pre-SBRT {sup 18}F-fluorodeoxyglucose positron emission tomography, including statistical, morphologic, and texture features. A Cox proportional hazard regression model was built to predict overall survival (OS) in the training cohort using 162more » robust image features. To avoid over-fitting, we applied the elastic net to obtain a sparse set of image features, whose linear combination constitutes a prognostic imaging signature. Univariate and multivariate Cox regression analyses were used to evaluate the association with OS, and concordance index (CI) was used to evaluate the survival prediction accuracy. Results: The prognostic imaging signature included 7 features characterizing different tumor phenotypes, including shape, intensity, and texture. On the validation cohort, univariate analysis showed that this prognostic signature was significantly associated with OS (P=.002, hazard ratio 2.74), which improved upon conventional imaging predictors including tumor volume, maximum standardized uptake value, and total legion glycolysis (P=.018-.028, hazard ratio 1.51-1.57). On multivariate analysis, the proposed signature was the only significant prognostic index (P=.037, hazard ratio 3.72) when adjusted for conventional imaging and clinical factors (P=.123-.870, hazard ratio 0.53-1.30). In terms of CI, the proposed signature scored 0.66 and was significantly better than competing prognostic indices (CI 0.48-0.64, Wilcoxon rank sum test P<1e-6). Conclusion: Quantitative analysis identified novel {sup 18}F-fluorodeoxyglucose positron emission tomography image features that showed improved prognostic value over conventional imaging metrics. If validated in large, prospective cohorts, the new prognostic signature might be used to identify patients for individualized risk-adaptive therapy.« less

Cohort Profile: Sympathetic activity and Ambulatory Blood Pressure in Africans (SABPA) prospective cohort study.

PubMed

Malan, Leoné; Hamer, Mark; Frasure-Smith, Nancy; Steyn, Hendrik S; Malan, Nicolaas T

2015-12-01

Adapting to an over-demanding stressful urban environment may exhaust the psychophysiological resources to cope with these demands, and lead to sympathetic nervous system dysfunction. The evidence that an urban-dwelling lifestyle may be detrimental to the cardiometabolic health of Africans motivated the design of the Sympathetic activity and Ambulatory Blood Pressure in African Prospective cohort study. We aimed to determine neural mechanistic pathways involved in emotional distress and vascular remodelling. The baseline sample included 409 teachers representing a bi-ethnic sex cohort from South Africa. The study was conducted in 2008-09 and repeated after 3-year follow-up in 2011-12, with an 87.8% successful follow-up rate. Seasonal changes were avoided and extensive clinical assessments were performed in a well-controlled setting. Data collection included sociodemographics, lifestyle habits, psychosocial battery and genetic analysis, mental stress responses mimicking daily life stress (blood pressure and haemostatic, cardiometabolic, endothelial and stress hormones). Target organ damage was assessed in the brain, heart, kidney, blood vessels and retina. A unique highly phenotyped cohort is presented that can address the role of a hyperactive sympathetic nervous system and neural response pathways contributing to the burden of cardiometabolic diseases in Africans. © The Author 2014. Published by Oxford University Press on behalf of the International Epidemiological Association.

Coffee, decaffeinated coffee, tea and cancer of the colon and rectum: a review of epidemiological studies, 1990-2003.

PubMed

Tavani, Alessandra; La Vecchia, Carlo

2004-10-01

The literature from 1990 to 2003 on the relation between coffee, decaffeinated coffee, tea and colorectal cancer risk has been reviewed. For the relation with coffee, three cohort (517 total cases) and nine case-control studies (7555 cases) analysed colon cancer; three cohort (307 cases) and four case-control studies (2704 cases) rectal cancer; six case-control studies (854 cases) colorectal cancer. For colon cancer most case-control studies found risk estimates below unity; the results are less clear for cohort studies. No relation emerged for rectal cancer. A meta-analysis, including five cohort and twelve case-control studies, reported a pooled relative risk of 0.76 (significant). Any methodological artefact is unlikely to account for the consistent inverse association in different countries and settings. Plausible biological explanations include coffee-related reductions of cholesterol, bile acids and neutral sterol secretion in the colon; antimutagenic properties of selected coffee components; increased colonic motility. Decaffeinated coffee was not related to either colon or rectal cancer in three case-control studies. No overall association between tea and either colon or rectal cancer risk emerged in seven cohort (1756 total cases of colon, 759 of rectal and 60 of colorectal cancer) and 12 case-control studies (8058 cases of colon, 4865 of rectal, 604 of colorectal cancer).

Genome-wide association study identifies SNPs in the MHC class II loci that are associated with self-reported history of whooping cough.

PubMed

McMahon, George; Ring, Susan M; Davey-Smith, George; Timpson, Nicholas J

2015-10-15

Whooping cough is currently seeing resurgence in countries despite high vaccine coverage. There is considerable variation in subject-specific response to infection and vaccine efficacy, but little is known about the role of human genetics. We carried out a case-control genome-wide association study of adult or parent-reported history of whooping cough in two cohorts from the UK: the ALSPAC cohort and the 1958 British Birth Cohort (815/758 cases and 6341/4308 controls, respectively). We also imputed HLA alleles using dense SNP data in the MHC region and carried out gene-based and gene-set tests of association and estimated the amount of additive genetic variation explained by common SNPs. We observed a novel association at SNPs in the MHC class II region in both cohorts [lead SNP rs9271768 after meta-analysis, odds ratio [95% confidence intervals (CIs)] 1.47 (1.35, 1.6), P-value 1.21E - 18]. Multiple strong associations were also observed at alleles at the HLA class II loci. The majority of these associations were explained by the lead SNP rs9271768. Gene-based and gene-set tests and estimates of explainable common genetic variation could not establish the presence of additional associations in our sample. Genetic variation at the MHC class II region plays a role in susceptibility to whooping cough. These findings provide additional perspective on mechanisms of whooping cough infection and vaccine efficacy. © The Author 2015. Published by Oxford University Press.

Expression and prognostic significance of CCL11/CCR3 in glioblastoma.

PubMed

Tian, Min; Chen, Lina; Ma, Li; Wang, Dandan; Shao, Bin; Wu, Jianyu; Wu, Hangyu; Jin, Yimin

2016-05-31

Glioblastoma (GBM) is the most lethal primary nervous system cancer, but due to its rarity and complexity, its pathogenesis is poorly understood. To identify potential tumorigenic factors in GBM, we screened antibody-based cytokine arrays and found that CCL11 was upregulated. We then demonstrated in vitro that both CCL11 and its receptor, CCR3, were overexpressed and promoted the proliferation, migration and invasion of cancer cells. To examine the clinical significance of CCL11/CCR3, 458 GBM samples were divided into a training cohort with 225 cases and a test cohort containing 233 cases. In the training set, immunohistochemical analysis showed overexpression of CCL11 and CCR3 were correlated with unfavorable overall survival (OS). We further developed a prognostic classifier combining CCL11 and CCR3 expression and Karnofsky performance status (KPS) for predicting one-year survival in GBM patients. Receiver operating characteristic (ROC) analysis demonstrated that this predictor achieved 90.7% sensitivity and 73.4% specificity. These results were validated with the test sample set. Our findings suggest that CCL11-CCR3 binding is involved in the progression of GBM and may prompt a novel therapeutic approach. In addition, CCL11 and CCR3 expression, combined with KPS, may be used as an accurate predictor of one-year survival in GBM patients.

Expression and prognostic significance of CCL11/CCR3 in glioblastoma

PubMed Central

Tian, Min; Chen, Lina; Ma, Li; Wang, Dandan; Shao, Bin; Wu, Jianyu; Wu, Hangyu; Jin, Yimin

2016-01-01

Glioblastoma (GBM) is the most lethal primary nervous system cancer, but due to its rarity and complexity, its pathogenesis is poorly understood. To identify potential tumorigenic factors in GBM, we screened antibody-based cytokine arrays and found that CCL11 was upregulated. We then demonstrated in vitro that both CCL11 and its receptor, CCR3, were overexpressed and promoted the proliferation, migration and invasion of cancer cells. To examine the clinical significance of CCL11/CCR3, 458 GBM samples were divided into a training cohort with 225 cases and a test cohort containing 233 cases. In the training set, immunohistochemical analysis showed overexpression of CCL11 and CCR3 were correlated with unfavorable overall survival (OS). We further developed a prognostic classifier combining CCL11 and CCR3 expression and Karnofsky performance status (KPS) for predicting one-year survival in GBM patients. Receiver operating characteristic (ROC) analysis demonstrated that this predictor achieved 90.7% sensitivity and 73.4% specificity. These results were validated with the test sample set. Our findings suggest that CCL11-CCR3 binding is involved in the progression of GBM and may prompt a novel therapeutic approach. In addition, CCL11 and CCR3 expression, combined with KPS, may be used as an accurate predictor of one-year survival in GBM patients. PMID:27119233

An analysis of gene expression in PTSD implicates genes involved in the glucocorticoid receptor pathway and neural responses to stress

PubMed Central

Logue, Mark W.; Smith, Alicia K.; Baldwin, Clinton; Wolf, Erika J.; Guffanti, Guia; Ratanatharathorn, Andrew; Stone, Annjanette; Schichman, Steven A.; Humphries, Donald; Binder, Elisabeth B.; Arloth, Janine; Menke, Andreas; Uddin, Monica; Wildman, Derek; Galea, Sandro; Aiello, Allison E.; Koenen, Karestan C.; Miller, Mark W.

2015-01-01

We examined the association between posttraumatic stress disorder (PTSD) and gene expression using whole blood samples from a cohort of trauma-exposed white non-Hispanic male veterans (115 cases and 28 controls). 10,264 probes of genes and gene transcripts were analyzed. We found 41 that were differentially expressed in PTSD cases versus controls (multiple-testing corrected p<0.05). The most significant was DSCAM, a neurological gene expressed widely in the developing brain and in the amygdala and hippocampus of the adult brain. We then examined the 41 differentially expressed genes in a meta-analysis using two replication cohorts and found significant associations with PTSD for 7 of the 41 (p<0.05), one of which (ATP6AP1L) survived multiple-testing correction. There was also broad evidence of overlap across the discovery and replication samples for the entire set of genes implicated in the discovery data based on the direction of effect and an enrichment of p<0.05 significant probes beyond what would be expected under the null. Finally, we found that the set of differentially expressed genes from the discovery sample was enriched for genes responsive to glucocorticoid signaling with most showing reduced expression in PTSD cases compared to controls. PMID:25867994

Performance of amplicon-based next generation DNA sequencing for diagnostic gene mutation profiling in oncopathology.

PubMed

Sie, Daoud; Snijders, Peter J F; Meijer, Gerrit A; Doeleman, Marije W; van Moorsel, Marinda I H; van Essen, Hendrik F; Eijk, Paul P; Grünberg, Katrien; van Grieken, Nicole C T; Thunnissen, Erik; Verheul, Henk M; Smit, Egbert F; Ylstra, Bauke; Heideman, Daniëlle A M

2014-10-01

Next generation DNA sequencing (NGS) holds promise for diagnostic applications, yet implementation in routine molecular pathology practice requires performance evaluation on DNA derived from routine formalin-fixed paraffin-embedded (FFPE) tissue specimens. The current study presents a comprehensive analysis of TruSeq Amplicon Cancer Panel-based NGS using a MiSeq Personal sequencer (TSACP-MiSeq-NGS) for somatic mutation profiling. TSACP-MiSeq-NGS (testing 212 hotspot mutation amplicons of 48 genes) and a data analysis pipeline were evaluated in a retrospective learning/test set approach (n = 58/n = 45 FFPE-tumor DNA samples) against 'gold standard' high-resolution-melting (HRM)-sequencing for the genes KRAS, EGFR, BRAF and PIK3CA. Next, the performance of the validated test algorithm was assessed in an independent, prospective cohort of FFPE-tumor DNA samples (n = 75). In the learning set, a number of minimum parameter settings was defined to decide whether a FFPE-DNA sample is qualified for TSACP-MiSeq-NGS and for calling mutations. The resulting test algorithm revealed 82% (37/45) compliance to the quality criteria and 95% (35/37) concordant assay findings for KRAS, EGFR, BRAF and PIK3CA with HRM-sequencing (kappa = 0.92; 95% CI = 0.81-1.03) in the test set. Subsequent application of the validated test algorithm to the prospective cohort yielded a success rate of 84% (63/75), and a high concordance with HRM-sequencing (95% (60/63); kappa = 0.92; 95% CI = 0.84-1.01). TSACP-MiSeq-NGS detected 77 mutations in 29 additional genes. TSACP-MiSeq-NGS is suitable for diagnostic gene mutation profiling in oncopathology.

A hybrid Bayesian hierarchical model combining cohort and case-control studies for meta-analysis of diagnostic tests: Accounting for partial verification bias.

PubMed

Ma, Xiaoye; Chen, Yong; Cole, Stephen R; Chu, Haitao

2016-12-01

To account for between-study heterogeneity in meta-analysis of diagnostic accuracy studies, bivariate random effects models have been recommended to jointly model the sensitivities and specificities. As study design and population vary, the definition of disease status or severity could differ across studies. Consequently, sensitivity and specificity may be correlated with disease prevalence. To account for this dependence, a trivariate random effects model had been proposed. However, the proposed approach can only include cohort studies with information estimating study-specific disease prevalence. In addition, some diagnostic accuracy studies only select a subset of samples to be verified by the reference test. It is known that ignoring unverified subjects may lead to partial verification bias in the estimation of prevalence, sensitivities, and specificities in a single study. However, the impact of this bias on a meta-analysis has not been investigated. In this paper, we propose a novel hybrid Bayesian hierarchical model combining cohort and case-control studies and correcting partial verification bias at the same time. We investigate the performance of the proposed methods through a set of simulation studies. Two case studies on assessing the diagnostic accuracy of gadolinium-enhanced magnetic resonance imaging in detecting lymph node metastases and of adrenal fluorine-18 fluorodeoxyglucose positron emission tomography in characterizing adrenal masses are presented. © The Author(s) 2014.

A Hybrid Bayesian Hierarchical Model Combining Cohort and Case-control Studies for Meta-analysis of Diagnostic Tests: Accounting for Partial Verification Bias

PubMed Central

Ma, Xiaoye; Chen, Yong; Cole, Stephen R.; Chu, Haitao

2014-01-01

To account for between-study heterogeneity in meta-analysis of diagnostic accuracy studies, bivariate random effects models have been recommended to jointly model the sensitivities and specificities. As study design and population vary, the definition of disease status or severity could differ across studies. Consequently, sensitivity and specificity may be correlated with disease prevalence. To account for this dependence, a trivariate random effects model had been proposed. However, the proposed approach can only include cohort studies with information estimating study-specific disease prevalence. In addition, some diagnostic accuracy studies only select a subset of samples to be verified by the reference test. It is known that ignoring unverified subjects may lead to partial verification bias in the estimation of prevalence, sensitivities and specificities in a single study. However, the impact of this bias on a meta-analysis has not been investigated. In this paper, we propose a novel hybrid Bayesian hierarchical model combining cohort and case-control studies and correcting partial verification bias at the same time. We investigate the performance of the proposed methods through a set of simulation studies. Two case studies on assessing the diagnostic accuracy of gadolinium-enhanced magnetic resonance imaging in detecting lymph node metastases and of adrenal fluorine-18 fluorodeoxyglucose positron emission tomography in characterizing adrenal masses are presented. PMID:24862512

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.

Cerebrospinal Fluid Peptides as Potential Parkinson Disease Biomarkers: A Staged Pipeline for Discovery and Validation*

PubMed Central

Shi, Min; Movius, James; Dator, Romel; Aro, Patrick; Zhao, Yanchun; Pan, Catherine; Lin, Xiangmin; Bammler, Theo K.; Stewart, Tessandra; Zabetian, Cyrus P.; Peskind, Elaine R.; Hu, Shu-Ching; Quinn, Joseph F.; Galasko, Douglas R.; Zhang, Jing

2015-01-01

Finding robust biomarkers for Parkinson disease (PD) is currently hampered by inherent technical limitations associated with imaging or antibody-based protein assays. To circumvent the challenges, we adapted a staged pipeline, starting from our previous proteomic profiling followed by high-throughput targeted mass spectrometry (MS), to identify peptides in human cerebrospinal fluid (CSF) for PD diagnosis and disease severity correlation. In this multicenter study consisting of training and validation sets, a total of 178 subjects were randomly selected from a retrospective cohort, matching age and sex between PD patients, healthy controls, and neurological controls with Alzheimer disease (AD). From ∼14,000 unique peptides displaying differences between PD and healthy control in proteomic investigations, 126 peptides were selected based on relevance and observability in CSF using bioinformatic analysis and MS screening, and then quantified by highly accurate and sensitive selected reaction monitoring (SRM) in the CSF of 30 PD patients versus 30 healthy controls (training set), followed by diagnostic (receiver operating characteristics) and disease severity correlation analyses. The most promising candidates were further tested in an independent cohort of 40 PD patients, 38 AD patients, and 40 healthy controls (validation set). A panel of five peptides (derived from SPP1, LRP1, CSF1R, EPHA4, and TIMP1) was identified to provide an area under curve (AUC) of 0.873 (sensitivity = 76.7%, specificity = 80.0%) for PD versus healthy controls in the training set. The performance was essentially confirmed in the validation set (AUC = 0.853, sensitivity = 82.5%, specificity = 82.5%). Additionally, this panel could also differentiate the PD and AD groups (AUC = 0.990, sensitivity = 95.0%, specificity = 97.4%). Furthermore, a combination of two peptides belonging to proteins TIMP1 and APLP1 significantly correlated with disease severity as determined by the Unified Parkinson's Disease Rating Scale motor scores in both the training (r = 0.381, p = 0.038)j and the validation (r = 0.339, p = 0.032) sets. The novel panel of CSF peptides, if validated in independent cohorts, could be used to assist in clinical diagnosis of PD and has the potential to help monitoring or predicting disease progression. PMID:25556233

A predictive signature gene set for discriminating active from latent tuberculosis in Warao Amerindian children.

PubMed

Verhagen, Lilly M; Zomer, Aldert; Maes, Mailis; Villalba, Julian A; Del Nogal, Berenice; Eleveld, Marc; van Hijum, Sacha Aft; de Waard, Jacobus H; Hermans, Peter Wm

2013-02-01

Tuberculosis (TB) continues to cause a high toll of disease and death among children worldwide. The diagnosis of childhood TB is challenged by the paucibacillary nature of the disease and the difficulties in obtaining specimens. Whereas scientific and clinical research efforts to develop novel diagnostic tools have focused on TB in adults, childhood TB has been relatively neglected. Blood transcriptional profiling has improved our understanding of disease pathogenesis of adult TB and may offer future leads for diagnosis and treatment. No studies applying gene expression profiling of children with TB have been published so far. We identified a 116-gene signature set that showed an average prediction error of 11% for TB vs. latent TB infection (LTBI) and for TB vs. LTBI vs. healthy controls (HC) in our dataset. A minimal gene set of only 9 genes showed the same prediction error of 11% for TB vs. LTBI in our dataset. Furthermore, this minimal set showed a significant discriminatory value for TB vs. LTBI for all previously published adult studies using whole blood gene expression, with average prediction errors between 17% and 23%. In order to identify a robust representative gene set that would perform well in populations of different genetic backgrounds, we selected ten genes that were highly discriminative between TB, LTBI and HC in all literature datasets as well as in our dataset. Functional annotation of these genes highlights a possible role for genes involved in calcium signaling and calcium metabolism as biomarkers for active TB. These ten genes were validated by quantitative real-time polymerase chain reaction in an additional cohort of 54 Warao Amerindian children with LTBI, HC and non-TB pneumonia. Decision tree analysis indicated that five of the ten genes were sufficient to classify 78% of the TB cases correctly with no LTBI subjects wrongly classified as TB (100% specificity). Our data justify the further exploration of our signature set as biomarkers for potential childhood TB diagnosis. We show that, as the identification of different biomarkers in ethnically distinct cohorts is apparent, it is important to cross-validate newly identified markers in all available cohorts.

A predictive signature gene set for discriminating active from latent tuberculosis in Warao Amerindian children

PubMed Central

2013-01-01

Background Tuberculosis (TB) continues to cause a high toll of disease and death among children worldwide. The diagnosis of childhood TB is challenged by the paucibacillary nature of the disease and the difficulties in obtaining specimens. Whereas scientific and clinical research efforts to develop novel diagnostic tools have focused on TB in adults, childhood TB has been relatively neglected. Blood transcriptional profiling has improved our understanding of disease pathogenesis of adult TB and may offer future leads for diagnosis and treatment. No studies applying gene expression profiling of children with TB have been published so far. Results We identified a 116-gene signature set that showed an average prediction error of 11% for TB vs. latent TB infection (LTBI) and for TB vs. LTBI vs. healthy controls (HC) in our dataset. A minimal gene set of only 9 genes showed the same prediction error of 11% for TB vs. LTBI in our dataset. Furthermore, this minimal set showed a significant discriminatory value for TB vs. LTBI for all previously published adult studies using whole blood gene expression, with average prediction errors between 17% and 23%. In order to identify a robust representative gene set that would perform well in populations of different genetic backgrounds, we selected ten genes that were highly discriminative between TB, LTBI and HC in all literature datasets as well as in our dataset. Functional annotation of these genes highlights a possible role for genes involved in calcium signaling and calcium metabolism as biomarkers for active TB. These ten genes were validated by quantitative real-time polymerase chain reaction in an additional cohort of 54 Warao Amerindian children with LTBI, HC and non-TB pneumonia. Decision tree analysis indicated that five of the ten genes were sufficient to classify 78% of the TB cases correctly with no LTBI subjects wrongly classified as TB (100% specificity). Conclusions Our data justify the further exploration of our signature set as biomarkers for potential childhood TB diagnosis. We show that, as the identification of different biomarkers in ethnically distinct cohorts is apparent, it is important to cross-validate newly identified markers in all available cohorts. PMID:23375113

A Discovery Resource of Rare Copy Number Variations in Individuals with Autism Spectrum Disorder

PubMed Central

Prasad, Aparna; Merico, Daniele; Thiruvahindrapuram, Bhooma; Wei, John; Lionel, Anath C.; Sato, Daisuke; Rickaby, Jessica; Lu, Chao; Szatmari, Peter; Roberts, Wendy; Fernandez, Bridget A.; Marshall, Christian R.; Hatchwell, Eli; Eis, Peggy S.; Scherer, Stephen W.

2012-01-01

The identification of rare inherited and de novo copy number variations (CNVs) in human subjects has proven a productive approach to highlight risk genes for autism spectrum disorder (ASD). A variety of microarrays are available to detect CNVs, including single-nucleotide polymorphism (SNP) arrays and comparative genomic hybridization (CGH) arrays. Here, we examine a cohort of 696 unrelated ASD cases using a high-resolution one-million feature CGH microarray, the majority of which were previously genotyped with SNP arrays. Our objective was to discover new CNVs in ASD cases that were not detected by SNP microarray analysis and to delineate novel ASD risk loci via combined analysis of CGH and SNP array data sets on the ASD cohort and CGH data on an additional 1000 control samples. Of the 615 ASD cases analyzed on both SNP and CGH arrays, we found that 13,572 of 21,346 (64%) of the CNVs were exclusively detected by the CGH array. Several of the CGH-specific CNVs are rare in population frequency and impact previously reported ASD genes (e.g., NRXN1, GRM8, DPYD), as well as novel ASD candidate genes (e.g., CIB2, DAPP1, SAE1), and all were inherited except for a de novo CNV in the GPHN gene. A functional enrichment test of gene-sets in ASD cases over controls revealed nucleotide metabolism as a potential novel pathway involved in ASD, which includes several candidate genes for follow-up (e.g., DPYD, UPB1, UPP1, TYMP). Finally, this extensively phenotyped and genotyped ASD clinical cohort serves as an invaluable resource for the next step of genome sequencing for complete genetic variation detection. PMID:23275889

Discovering Cohorts of Pregnant Women From Social Media for Safety Surveillance and Analysis.

PubMed

Sarker, Abeed; Chandrashekar, Pramod; Magge, Arjun; Cai, Haitao; Klein, Ari; Gonzalez, Graciela

2017-10-30

Pregnancy exposure registries are the primary sources of information about the safety of maternal usage of medications during pregnancy. Such registries enroll pregnant women in a voluntary fashion early on in pregnancy and follow them until the end of pregnancy or longer to systematically collect information regarding specific pregnancy outcomes. Although the model of pregnancy registries has distinct advantages over other study designs, they are faced with numerous challenges and limitations such as low enrollment rate, high cost, and selection bias. The primary objectives of this study were to systematically assess whether social media (Twitter) can be used to discover cohorts of pregnant women and to develop and deploy a natural language processing and machine learning pipeline for the automatic collection of cohort information. In addition, we also attempted to ascertain, in a preliminary fashion, what types of longitudinal information may potentially be mined from the collected cohort information. Our discovery of pregnant women relies on detecting pregnancy-indicating tweets (PITs), which are statements posted by pregnant women regarding their pregnancies. We used a set of 14 patterns to first detect potential PITs. We manually annotated a sample of 14,156 of the retrieved user posts to distinguish real PITs from false positives and trained a supervised classification system to detect real PITs. We optimized the classification system via cross validation, with features and settings targeted toward optimizing precision for the positive class. For users identified to be posting real PITs via automatic classification, our pipeline collected all their available past and future posts from which other information (eg, medication usage and fetal outcomes) may be mined. Our rule-based PIT detection approach retrieved over 200,000 posts over a period of 18 months. Manual annotation agreement for three annotators was very high at kappa (κ)=.79. On a blind test set, the implemented classifier obtained an overall F 1 score of 0.84 (0.88 for the pregnancy class and 0.68 for the nonpregnancy class). Precision for the pregnancy class was 0.93, and recall was 0.84. Feature analysis showed that the combination of dense and sparse vectors for classification achieved optimal performance. Employing the trained classifier resulted in the identification of 71,954 users from the collected posts. Over 250 million posts were retrieved for these users, which provided a multitude of longitudinal information about them. Social media sources such as Twitter can be used to identify large cohorts of pregnant women and to gather longitudinal information via automated processing of their postings. Considering the many drawbacks and limitations of pregnancy registries, social media mining may provide beneficial complementary information. Although the cohort sizes identified over social media are large, future research will have to assess the completeness of the information available through them. ©Abeed Sarker, Pramod Chandrashekar, Arjun Magge, Haitao Cai, Ari Klein, Graciela Gonzalez. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 30.10.2017.

Length Distributions of Identity by Descent Reveal Fine-Scale Demographic History

PubMed Central

Palamara, Pier Francesco; Lencz, Todd; Darvasi, Ariel; Pe’er, Itsik

2012-01-01

Data-driven studies of identity by descent (IBD) were recently enabled by high-resolution genomic data from large cohorts and scalable algorithms for IBD detection. Yet, haplotype sharing currently represents an underutilized source of information for population-genetics research. We present analytical results on the relationship between haplotype sharing across purportedly unrelated individuals and a population’s demographic history. We express the distribution of IBD sharing across pairs of individuals for segments of arbitrary length as a function of the population’s demography, and we derive an inference procedure to reconstruct such demographic history. The accuracy of the proposed reconstruction methodology was extensively tested on simulated data. We applied this methodology to two densely typed data sets: 500 Ashkenazi Jewish (AJ) individuals and 56 Kenyan Maasai (MKK) individuals (HapMap 3 data set). Reconstructing the demographic history of the AJ cohort, we recovered two subsequent population expansions, separated by a severe founder event, consistent with previous analysis of lower-throughput genetic data and historical accounts of AJ history. In the MKK cohort, high levels of cryptic relatedness were detected. The spectrum of IBD sharing is consistent with a demographic model in which several small-sized demes intermix through high migration rates and result in enrichment of shared long-range haplotypes. This scenario of historically structured demographies might explain the unexpected abundance of runs of homozygosity within several populations. PMID:23103233

Identification of somatic mutations in EGFR/KRAS/ALK-negative lung adenocarcinoma in never-smokers

PubMed Central

2014-01-01

Background Lung adenocarcinoma is a highly heterogeneous disease with various etiologies, prognoses, and responses to therapy. Although genome-scale characterization of lung adenocarcinoma has been performed, a comprehensive somatic mutation analysis of EGFR/KRAS/ALK-negative lung adenocarcinoma in never-smokers has not been conducted. Methods We analyzed whole exome sequencing data from 16 EGFR/KRAS/ALK-negative lung adenocarcinomas and additional 54 tumors in two expansion cohort sets. Candidate loci were validated by target capture and Sanger sequencing. Gene set analysis was performed using Ingenuity Pathway Analysis. Results We identified 27 genes potentially implicated in the pathogenesis of lung adenocarcinoma. These included targetable genes involved in PI3K/mTOR signaling (TSC1, PIK3CA, AKT2) and receptor tyrosine kinase signaling (ERBB4) and genes not previously highlighted in lung adenocarcinomas, such as SETD2 and PBRM1 (chromatin remodeling), CHEK2 and CDC27 (cell cycle), CUL3 and SOD2 (oxidative stress), and CSMD3 and TFG (immune response). In the expansion cohort (N = 70), TP53 was the most frequently altered gene (11%), followed by SETD2 (6%), CSMD3 (6%), ERBB2 (6%), and CDH10 (4%). In pathway analysis, the majority of altered genes were involved in cell cycle/DNA repair (P <0.001) and cAMP-dependent protein kinase signaling (P <0.001). Conclusions The genomic makeup of EGFR/KRAS/ALK-negative lung adenocarcinomas in never-smokers is remarkably diverse. Genes involved in cell cycle regulation/DNA repair are implicated in tumorigenesis and represent potential therapeutic targets. PMID:24576404

Multimodal neural correlates of cognitive control in the Human Connectome Project.

PubMed

Lerman-Sinkoff, Dov B; Sui, Jing; Rachakonda, Srinivas; Kandala, Sridhar; Calhoun, Vince D; Barch, Deanna M

2017-12-01

Cognitive control is a construct that refers to the set of functions that enable decision-making and task performance through the representation of task states, goals, and rules. The neural correlates of cognitive control have been studied in humans using a wide variety of neuroimaging modalities, including structural MRI, resting-state fMRI, and task-based fMRI. The results from each of these modalities independently have implicated the involvement of a number of brain regions in cognitive control, including dorsal prefrontal cortex, and frontal parietal and cingulo-opercular brain networks. However, it is not clear how the results from a single modality relate to results in other modalities. Recent developments in multimodal image analysis methods provide an avenue for answering such questions and could yield more integrated models of the neural correlates of cognitive control. In this study, we used multiset canonical correlation analysis with joint independent component analysis (mCCA + jICA) to identify multimodal patterns of variation related to cognitive control. We used two independent cohorts of participants from the Human Connectome Project, each of which had data from four imaging modalities. We replicated the findings from the first cohort in the second cohort using both independent and predictive analyses. The independent analyses identified a component in each cohort that was highly similar to the other and significantly correlated with cognitive control performance. The replication by prediction analyses identified two independent components that were significantly correlated with cognitive control performance in the first cohort and significantly predictive of performance in the second cohort. These components identified positive relationships across the modalities in neural regions related to both dynamic and stable aspects of task control, including regions in both the frontal-parietal and cingulo-opercular networks, as well as regions hypothesized to be modulated by cognitive control signaling, such as visual cortex. Taken together, these results illustrate the potential utility of multi-modal analyses in identifying the neural correlates of cognitive control across different indicators of brain structure and function. Copyright © 2017 Elsevier Inc. All rights reserved.

Nature versus nurture: identical twins and bariatric surgery.

PubMed

Hagedorn, Judith C; Morton, John M

2007-06-01

Genetics and environment both play a role in weight maintenance. Twin studies may help clarify the influence of nature vs nurture in weight loss. We present the largest U.S. experience with monozygotic (MZ) twins undergoing bariatric surgery. We retrospectively reviewed the charts of four sets of MZ twins who underwent Roux-en-Y gastric bypass (RYGBP) surgery and laparoscopic adjustable gastric band (LAGB) placement at three different institutions. BMI and co-morbidities were examined pre- and postoperatively, and laboratory values were recorded. All four sets of twins are female, live together, and have similar professions. Twin cohort 1 had near identical weight loss patterns after open RYGBP surgery in 1996 (preop 146/142 kg; 2 years 82/82; and 10 years 108/107). Twin cohort 1 also both underwent cholecystectomies within the first year postoperatively. Twin cohort 2 underwent laparoscopic RYGBP surgery and also required cholecystectomies in the first postoperative year. Cohort 2 also experienced nearly identical weight loss at 1 year (36.7% vs 37.0% BMI loss). Twin cohort 3 underwent LAGB placement with two different surgeons with differing amounts of weight loss at 6 months (6.5% vs 15.7% BMI loss). Finally, twin cohort 4 underwent laparoscopic RYGBP with 2-year BMI loss of 39% vs 34%. In twin cohort 4, the twin who lost less weight lived apart from her twin and extended family, and her weight loss was less than the twin living with her family. Two sets of MZ twins had identical responses to bariatric surgery. The other two sets of identical twins had differential weight loss results, possibly due to differences in surgical approach and social support. While genetics do exert a strong influence on weight loss and maintenance, this case series demonstrates the potential effect of social support and postoperative management upon postoperative weight loss in the presence of identical genetics.

The Baux score is dead. Long live the Baux score: a 27-year retrospective cohort study of mortality at a regional burns service.

PubMed

Roberts, Geoffrey; Lloyd, Mark; Parker, Mike; Martin, Rebecca; Philp, Bruce; Shelley, Odhran; Dziewulski, Peter

2012-01-01

To assess trends in mortality after burn injuries treated in a regional specialist burns service between 1982 and 2008. Patient and burn-specific information and mortality were collated from written admission ledgers and the hospital coding department for 11,109 patients. The data set was divided into age cohorts (0-14, 15-44, 45-64, and >65 years) and time cohorts (1982-1991, 1992-2000, and 2000-2008). Lethal area 50 (LA50) was calculated by logistic regression and probit analysis. Mortality was related to the Baux score (age + total % burned surface area) by logistic regression. In the time period 2000 to 2008, the LA50 values with approximate 95% confidence intervals (CIs) were 100% (CI, 85.5-100%) in the 0 to 14 cohort (LA10, 78.3%; CI, 64.1-92.5%), 76.4% (CI, 69.1-83.8%) in the 15 to 44 cohort, 58.6% (CI, 50.8-66.5%) in the 45 to 64 cohort, and 30.8% (CI, 24.7-36.9%) in the >65 cohort. The point of futility (the Baux Score at which predicted mortality is 100%) was 160 and the Baux50 (the Baux score at which predicted mortality is 50%) was 109.6 (CI, 105.9-113.4) in the 2000 to 2008 cohort. Mortality is markedly improved over earlier data from this study and other historical series and compares favorably with outcomes published from the US National Burn Repository. The Baux Score continues to provide an indication of the risk of mortality. Survival after major burn injury is increasingly common, and decisions by nonspecialist about initial triage, management, and futility of care should be made after consultation with a specialist burn service.

Factor Structure and Psychometric Properties of the Posttraumatic Stress Disorder (PTSD) Checklist and DSM-5 PTSD Symptom Set in a Long-Term Postearthquake Cohort in Armenia.

PubMed

Demirchyan, Anahit; Goenjian, Armen K; Khachadourian, Vahe

2015-10-01

Psychometric properties of the Armenian-language posttraumatic stress disorder (PTSD) Checklist-Civilian version (PCL-C) and the DSM-5 PTSD symptom set were examined in a long-term cohort of earthquake survivors. In 2012, 725 survivors completed the instruments. Item-/scale-level analysis and confirmatory factor analysis (CFA) were performed for both scales. In addition, exploratory factor analysis (EFA) was conducted for DSM-5 symptoms. Also, the differential internal versus external specificity of PTSD symptom clusters taken from the most supported PTSD structural models was examined. Both scales had Cronbach's alpha greater than .9. CFA of PCL-C structure demonstrated an excellent fit by a four-factor (reexperiencing, avoidance, numbing, and hyperarousal) model known as numbing model; however, a superior fit was achieved by a five-factor model (Elhai et al.). EFA yielded a five-factor structure for DSM-5 symptoms with the aforementioned four domains plus a negative state domain. This model achieved an acceptable fit during CFA, whereas the DSM-5 criteria-based model did not. The Armenian-language PCL-C was recommended as a valid PTSD screening tool. The study findings provided support to the proposed new classification of common mental disorders, where PTSD, depression, and generalized anxiety are grouped together as a subclass of distress disorders. Recommendations were made to further improve the PTSD diagnostic criteria. © The Author(s) 2014.

Risk factors for amendment in type, duration and setting of prescribed outpatient parenteral antimicrobial therapy (OPAT) for adult patients with cellulitis: a retrospective cohort study and CART analysis.

PubMed

Quirke, Michael; Curran, Emma May; O'Kelly, Patrick; Moran, Ruth; Daly, Eimear; Aylward, Seamus; McElvaney, Gerry; Wakai, Abel

2018-01-01

To measure the percentage rate and risk factors for amendment in the type, duration and setting of outpatient parenteral antimicrobial therapy ( OPAT) for the treatment of cellulitis. A retrospective cohort study of adult patients receiving OPAT for cellulitis was performed. Treatment amendment (TA) was defined as hospital admission or change in antibiotic therapy in order to achieve clinical response. Multivariable logistic regression (MVLR) and classification and regression tree (CART) analysis were performed. There were 307 patients enrolled. TA occurred in 36 patients (11.7%). Significant risk factors for TA on MVLR were increased age, increased Numerical Pain Scale Score (NPSS) and immunocompromise. The median OPAT duration was 7 days. Increased age, heart rate and C reactive protein were associated with treatment prolongation. CART analysis selected age <64.5 years, female gender and NPSS <2.5 in the final model, generating a low-sensitivity (27.8%), high-specificity (97.1%) decision tree. Increased age, NPSS and immunocompromise were associated with OPAT amendment. These identified risk factors can be used to support an evidence-based approach to patient selection for OPAT in cellulitis. The CART algorithm has good specificity but lacks sensitivity and is shown to be inferior in this study to logistic regression modelling. © 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.

Latent class analysis reveals clinically relevant atopy phenotypes in 2 birth cohorts.

PubMed

Hose, Alexander J; Depner, Martin; Illi, Sabina; Lau, Susanne; Keil, Thomas; Wahn, Ulrich; Fuchs, Oliver; Pfefferle, Petra Ina; Schmaußer-Hechfellner, Elisabeth; Genuneit, Jon; Lauener, Roger; Karvonen, Anne M; Roduit, Caroline; Dalphin, Jean-Charles; Riedler, Josef; Pekkanen, Juha; von Mutius, Erika; Ege, Markus J

2017-06-01

Phenotypes of childhood-onset asthma are characterized by distinct trajectories and functional features. For atopy, definition of phenotypes during childhood is less clear. We sought to define phenotypes of atopic sensitization over the first 6 years of life using a latent class analysis (LCA) integrating 3 dimensions of atopy: allergen specificity, time course, and levels of specific IgE (sIgE). Phenotypes were defined by means of LCA in 680 children of the Multizentrische Allergiestudie (MAS) and 766 children of the Protection against allergy: Study in Rural Environments (PASTURE) birth cohorts and compared with classical nondisjunctive definitions of seasonal, perennial, and food sensitization with respect to atopic diseases and lung function. Cytokine levels were measured in the PASTURE cohort. The LCA classified predominantly by type and multiplicity of sensitization (food vs inhalant), allergen combinations, and sIgE levels. Latent classes were related to atopic disease manifestations with higher sensitivity and specificity than the classical definitions. LCA detected consistently in both cohorts a distinct group of children with severe atopy characterized by high seasonal sIgE levels and a strong propensity for asthma; hay fever; eczema; and impaired lung function, also in children without an established asthma diagnosis. Severe atopy was associated with an increased IL-5/IFN-γ ratio. A path analysis among sensitized children revealed that among all features of severe atopy, only excessive sIgE production early in life affected asthma risk. LCA revealed a set of benign, symptomatic, and severe atopy phenotypes. The severe phenotype emerged as a latent condition with signs of a dysbalanced immune response. It determined high asthma risk through excessive sIgE production and directly affected impaired lung function. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

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 Trail Making Test elucidates neural substrates of specific post-stroke executive dysfunctions

PubMed Central

Muir, Ryan T.; Lam, Benjamin; Honjo, Kie; Harry, Robin D.; McNeely, Alicia A.; Gao, Fu-Qiang; Ramirez, Joel; Scott, Christopher J.M; Ganda, Anoop; Zhao, Jiali; Zhou, X. Joe; Graham, Simon J.; Rangwala, Novena; Gibson, Erin; Lobaugh, Nancy J.; Kiss, Alex; Stuss, Donald T.; Nyenhuis, David L.; Lee, Byung-Chul; Kang, Yeonwook; Black, Sandra E.

2015-01-01

Background and Purpose Post-stroke cognitive impairment (PSCI) is typified by prominent deficits in processing speed and executive function. However, the underlying neuroanatomical substrates of executive deficits are not well understood and further elucidation is needed. There may be utility in fractionating executive functions to delineate neural substrates. Methods One test amenable to fine delineation is the Trail Making Test (TMT), which emphasizes processing speed (TMT-A) and set-shifting (TMT-B-A difference, proportion, quotient scores and TMT-B set-shifting errors). The TMT was administered to two overt ischemic stroke cohorts from a multinational study: (i) a chronic stroke cohort (N=61) and (ii) an acute-sub-acute stroke cohort (N=45). Volumetric quantification of ischemic stroke and White Matter HyperIntensities (WMH) was done on MRI, along with ratings of involvement of cholinergic projections, using the previously published Cholinergic Hyperintensities Projections Scale (CHIPS). Damage to the superior longitudinal fasciculus (SLF), which co-localizes with some cholinergic projections, was also documented. Results Multiple linear regression analyses were completed. While larger infarcts (β=0.37, p<0.0001) were associated with slower processing speed, CHIPS severity (β=0.39, p<0.0001) was associated with all metrics of set shifting. Left SLF damage, however, was only associated with the difference score (β=0.17, p=0.03). These findings were replicated in both cohorts. Patients with ≥2 TMT-B set shifting errors also had greater CHIPS severity. Conclusions In this multinational stroke cohort study, damage to lateral cholinergic pathways and the SLF emerged as significant neuroanatomical correlates for executive deficits in set shifting. PMID:26382176

Trail Making Test Elucidates Neural Substrates of Specific Poststroke Executive Dysfunctions.

PubMed

Muir, Ryan T; Lam, Benjamin; Honjo, Kie; Harry, Robin D; McNeely, Alicia A; Gao, Fu-Qiang; Ramirez, Joel; Scott, Christopher J M; Ganda, Anoop; Zhao, Jiali; Zhou, X Joe; Graham, Simon J; Rangwala, Novena; Gibson, Erin; Lobaugh, Nancy J; Kiss, Alex; Stuss, Donald T; Nyenhuis, David L; Lee, Byung-Chul; Kang, Yeonwook; Black, Sandra E

2015-10-01

Poststroke cognitive impairment is typified by prominent deficits in processing speed and executive function. However, the underlying neuroanatomical substrates of executive deficits are not well understood, and further elucidation is needed. There may be utility in fractionating executive functions to delineate neural substrates. One test amenable to fine delineation is the Trail Making Test (TMT), which emphasizes processing speed (TMT-A) and set shifting (TMT-B-A difference, proportion, quotient scores, and TMT-B set-shifting errors). The TMT was administered to 2 overt ischemic stroke cohorts from a multinational study: (1) a chronic stroke cohort (N=61) and (2) an acute-subacute stroke cohort (N=45). Volumetric quantification of ischemic stroke and white matter hyperintensities was done on magnetic resonance imaging, along with ratings of involvement of cholinergic projections, using the previously published cholinergic hyperintensities projections scale. Damage to the superior longitudinal fasciculus, which colocalizes with some cholinergic projections, was also documented. Multiple linear regression analyses were completed. Although larger infarcts (β=0.37, P<0.0001) were associated with slower processing speed, cholinergic hyperintensities projections scale severity (β=0.39, P<0.0001) was associated with all metrics of set shifting. Left superior longitudinal fasciculus damage, however, was only associated with the difference score (β=0.17, P=0.03). These findings were replicated in both cohorts. Patients with ≥2 TMT-B set-shifting errors also had greater cholinergic hyperintensities projections scale severity. In this multinational stroke cohort study, damage to lateral cholinergic pathways and the superior longitudinal fasciculus emerged as significant neuroanatomical correlates for executive deficits in set shifting. © 2015 American Heart Association, Inc.

Prevention of postpartum haemorrhage: cost consequences analysis of misoprostol in low-resource settings.

PubMed

Lang, Danielle L; Zhao, Fei-Li; Robertson, Jane

2015-11-23

While inferior to oxytocin injection in both efficacy and safety, orally administered misoprostol has been included in the World Health Organization Model List of Essential Medicines for use in the prevention of postpartum haemorrhage (PPH) in low-resource settings. This study evaluates the costs and health outcomes of use of oral misoprostol to prevent PPH in settings where injectable uterotonics are not available. A cost-consequences analysis was conducted from the international health system perspective, using data from a recent Cochrane systematic review and WHO's Mother-Baby Package Costing Spreadsheet in a hypothetical cohort of 1000 births in a mixed hospital (40% births)/community setting (60% births). Costs were estimated based on 2012 US dollars. Using oxytocin in the hospital setting and misoprostol in the community setting in a cohort of 1000 births, instead of oxytocin (hospital setting) and no treatment (community setting), 22 cases of PPH could be prevented. Six fewer women would require additional uterotonics and four fewer women a blood transfusion. An additional 130 women would experience shivering and an extra 42 women fever. Oxytocin/misoprostol was found to be cost saving (US$320) compared to oxytocin/no treatment. If misoprostol is used in both the hospital and community setting compared with no treatment (i.e. oxytocin not available in the hospital setting), 37 cases of PPH could be prevented; ten fewer women would require additional uterotonics; and six fewer women a blood transfusion. An additional 217 women would experience shivering and 70 fever. The cost savings would be US$533. Sensitivity analyses indicate that the results are sensitive to the incidence of PPH-related outcomes, drug costs and the proportion of hospital births. Our findings confirm that, even though misoprostol is not the optimum choice in the prevention of PPH, misoprostol could be an effective and cost-saving choice where oxytocin is not or cannot be used due to a lack of skilled birth attendants, inadequate transport and storage facilities or where a quality assured oxytocin product is not available. These benefits need to be weighed against the large number of additional side effects such as shivering and fever, which have been described as tolerable and of short duration.

Validation of serum amyloid α as an independent biomarker for progression-free and overall survival in metastatic renal cell cancer patients.

PubMed

Vermaat, Joost S; Gerritse, Frank L; van der Veldt, Astrid A; Roessingh, Wijnand M; Niers, Tatjana M; Oosting, Sjoukje F; Sleijfer, Stefan; Roodhart, Jeanine M; Beijnen, Jos H; Schellens, Jan H; Gietema, Jourik A; Boven, Epie; Richel, Dick J; Haanen, John B; Voest, Emile E

2012-10-01

We recently identified apolipoprotein A2 (ApoA2) and serum amyloid α (SAA) as independent prognosticators in metastatic renal cell carcinoma (mRCC) patients, thereby improving the accuracy of the Memorial-Sloan Kettering Cancer Center (MSKCC) model. Validate these results prospectively in a separate cohort of mRCC patients treated with tyrosine kinase inhibitors (TKIs). For training we used 114 interferon-treated mRCC patients (inclusion 2001-2006). For validation we studied 151 TKI-treated mRCC patients (inclusion 2003-2009). Using Cox proportional hazards regression analysis, SAA and ApoA2 were associated with progression-free survival (PFS) and overall survival (OS). In 72 TKI-treated patients, SAA levels were analyzed longitudinally as a potential early marker for treatment effect. Baseline ApoA2 and SAA levels significantly predicted PFS and OS in the training and validation cohorts. Multivariate analysis identified SAA in both separate patient sets as a robust and independent prognosticator for PFS and OS. In contrast to our previous findings, ApoA2 interacted with SAA in the validation cohort and did not contribute to a better predictive accuracy than SAA alone and was therefore excluded from further analysis. According to the tertiles of SAA levels, patients were categorized in three risk groups, demonstrating accurate risk prognostication. SAA as a single biomarker showed equal prognostic accuracy when compared with the multifactorial MSKCC risk mode. Using receiver operating characteristic analysis, SAA levels >71 ng/ml were designated as the optimal cut-off value in the training cohort, which was confirmed for its significant sensitivity and specificity in the validation cohort. Applying SAA >71 ng/ml as an additional risk factor significantly improved the predictive accuracy of the MSKCC model in both independent cohorts. Changes in SAA levels after 6-8 wk of TKI treatment had no value in predicting treatment outcome. SAA but not ApoA2 was shown to be a robust and independent prognosticator for PFS and OS in mRCC patients. When incorporated in the MSKCC model, SAA showed additional prognostic value for patient management. Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Cross-cultural comparisons of the Mini-mental State Examination between Japanese and U.S. cohorts

PubMed Central

Meguro, Kenichi; Ishii, Hiroshi; Yamaguchi, Satoshi; Saxton, Judith A.; Ganguli, Mary

2009-01-01

Background The Mini-mental State Examination (MMSE) is widely used in Japan and the U.S.A. for cognitive screening in the clinical setting and in epidemiological studies. A previous Japanese community study reported distributions of the MMSE total score very similar to that of the U.S.A. Methods Data were obtained from the Monongahela Valley Independent Elder's Study (MoVIES), a representative sample of community-dwelling elderly people aged 65 and older living near Pittsburgh, U.S.A., and from the Tajiri Project, with similar aims in Tajiri, Japan. We examined item-by-item distributions of the MMSE between two cohorts, comparing (1) percentage of correct answers for each item within each cohort, and (2) relative difficulty of each item measured by Item Characteristic Curve analysis (ICC), which estimates log odds of obtaining a correct answer adjusted for the remaining MMSE items, demographic variables (age, gender, education) and interactions of demographic variables and cohort. Results Median MMSE scores were very similar between the two samples within the same education groups. However, the relative difficulty of each item differed substantially between the two cohorts. Specifically, recall and auditory comprehension were easier for the Tajiri group, but reading comprehension and sentence construction were easier for the MoVIES group. Conclusions Our results reaffirm the importance of validation and examination of thresholds in each cohort to be studied when a common instrument is used as a dementia screening tool or for defining cognitive impairment. PMID:18925977

Mortality from Cardiovascular Diseases in the Semipalatinsk Historical Cohort, 1960–1999, and its Relationship to Radiation Exposure

PubMed Central

Grosche, Bernd; Lackland, Daniel T.; Land, Charles E.; Simon, Steven L.; Apsalikov, Kazbek N.; Pivina, Ludmilla M.; Bauere, Susanne; Gusev, Boris I.

2013-01-01

The data on risk of mortality from cardiovascular disease due to radiation exposure at low or medium doses are inconsistent. This paper reports an analysis of the Semipalatinsk historical cohort exposed to radioactive fallout from nuclear testing in the vicinity of the Semipalatinsk Nuclear Test Site, Kazakhstan. The cohort study, which includes 19,545 persons of exposed and comparison villages in the Semipalatinsk region, had been set up in the 1960s and comprises 582,656 person-years of follow-up between 1960 and 1999. A dosimetric approach developed by the U.S. National Cancer Institute (NCI) has been used. Radiation dose estimates in this cohort range from 0 to 630 mGy (wholebody external). Overall, the exposed population showed a high mortality from cardiovascular disease. Rates of mortality from cardiovascular disease in the exposed group substantially exceeded those of the comparison group. Dose–response analyses were conducted for both the entire cohort and the exposed group only. A dose–response relationship that was found when analyzing the entire cohort could be explained completely by differences between the baseline rates in exposed and unexposed groups. When taking this difference into account, no statistically significant dose–response relationship for all cardiovascular disease, for heart disease, or for stroke was found. Our results suggest that within this population and at the level of doses estimated, there is no detectable risk of radiation related mortality from cardiovascular disease. PMID:21787182

Mortality from cardiovascular diseases in the Semipalatinsk historical cohort, 1960-1999, and its relationship to radiation exposure.

PubMed

Grosche, Bernd; Lackland, Daniel T; Land, Charles E; Simon, Steven L; Apsalikov, Kazbek N; Pivina, Ludmilla M; Bauer, Susanne; Gusev, Boris I

2011-11-01

The data on risk of mortality from cardiovascular disease due to radiation exposure at low or medium doses are inconsistent. This paper reports an analysis of the Semipalatinsk historical cohort exposed to radioactive fallout from nuclear testing in the vicinity of the Semipalatinsk Nuclear Test Site, Kazakhstan. The cohort study, which includes 19,545 persons of exposed and comparison villages in the Semipalatinsk region, had been set up in the 1960s and comprises 582,656 person-years of follow-up between 1960 and 1999. A dosimetric approach developed by the U.S. National Cancer Institute (NCI) has been used. Radiation dose estimates in this cohort range from 0 to 630 mGy (whole-body external). Overall, the exposed population showed a high mortality from cardiovascular disease. Rates of mortality from cardiovascular disease in the exposed group substantially exceeded those of the comparison group. Dose-response analyses were conducted for both the entire cohort and the exposed group only. A dose-response relationship that was found when analyzing the entire cohort could be explained completely by differences between the baseline rates in exposed and unexposed groups. When taking this difference into account, no statistically significant dose-response relationship for all cardiovascular disease, for heart disease, or for stroke was found. Our results suggest that within this population and at the level of doses estimated, there is no detectable risk of radiation-related mortality from cardiovascular disease.

Salmonella enterica serovar Enteritidis phage type 4 outbreak associated with eggs in a large prison, London 2009: an investigation using cohort and case/non-case study methodology.

PubMed

Davies, A R; Ruggles, R; Young, Y; Clark, H; Reddell, P; Verlander, N Q; Arnold, A; Maguire, H

2013-05-01

In September 2009, an outbreak of Salmonella enterica serovar Enteritidis affected 327 of 1419 inmates at a London prison. We applied a cohort design using aggregated data from the kitchen about portions of food distributed, aligned this with individual food histories from 124 cases (18 confirmed, 106 probable) and deduced the exposures of those remaining well. Results showed that prisoners eating egg cress rolls were 26 times more likely to be ill [risk ratio 25.7, 95% confidence interval (CI) 15.5-42.8, P<0.001]. In a case/non-case multivariable analysis the adjusted odds ratio for egg cress rolls was 41.1 (95% CI 10.3-249.7, P<0.001). The epidemiological investigation was strengthened by environmental and microbiological investigations. This paper outlines an approach to investigations in large complex settings where aggregate data for exposures may be available, and led to the development of guidelines for the management of future gastrointestinal outbreaks in prison settings.

Detection and treatment rates for perinatal depression in a state Medicaid population.

PubMed

Geier, Michelle L; Hills, Nancy; Gonzales, Marco; Tum, Karoline; Finley, Patrick R

2015-02-01

The purpose of this investigation was to assess detection and treatment rates for perinatal depression among women enrolled in the California State Medicaid (Medi-Cal) program in comparison to female beneficiaries of reproductive age who did not give birth during the same study period. Investigators conducted a retrospective longitudinal cohort analysis of women between the ages of 18 and 39 years old who were continuously enrolled in the Medi-Cal fee-for-service program between January 2006 and December 2009. The perinatal cohort consisted of women with evidence of a live birth occurring between October 2007 and March 2009. The control cohort consisted of women in the same age group and health plan without evidence of pregnancy during this time frame. The primary outcome of this investigation was diagnosis of depression during 3 contiguous 9-month time frames: immediately prior to presumed conception, during pregnancy, and throughout the postpartum period. Secondary outcomes included within-group and cohort comparisons of treatment patterns (antidepressant or psychotherapy). A multivariable analysis of demographic factors predicting depression diagnosis or treatment was conducted as well. A total of 6030 women was identified in the perinatal cohort, and 56,709 women were included in the control group. The perinatal cohort was significantly less likely than nonpregnant controls to receive a diagnosis of depression both during pregnancy (prevalence=1.6% vs 3.5%; OR=0.45; 95% CI=0.35-0.55) and postpartum (2.2% vs 3.6%; OR=0.59; 95% CI=0.50-0.71). Similar differences were noted in antidepressant prescribing patterns apparent during these 2 time frames. A subgroup analysis of women who received a depression diagnosis revealed that only 48% of the perinatal cohort was provided any treatment during pregnancy (vs 72% of the control group; p<0.0001) or postpartum (57% vs 73%; p<0.0001). Specific demographic factors predicting a lower prevalence of depression detection or treatment included Hispanic descent, age <25 years, or primary residence in an rural setting. Depression was often overlooked and undertreated among women who are pregnant or postpartum in comparison to services delivered to similar nonpregnant controls. Significant disparities in the healthcare received by certain subpopulations of perinatal women suggest that research into barriers to care and subsequent interventions are warranted.

Is beryllium-induced lung cancer caused only by soluble forms and high exposure levels?

PubMed

Schubauer-Berigan, Mary K; Couch, James R; Deddens, James A

2017-08-01

The US Occupational Safety and Health Administration (OSHA) recently proposed a permissible exposure limit of 0.2 µg/m 3 for beryllium, based partly on extrapolated estimates of lung cancer risk from a pooled occupational cohort. The purpose of the present analysis was to evaluate whether cohort members exposed at lower levels to mainly insoluble forms of beryllium exhibit increased risk of lung cancer. We conducted Cox proportional hazards regression analyses among 75 lung cancer cases in age-based risk sets within two lower exposure plants in the pooled cohort followed from 1940 to 2005. We used categorical and power models to evaluate exposure-response patterns for mean and cumulative beryllium exposures in the two-plant cohort, comparing findings with the full pooled cohort. We also evaluated the distribution of exposure-years in each cohort by solubility class (soluble, insoluble and mixed). 98% of workers in the two-plant cohort were hired between 1955 and 1969. The mean beryllium exposure averaged 1.3 µg/m 3 and the predominant form was insoluble. Adjusting for confounders, we observed a monotonic increase in lung cancer mortality across exposure categories in the two-plant cohort. The exposure-response coefficients (per unit ln exposure) were 0.270 (p=0.061) for mean exposure and 0.170 (p=0.033) for cumulative exposure, compared with 0.155 and 0.094 (respectively) in the full cohort. The low-exposure levels at these two plants and the predominance of insoluble beryllium suggest that the overall pooled cohort findings on which OSHA's lung cancer risk assessment is based are relevant for current workers exposed to any form of beryllium. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Breast feeding and intergenerational social mobility: what are the mechanisms?

PubMed Central

Sacker, A; Kelly, Y; Iacovou, M; Cable, N; Bartley, M

2013-01-01

Objective To investigate the association between breast feeding and intergenerational social mobility and the possible mediating role of neurological and stress mechanisms. Design Secondary analysis of data from the 1958 and the 1970 British Cohort Studies. Setting Longitudinal study of individuals born in Britain during 1 week in 1958 and 1970. Participants 17 419 individuals participated in the 1958 cohort and 16 771 in the 1970 cohort. The effect of breast feeding on intergenerational social mobility from age 10/11 to age 33/34 was analysed after multiple imputations to fill in missing data and propensity score matching on a wide range of confounders measured in childhood (1958 cohort N=16 039–16 154; 1970 cohort N=16 255–16 361). Main outcome measures Own Registrar General's Social Class (RGSC) at 33/34 years adjusted for father's RGSC at 10/11 years, gender and their interaction. Results Breastfed individuals were more likely to be upwardly mobile (1958 cohort: OR 1.24 95% CI 1.12 to 1.38; 1970 cohort: OR 1.24 95% CI 1.12 to 1.37) and less likely to be downwardly mobile (1958 cohort: OR 0.81 95% CI 0.73 to 0.90; 1970 cohort: OR 0.79 95% CI 0.71 to 0.88). In an ordinal regression model, markers of neurological development (cognitive test scores) and stress (emotional stress scores) accounted for approximately 36% of the relationship between breast feeding and social mobility. Conclusions Breast feeding increased the odds of upward social mobility and decreased the odds of downward mobility. Consistent with a causal explanation, the findings were robust to matching on a large number of observable variables and effect sizes were alike for two cohorts with different social distributions of breast feeding. The effect was mediated in part through neurological and stress mechanisms. PMID:23798701

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

Emms, David M.; Covshoff, Sarah; Hibberd, Julian M.

C4 photosynthesis is considered one of the most remarkable examples of evolutionary convergence in eukaryotes. However, it is unknown whether the evolution of C4 photosynthesis required the evolution of new genes. Genome-wide gene-tree species-tree reconciliation of seven monocot species that span two origins of C4 photosynthesis revealed that there was significant parallelism in the duplication and retention of genes coincident with the evolution of C4 photosynthesis in these lineages. Specifically, 21 orthologous genes were duplicated and retained independently in parallel at both C4 origins. Analysis of this gene cohort revealed that the set of parallel duplicated and retained genes ismore » enriched for genes that are preferentially expressed in bundle sheath cells, the cell type in which photosynthesis was activated during C4 evolution. Moreover, functional analysis of the cohort of parallel duplicated genes identified SWEET-13 as a potential key transporter in the evolution of C4 photosynthesis in grasses, and provides new insight into the mechanism of phloem loading in these C4 species.« less

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.

Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study.

PubMed

Perl, Alexander E; Altman, Jessica K; Cortes, Jorge; Smith, Catherine; Litzow, Mark; Baer, Maria R; Claxton, David; Erba, Harry P; Gill, Stan; Goldberg, Stuart; Jurcic, Joseph G; Larson, Richard A; Liu, Chaofeng; Ritchie, Ellen; Schiller, Gary; Spira, Alexander I; Strickland, Stephen A; Tibes, Raoul; Ustun, Celalettin; Wang, Eunice S; Stuart, Robert; Röllig, Christoph; Neubauer, Andreas; Martinelli, Giovanni; Bahceci, Erkut; Levis, Mark

2017-08-01

Internal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia. In this phase 1-2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations (FLT3 mut+ ) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3 mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number NCT02014558, and is ongoing. Between Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3-4 adverse events irrespective of relation to treatment were febrile neutropenia (97 [39%] of 252), anaemia (61 [24%]), thrombocytopenia (33 [13%]), sepsis (28 [11%]), and pneumonia (27 [11%]). Commonly reported treatment-related adverse events were diarrhoea (92 [37%] of 252]), anaemia (86 [34%]), fatigue (83 [33%]), elevated aspartate aminotransferase (65 [26%]), and increased alanine aminotransferase (47 [19%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (98 [39%] of 252; five related to treatment), progressive disease (43 [17%]), sepsis (36 [14%]; two related to treatment), pneumonia (27 [11%]), acute renal failure (25 [10%]; five related to treatment), pyrexia (21 [8%]; three related to treatment), bacteraemia (14 [6%]; one related to treatment), and respiratory failure (14 [6%]). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism [200 mg/day], respiratory failure [120 mg/day], haemoptysis [80 mg/day], intracranial haemorrhage [20 mg/day], ventricular fibrillation [120 mg/day], septic shock [80 mg/day], and neutropenia [120 mg/day]). An exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission INTERPRETATION: Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials. Astellas Pharma, National Cancer Institute (Leukemia Specialized Program of Research Excellence grant), Associazione Italiana Ricerca sul Cancro. Copyright © 2017 Elsevier Ltd. All rights reserved.

Use and limitations of malaria rapid diagnostic testing by community health workers in war-torn Democratic Republic of Congo.

PubMed

Hawkes, Michael; Katsuva, Jean Paul; Masumbuko, Claude K

2009-12-23

Accurate and practical malaria diagnostics, such as immunochromatographic rapid diagnostic tests (RDTs), have the potential to avert unnecessary treatments and save lives. Volunteer community health workers (CHWs) represent a potentially valuable human resource for expanding this technology to where it is most needed, remote rural communities in sub-Saharan Africa with limited health facilities and personnel. This study reports on a training programme for CHWs to incorporate RDTs into their management strategy for febrile children in the Democratic Republic of Congo, a tropical African setting ravaged by human conflict. Prospective cohort study, satisfaction questionnaire and decision analysis. Twelve CHWs were trained to safely and accurately perform and interpret RDTs, then successfully implemented rapid diagnostic testing in their remote community in a cohort of 357 febrile children. CHWs were uniformly positive in evaluating RDTs for their utility and ease of use. However, high malaria prevalence in this cohort (93% by RDTs, 88% by light microscopy) limited the cost-effectiveness of RDTs compared to presumptive treatment of all febrile children, as evidenced by findings from a simplified decision analysis. CHWs can safely and effectively use RDTs in their management of febrile children; however, cost-effectiveness of RDTs is limited in zones of high malaria prevalence.

Use and limitations of malaria rapid diagnostic testing by community health workers in war-torn Democratic Republic of Congo

PubMed Central

2009-01-01

Background Accurate and practical malaria diagnostics, such as immunochromatographic rapid diagnostic tests (RDTs), have the potential to avert unnecessary treatments and save lives. Volunteer community health workers (CHWs) represent a potentially valuable human resource for expanding this technology to where it is most needed, remote rural communities in sub-Saharan Africa with limited health facilities and personnel. This study reports on a training programme for CHWs to incorporate RDTs into their management strategy for febrile children in the Democratic Republic of Congo, a tropical African setting ravaged by human conflict. Methods Prospective cohort study, satisfaction questionnaire and decision analysis. Results Twelve CHWs were trained to safely and accurately perform and interpret RDTs, then successfully implemented rapid diagnostic testing in their remote community in a cohort of 357 febrile children. CHWs were uniformly positive in evaluating RDTs for their utility and ease of use. However, high malaria prevalence in this cohort (93% by RDTs, 88% by light microscopy) limited the cost-effectiveness of RDTs compared to presumptive treatment of all febrile children, as evidenced by findings from a simplified decision analysis. Conclusions CHWs can safely and effectively use RDTs in their management of febrile children; however, cost-effectiveness of RDTs is limited in zones of high malaria prevalence. PMID:20028563

Linking Investigations in Trauma and Emergency Services (LITES)

DTIC Science & Technology

2017-10-01

observational cohort that will have a limited data set from trauma registry data and electronic health records. Specific Aim one is to characterize the...epidemiology of moderate and severe physical injury in the U.S. and across the LITES network and investigate regional variations of presenting...observational cohort that will have a limited data set from trauma registry data and electronic health records. Specific Aim one is to characterize the

Hypoglycemia in patients with type 2 diabetes newly initiated on basal insulin in the US in a community setting: impact on treatment discontinuation and hospitalization.

PubMed

Dalal, Mehul R; Kazemi, Mahmood R; Ye, Fen

2017-02-01

To evaluate the impact of 6 month hypoglycemia on treatment discontinuation and hospitalization of patients initiating basal insulin for type 2 diabetes (T2D) in real-world practice. This was a retrospective cohort study of patient-level data using electronic medical records (EMRs) in the Predictive Health Intelligence diabetes dataset. Data from adult patients with T2D initiating basal insulin glargine, insulin detemir, or Neutral Protamine Hagedorn insulin between January 2008 and March 2014 was analyzed. The date of first basal insulin prescription in an outpatient setting was the index date. A 12 month baseline prior to the index date was established; follow-up was 6-24 months from the index date. Patients were assigned to cohorts by experience of hypoglycemia (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code or blood glucose test) in the first 6 months following the index date; with hypoglycemia and without hypoglycemia cohorts were compared for basal insulin treatment discontinuation and hospitalization. Overall, 49,062 patients were included; 5159 (10.5%) experienced hypoglycemia in the 6 months following basal insulin initiation. In the first 12 months, 68.1% of patients in the with hypoglycemia cohort discontinued basal insulin versus 53.9% in the without hypoglycemia cohort (p < .0001); more patients in the with hypoglycemia cohort had at least one hospitalization in the first year of follow-up (50.1% vs. 14.6%; p < .0001). Patients with hypoglycemia soon after initiating basal insulin are at greater risk of discontinuation of their basal insulin therapy and hospitalization versus those who did not have hypoglycemic events within the first 6 months of basal insulin initiation. A limitation of this study is that it was a retrospective analysis of EMR data and the study may not be representative of all US patients with T2D on basal insulin and it cannot be assumed that every hypoglycemic event was recorded.

Outpatient and Inpatient Single-Level Cervical Total Disc Replacement: A Comparison of 30-day Outcomes.

PubMed

Segal, Dale N; Wilson, Jacob M; Staley, Christopher; Yoon, Tim S

2018-06-11

Retrospective cohort study. To compare 30-day postoperative outcomes between patients undergoing outpatient and inpatient single-level cervical total disc replacement surgery. Cervical total disc replacement (TDR) is a motion sparing treatment for cervical radiculopathy and myelopathy. It is an alternative to anterior cervical discectomy and fusion (ACDF) with a similar complication rate. Like ACDF, it may be performed in the inpatient or outpatient setting. Efforts to reduce healthcare costs are driving spine surgery to be performed in the outpatient setting. As cervical total disc replacement surgery continues to gain popularity, the safety of treating patients on an outpatient basis needs to be validated. The National Surgical Quality Improvement Program (NSQIP) database was queried for patients who underwent single-level cervical disc replacement surgery between 2006-2015. Complication data including 30-day complications, reoperation rate, readmission rate, and length of stay data was compared between the inpatient and outpatient cohort using univariate analysis. There were 531 (34.2%) patients treated as outpatients and 1,022 (65.8%) were treated on an inpatient basis. The two groups had similar baseline characteristics. The overall 30-day complication rate was 1.4% for inpatients and 0.6% for outpatients. Reoperation rate was 0.6% for inpatient and 0.4% for outpatients. Readmission rate was 0.9% and 0.8% for inpatient and outpatient, respectively. There were no statistical differences identified in rates of readmission, reoperation, or complication between the inpatient and outpatient cohorts. There was no difference between 30-day complications, readmission and reoperation rates between inpatients and outpatients who underwent a single-level cervical total disc replacement. Furthermore, the overall 30-day complication rates were low. This study supports that single-level cervical TDR can be performed safely in an outpatient setting. 3.

Exclusion and Inclusion of Nonwhite Ethnic Minority Groups in 72 North American and European Cardiovascular Cohort Studies

PubMed Central

Ranganathan, Meghna; Bhopal, Raj

2006-01-01

Background Cohort studies are recommended for understanding ethnic disparities in cardiovascular disease. Our objective was to review the process for identifying, including, and excluding ethnic minority populations in published cardiovascular cohort studies in Europe and North America. Methods and Findings We found the literature using Medline (1966–2005), Embase (1980–2001), Cinahl, Web of Science, and citations from references; consultations with colleagues; Internet searches; and RB's personal files. A total of 72 studies were included, 39 starting after 1975. Decision-making on inclusion and exclusion of racial/ethnic groups, the conceptual basis of race/ethnicity, and methods of classification of racial/ethnic groups were rarely explicit. Few publications provided details on the racial/ethnic composition of the study setting or sample, and 39 gave no description. Several studies were located in small towns or in occupational settings, where ethnic minority populations are underrepresented. Studies on general populations usually had too few participants for analysis by race/ethnicity. Eight studies were explicitly on Caucasians/whites, and two excluded ethnic minority groups from the whole or part of the study on the basis of language or birthplace criteria. Ten studies were designed to compare white and nonwhite populations, while five studies focused on one nonwhite racial/ethnic group; all 15 of these were performed in the US. Conclusions There is a shortage of information from cardiovascular cohort studies on racial/ethnic minority populations, although this has recently changed in the US. There is, particularly in Europe, an inequity resulting from a lack of research data in nonwhite populations. Urgent action is now required in Europe to address this disparity. PMID:16379500

Can HIV reverse transcriptase activity assay be a low-cost alternative for viral load monitoring in resource-limited settings?

PubMed

Gupta, Soham; Palchaudhuri, Riya; Neogi, Ujjwal; Srinivasa, Hiresave; Ashorn, Per; De Costa, Ayesha; Källander, Clas; Shet, Anita

2016-01-27

To evaluate the performance and cost of an HIV reverse transcriptase-enzyme activity (HIV-RT) assay in comparison to an HIV-1 RNA assay for routine viral load monitoring in resource limited settings. A cohort-based longitudinal study. Two antiretroviral therapy (ART) centres in Karnataka state, South India, providing treatment under the Indian AIDS control programme. A cohort of 327 HIV-1-infected Indian adult patients initiating first-line ART. Performance and cost of an HIV-RT assay (ExaVir Load V3) in comparison to a gold standard HIV-1 RNA assay (Abbott m2000rt) in a cohort of 327 Indian patients before (WK00) and 4 weeks (WK04) after initiation of first-line therapy. Plasma viral load was determined by an HIV-1 RNA assay and an HIV-RT assay in 629 samples (302 paired samples and 25 single time point samples at WK00) obtained from 327 patients. Overall, a strong correlation of r=0.96 was observed, with good correlation at WK00 (r=0.84) and at WK04 (r=0.77). Bland-Altman analysis of all samples showed a good level of agreement with a mean difference (bias) of 0.22 log10copies/mL. The performance of ExaVir Load V3 was not negatively affected by a nevirapine/efavirenz based antiretroviral regimen. The per test cost of measuring plasma viral load by the Abbott m2000rt and ExaVir Load V3 assays in a basic lab setting was $36.4 and $16.8, respectively. The strong correlation between the HIV-RT and HIV-1 RNA assays suggests that the HIV-RT assay can be an affordable alternative option for monitoring patients on antiretroviral therapy in resource-limited settings. ISRCTN79261738. 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/

Latent Variable Regression 4-Level Hierarchical Model Using Multisite Multiple-Cohorts Longitudinal Data. CRESST Report 801

ERIC Educational Resources Information Center

Choi, Kilchan

2011-01-01

This report explores a new latent variable regression 4-level hierarchical model for monitoring school performance over time using multisite multiple-cohorts longitudinal data. This kind of data set has a 4-level hierarchical structure: time-series observation nested within students who are nested within different cohorts of students. These…

The Effectiveness of Inclusion in Texas High Schools

ERIC Educational Resources Information Center

Patterson, Steven T.

2013-01-01

The purpose of this study was to employ value-added methodology to determine which placement setting offered the ninth grade 2009 special education high school cohort the most academic growth as measured on the Texas Assessment of Knowledge and Skills (TAKS). This particular cohort was selected because it was the most recent cohort for which 3…

Social Origin and Graduation Age: A Cohort Comparison of Danish University Students

ERIC Educational Resources Information Center

Klausen, Trond Beldo

2016-01-01

This paper investigates whether social origin has an impact on graduation age among university students. A large number of social background factors are applied on a large data set of 4 successive cohorts of Danish university graduates born 1960-1975. These are cohorts for whom university attendance increased steeply. Contrary to recent findings…

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.

Diagnostic depressive symptoms of the mixed bipolar episode.

PubMed

Cassidy, F; Ahearn, E; Murry, E; Forest, K; Carroll, B J

2000-03-01

There is not yet consensus on the best diagnostic definition of mixed bipolar episodes. Many have suggested the DSM-III-R/-IV definition is too rigid. We propose alternative criteria using data from a large patient cohort. We evaluated 237 manic in-patients using DSM-III-R criteria and the Scale for Manic States (SMS). A bimodally distributed factor of dysphoric mood has been reported from the SMS data. We used both the factor and the DSM-III-R classifications to identify candidate depressive symptoms and then developed three candidate depressive symptom sets. Using ROC analysis we determined the optimal threshold number of symptoms in each set and compared the three ROC solutions. The optimal solution was tested against the DSM-III-R classification for crossvalidation. The optimal ROC solution was a set, derived from both the DSM-III-R and the SMS, and the optimal threshold for diagnosis was two or more symptoms. Applying this set iteratively to the DSM-III-R classification produced the identical ROC solution. The prevalence of mixed episodes in the cohort was 13.9% by DSM-III-R, 20.2% by the dysphoria factor and 27.4% by the new ROC solution. A diagnostic set of six dysphoric symptoms (depressed mood, anhedonia, guilt, suicide, fatigue and anxiety), with a threshold of two symptoms, is proposed for a mixed episode. This new definition has a foundation in clinical data, in the proved diagnostic performance of the qualifying symptoms, and in ROC validation against two previous definitions that each have face validity.

Set-up uncertainties: online correction with X-ray volume imaging.

PubMed

Kataria, Tejinder; Abhishek, Ashu; Chadha, Pranav; Nandigam, Janardhan

2011-01-01

To determine interfractional three-dimensional set-up errors using X-ray volumetric imaging (XVI). Between December 2007 and August 2009, 125 patients were taken up for image-guided radiotherapy using online XVI. After matching of reference and acquired volume view images, set-up errors in three translation directions were recorded and corrected online before treatment each day. Mean displacements, population systematic (Σ), and random (σ) errors were calculated and analyzed using SPSS (v16) software. Optimum clinical target volume (CTV) to planning target volume (PTV) margin was calculated using Van Herk's (2.5Σ + 0.7 σ) and Stroom's (2Σ + 0.7 σ) formula. Patients were grouped in 4 cohorts, namely brain, head and neck, thorax, and abdomen-pelvis. The mean vector displacement recorded were 0.18 cm, 0.15 cm, 0.36 cm, and 0.35 cm for brain, head and neck, thorax, and abdomen-pelvis, respectively. Analysis of individual mean set-up errors revealed good agreement with the proposed 0.3 cm isotropic margins for brain and 0.5 cm isotropic margins for head-neck. Similarly, 0.5 cm circumferential and 1 cm craniocaudal proposed margins were in agreement with thorax and abdomen-pelvic cases. The calculated mean displacements were well within CTV-PTV margin estimates of Van Herk (90% population coverage to minimum 95% prescribed dose) and Stroom (99% target volume coverage by 95% prescribed dose). Employing these individualized margins in a particular cohort ensure comparable target coverage as described in literature, which is further improved if XVI-aided set-up error detection and correction is used before treatment.

Cohort profile: The lidA Cohort Study—a German Cohort Study on Work, Age, Health and Work Participation

PubMed Central

Hasselhorn, Hans Martin; Peter, Richard; Rauch, Angela; Schröder, Helmut; Swart, Enno; Bender, Stefan; du Prel, Jean-Baptist; Ebener, Melanie; March, Stefanie; Trappmann, Mark; Steinwede, Jacob; Müller, Bernd Hans

2014-01-01

The lidA Cohort Study (German Cohort Study on Work, Age, Health and Work Participation) was set up to investigate and follow the effects of work and work context on the physical and psychological health of the ageing workforce in Germany and subsequently on work participation. Cohort participants are initially employed people subject to social security contributions and born in either 1959 (n = 2909) or 1965 (n = 3676). They were personally interviewed in their homes in 2011 and will be visited every 3 years. Data collection comprises socio-demographic data, work and private exposures, work ability, work and work participation attitudes, health, health-related behaviour, personality and attitudinal indicators. Employment biographies are assessed using register data. Subjective health reports and physical strength measures are complemented by health insurance claims data, where permission was given. A conceptual framework has been developed for the lidA Cohort Study within which three confirmatory sub-models assess the interdependencies of work and health considering age, gender and socioeconomic status. The first set of the data will be available to the scientific community by 2015. Access will be given by the Research Data Centre of the German Federal Employment Agency at the Institute for Employment Research (http://fdz.iab.de/en.aspx). PMID:24618186

Results of a Prospective Echocardiography Trial in International Space Station Crew

NASA Technical Reports Server (NTRS)

Hamilton, Douglas R.; Sargsyan, Ashot E.; Martin, David; Garcia, Kathleen M.; Melton, Shannon; Feiverson, Alan; Dulchavsky, Scott A.

2009-01-01

In the framework of an operationally oriented investigation, we conducted a prospective trial of a standard clinical echocardiography protocol in a cohort of long-duration crewmembers. The resulting primary and processed data appear to have no precedents. Our tele-echocardiography paradigm, including just-in-time e-training methods, was also assessed. A critical review of the imaging technique, equipment and setting limitations, and quality assurance is provided, as well as the analysis of "space normal" data.

Mitochondrial Haplogroup Influences Motor Function in Long-Term HIV-1-Infected Individuals

PubMed Central

Azar, Ashley; Giovannetti, Tania; Pirrone, Vanessa; Nonnemacher, Michael R.; Passic, Shendra; Kercher, Katherine; Williams, Jean W.; Wigdahl, Brian; Dampier, William; Libon, David J.; Sell, Christian

2016-01-01

Evolutionary divergence of the mitochondrial genome has given rise to distinct haplogroups. These haplogroups have arisen in specific geographical locations and are responsible for subtle functional changes in the mitochondria that may provide an evolutionary advantage in a given environment. Based on these functional differences, haplogroups could define disease susceptibility in chronic settings. In this study, we undertook a detailed neuropsychological analysis of a cohort of long-term HIV-1-infected individuals in conjunction with sequencing of their mitochondrial genomes. Stepwise regression analysis showed that the best model for predicting both working memory and declarative memory were age and years since diagnosis. In contrast, years since diagnosis and sub-haplogroup were significantly predictive of psychomotor speed. Consistent with this, patients with haplogroup L3e obtained better scores on psychomotor speed and dexterity tasks when compared to the remainder of the cohort, suggesting that this haplogroup provides a protective advantage when faced with the combined stress of HIV-1 infection and long-term antiretroviral therapies. Differential performance on declarative memory tasks was noted for individuals with other sub-L haplogroups, but these differences were not as robust as the association between L3e and psychomotor speed and dexterity tasks. This work provides evidence that mitochondrial haplogroup is related to neuropsychological test performance among patients in chronic disease settings such as HIV-1 infection. PMID:27711166

Wound healing outcomes: Using big data and a modified intent-to-treat method as a metric for reporting healing rates.

PubMed

Ennis, William J; Hoffman, Rachel A; Gurtner, Geoffrey C; Kirsner, Robert S; Gordon, Hanna M

2017-08-01

Chronic wounds are increasing in prevalence and are a costly problem for the US healthcare system and throughout the world. Typically outcomes studies in the field of wound care have been limited to small clinical trials, comparative effectiveness cohorts and attempts to extrapolate results from claims databases. As a result, outcomes in real world clinical settings may differ from these published studies. This study presents a modified intent-to-treat framework for measuring wound outcomes and measures the consistency of population based outcomes across two distinct settings. In this retrospective observational analysis, we describe the largest to date, cohort of patient wound outcomes derived from 626 hospital based clinics and one academic tertiary care clinic. We present the results of a modified intent-to-treat analysis of wound outcomes as well as demographic and descriptive data. After applying the exclusion criteria, the final analytic sample includes the outcomes from 667,291 wounds in the national sample and 1,788 wounds in the academic sample. We found a consistent modified intent to treat healing rate of 74.6% from the 626 clinics and 77.6% in the academic center. We recommend that a standard modified intent to treat healing rate be used to report wound outcomes to allow for consistency and comparability in measurement across providers, payers and healthcare systems. © 2017 by the Wound Healing Society.

Molecular Classifiers for Acute Kidney Transplant Rejection in Peripheral Blood by Whole Genome Gene Expression Profiling

PubMed Central

Kurian, S. M.; Williams, A. N.; Gelbart, T.; Campbell, D.; Mondala, T. S.; Head, S. R.; Horvath, S.; Gaber, L.; Thompson, R.; Whisenant, T.; Lin, W.; Langfelder, P.; Robison, E. H.; Schaffer, R. L.; Fisher, J. S.; Friedewald, J.; Flechner, S. M.; Chan, L. K.; Wiseman, A. C.; Shidban, H.; Mendez, R.; Heilman, R.; Abecassis, M. M.; Marsh, C. L.; Salomon, D. R.

2015-01-01

There are no minimally invasive diagnostic metrics for acute kidney transplant rejection (AR), especially in the setting of the common confounding diagnosis, acute dysfunction with no rejection (ADNR). Thus, though kidney transplant biopsies remain the gold standard, they are invasive, have substantial risks, sampling error issues and significant costs and are not suitable for serial monitoring. Global gene expression profiles of 148 peripheral blood samples from transplant patients with excellent function and normal histology (TX; n = 46), AR (n = 63) and ADNR (n = 39), from two independent cohorts were analyzed with DNA microarrays. We applied a new normalization tool, frozen robust multi-array analysis, particularly suitable for clinical diagnostics, multiple prediction tools to discover, refine and validate robust molecular classifiers and we tested a novel one-by-one analysis strategy to model the real clinical application of this test. Multiple three-way classifier tools identified 200 highest value probesets with sensitivity, specificity, positive predictive value, negative predictive value and area under the curve for the validation cohort ranging from 82% to 100%, 76% to 95%, 76% to 95%, 79% to 100%, 84% to 100% and 0.817 to 0.968, respectively. We conclude that peripheral blood gene expression profiling can be used as a minimally invasive tool to accurately reveal TX, AR and ADNR in the setting of acute kidney transplant dysfunction. PMID:24725967

An analysis of suicide trends in Scotland 1950-2014: comparison with England & Wales.

PubMed

Dougall, Nadine; Stark, Cameron; Agnew, Tim; Henderson, Rob; Maxwell, Margaret; Lambert, Paul

2017-12-20

Scotland has disproportionately high rates of suicide compared with England. An analysis of trends may help reveal whether rates appear driven more by birth cohort, period or age. A 'birth cohort effect' for England & Wales has been previously reported by Gunnell et al. (B J Psych 182:164-70, 2003). This study replicates this analysis for Scotland, makes comparisons between the countries, and provides information on 'vulnerable' cohorts. Suicide and corresponding general population data were obtained from the National Records of Scotland, 1950 to 2014. Age and gender specific mortality rates were estimated. Age, period and cohort patterns were explored graphically by trend analysis. A pattern was found whereby successive male birth cohorts born after 1940 experienced higher suicide rates, in increasingly younger age groups, echoing findings reported for England & Wales. Young men (aged 20-39) were found to have a marked and statistically significant increase in suicide between those in the 1960 and 1965 birth cohorts. The 1965 cohort peaked in suicide rate aged 35-39, and the subsequent 1970 cohort peaked even younger, aged 25-29; it is possible that these 1965 and 1970 cohorts are at greater mass vulnerability to suicide than earlier cohorts. This was reflected in data for England & Wales, but to a lesser extent. Suicide rates associated with male birth cohorts subsequent to 1975 were less severe, and not statistically significantly different from earlier cohorts, suggestive of an amelioration of any possible influential 'cohort' effect. Scottish female suicide rates for all age groups converged and stabilised over time. Women have not been as affected as men, with less variation in patterns by different birth cohorts and with a much less convincing corresponding pattern suggestive of a 'cohort' effect. Trend analysis is useful in identifying 'vulnerable' cohorts, providing opportunities to develop suicide prevention strategies addressing these cohorts as they age.

The Relationship Between Technical And Nontechnical Skills Within A Simulation-Based Ureteroscopy Training Environment.

PubMed

Brunckhorst, Oliver; Shahid, Shahab; Aydin, Abdullatif; Khan, Shahid; McIlhenny, Craig; Brewin, James; Sahai, Arun; Bello, Fernando; Kneebone, Roger; Shamim Khan, Muhammad; Dasgupta, Prokar; Ahmed, Kamran

2015-01-01

Little integration of technical and nontechnical skills (e.g., situational awareness, communication, decision making, teamwork, and leadership) teaching exists within surgery. We therefore aimed to (1) evaluate the relationship between these 2 skill sets within a simulation-based environment and (2) assess if certain nontechnical skill components are of particular relevance to technical performance. A prospective analysis of data acquired from a comparative study of simulation vs nonsimulation training was conducted. Half of the participants underwent training of technical and nontechnical skills within ureteroscopy, with the remaining half undergoing no training. All were assessed within a full immersion environment against both technical (time to completion, Objective Structured Assessment of Technical Skills, and task-specific checklist scores) and nontechnical parameters (Nontechnical Skills for Surgeons [NOTSS] rating scale). The data of whole and individual cohorts were analyzed using Pearson correlation coefficient. The trial took place within the Simulation and Interactive Learning Centre at Guy's Hospital, London, UK. In total, 32 novice participants with no prior practical ureteroscopy experience were included within the data analysis. A correlation was found within all outcome measures analyzed. For the whole cohort, a strong negative correlation was found between time to completion and NOTSS scores (r = -0.75, p < 0.001), with strong positive correlations identified when NOTSS scores were compared with Objective Structured Assessment of Technical Skills (r = 0.89, p < 0.001) and task-specific checklist scores (r = 0.91, p < 0.001). Similar results were observed when each cohort was analyzed separately. Finally, all individual nontechnical skill components demonstrated a strong correlation with all technical skill parameters, regardless of training. A strong correlation between technical and nontechnical performance exists, which was demonstrated to be irrespective of training received. This may suggest an inherent link between skill sets. Furthermore, all nontechnical skill sets are important in technical performance. This supports the notion that both of these skills should be trained and assessed together within 1 curriculum. Copyright © 2015 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.

A genome-wide association study of corneal astigmatism: The CREAM Consortium.

PubMed

Shah, Rupal L; Li, Qing; Zhao, Wanting; Tedja, Milly S; Tideman, J Willem L; Khawaja, Anthony P; Fan, Qiao; Yazar, Seyhan; Williams, Katie M; Verhoeven, Virginie J M; Xie, Jing; Wang, Ya Xing; Hess, Moritz; Nickels, Stefan; Lackner, Karl J; Pärssinen, Olavi; Wedenoja, Juho; Biino, Ginevra; Concas, Maria Pina; Uitterlinden, André; Rivadeneira, Fernando; Jaddoe, Vincent W V; Hysi, Pirro G; Sim, Xueling; Tan, Nicholas; Tham, Yih-Chung; Sensaki, Sonoko; Hofman, Albert; Vingerling, Johannes R; Jonas, Jost B; Mitchell, Paul; Hammond, Christopher J; Höhn, René; Baird, Paul N; Wong, Tien-Yin; Cheng, Chinfsg-Yu; Teo, Yik Ying; Mackey, David A; Williams, Cathy; Saw, Seang-Mei; Klaver, Caroline C W; Guggenheim, Jeremy A; Bailey-Wilson, Joan E

2018-01-01

To identify genes and genetic markers associated with corneal astigmatism. A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression. The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha ( PDGFRA ) gene: top SNP: rs7673984, odds ratio=1.12 (95% CI:1.08-1.16), p=5.55×10 -9 . No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans-claudin-7 ( CLDN7 ), acid phosphatase 2, lysosomal ( ACP2 ), and TNF alpha-induced protein 8 like 3 ( TNFAIP8L3 ). In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, gene-based analysis identified three novel candidate genes, CLDN7 , ACP2 , and TNFAIP8L3 , that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism.

Safety of stavudine in the treatment of HIV infection with a special focus on resource-limited settings.

PubMed

Makinson, Alain; Moing, Vincent Le; Kouanfack, Charles; Laurent, Christian; Delaporte, Eric

2008-05-01

Western randomized trials and prospective cohorts in resource-limited settings have proven virological success with stavudine-based highly active antiretroviral therapy. However, stavudine is no longer recommended in first-line treatments in these two settings due to its intrinsic toxicities and side effects. Yet it remains a cornerstone of treatment in resource-limited settings, due to lack of alternatives and its availability in generic fixed-dose combinations. To review the toxic effects of stavudine and their prevention and management strategies, especially in resource-limited settings. Data from clinical and pharmacological trials in Western countries, as well as prospective cohorts in resource-limited settings, were reviewed. Initiating or switching to less toxic nucleoside analogues whenever possible, or lowering stavudine doses to 30 mg b.i.d., is strongly recommended.

Prediction of persistent hemodynamic depression after carotid angioplasty and stenting using artificial neural network model.

PubMed

Jeon, Jin Pyeong; Kim, Chulho; Oh, Byoung-Doo; Kim, Sun Jeong; Kim, Yu-Seop

2018-01-01

To assess and compare predictive factors for persistent hemodynamic depression (PHD) after carotid artery angioplasty and stenting (CAS) using artificial neural network (ANN) and multiple logistic regression (MLR) or support vector machines (SVM) models. A retrospective data set of patients (n=76) who underwent CAS from 2007 to 2014 was used as input (training cohort) to a back-propagation ANN using TensorFlow platform. PHD was defined when systolic blood pressure was less than 90mmHg or heart rate was less 50 beats/min that lasted for more than one hour. The resulting ANN was prospectively tested in 33 patients (test cohort) and compared with MLR or SVM models according to accuracy and receiver operating characteristics (ROC) curve analysis. No significant difference in baseline characteristics between the training cohort and the test cohort was observed. PHD was observed in 21 (27.6%) patients in the training cohort and 10 (30.3%) patients in the test cohort. In the training cohort, the accuracy of ANN for the prediction of PHD was 98.7% and the area under the ROC curve (AUROC) was 0.961. In the test cohort, the number of correctly classified instances was 32 (97.0%) using the ANN model. In contrast, the accuracy rate of MLR or SVM model was both 75.8%. ANN (AUROC: 0.950; 95% CI [confidence interval]: 0.813-0.996) showed superior predictive performance compared to MLR model (AUROC: 0.796; 95% CI: 0.620-0.915, p<0.001) or SVM model (AUROC: 0.885; 95% CI: 0.725-0.969, p<0.001). The ANN model seems to have more powerful prediction capabilities than MLR or SVM model for persistent hemodynamic depression after CAS. External validation with a large cohort is needed to confirm our results. Copyright © 2017. Published by Elsevier B.V.

The cost-effectiveness of birth-cohort screening for hepatitis C antibody in U.S. primary care settings.

PubMed

Rein, David B; Smith, Bryce D; Wittenborn, John S; Lesesne, Sarah B; Wagner, Laura D; Roblin, Douglas W; Patel, Nita; Ward, John W; Weinbaum, Cindy M

2012-02-21

In the United States, hepatitis C virus (HCV) infection is most prevalent among adults born from 1945 through 1965, and approximately 50% to 75% of infected adults are unaware of their infection. To estimate the cost-effectiveness of birth-cohort screening. Cost-effectiveness simulation. National Health and Nutrition Examination Survey, U.S. Census, Medicare reimbursement schedule, and published sources. Adults born from 1945 through 1965 with 1 or more visits to a primary care provider annually. Lifetime. Societal, health care. One-time antibody test of 1945-1965 birth cohort. Numbers of cases that were identified and treated and that achieved a sustained viral response; liver disease and death from HCV; medical and productivity costs; quality-adjusted life-years (QALYs); incremental cost-effectiveness ratio (ICER). Compared with the status quo, birth-cohort screening identified 808,580 additional cases of chronic HCV infection at a screening cost of $2874 per case identified. Assuming that birth-cohort screening was followed by pegylated interferon and ribavirin (PEG-IFN+R) for treated patients, screening increased QALYs by 348,800 and costs by $5.5 billion, for an ICER of $15,700 per QALY gained. Assuming that birth-cohort screening was followed by direct-acting antiviral plus PEG-IFN+R treatment for treated patients, screening increased QALYs by 532,200 and costs by $19.0 billion, for an ICER of $35,700 per QALY saved. The ICER of birth-cohort screening was most sensitive to sustained viral response of antiviral therapy, the cost of therapy, the discount rate, and the QALY losses assigned to disease states. Empirical data on screening and direct-acting antiviral treatment in real-world clinical settings are scarce. Birth-cohort screening for HCV in primary care settings was cost-effective. Division of Viral Hepatitis, Centers for Disease Control and Prevention.

The significance of HIV 'blips' in resource-limited settings: is it the same? analysis of the treat Asia HIV Observational Database (TAHOD) and the Australian HIV Observational Database (AHOD).

PubMed

Kanapathipillai, Rupa; McManus, Hamish; Kamarulzaman, Adeeba; Lim, Poh Lian; Templeton, David J; Law, Matthew; Woolley, Ian

2014-01-01

Magnitude and frequency of HIV viral load blips in resource-limited settings, has not previously been assessed. This study was undertaken in a cohort from a high income country (Australia) known as AHOD (Australian HIV Observational Database) and another cohort from a mixture of Asian countries of varying national income per capita, TAHOD (TREAT Asia HIV Observational Database). Blips were defined as detectable VL (≥ 50 copies/mL) preceded and followed by undetectable VL (<50 copies/mL). Virological failure (VF) was defined as two consecutive VL ≥50 copies/ml. Cox proportional hazard models of time to first VF after entry, were developed. 5040 patients (AHOD n = 2597 and TAHOD n = 2521) were included; 910 (18%) of patients experienced blips. 744 (21%) and 166 (11%) of high- and middle/low-income participants, respectively, experienced blips ever. 711 (14%) experienced blips prior to virological failure. 559 (16%) and 152 (10%) of high- and middle/low-income participants, respectively, experienced blips prior to virological failure. VL testing occurred at a median frequency of 175 and 91 days in middle/low- and high-income sites, respectively. Longer time to VF occurred in middle/low income sites, compared with high-income sites (adjusted hazards ratio (AHR) 0.41; p<0.001), adjusted for year of first cART, Hepatitis C co-infection, cART regimen, and prior blips. Prior blips were not a significant predictor of VF in univariate analysis (AHR 0.97, p = 0.82). Differing magnitudes of blips were not significant in univariate analyses as predictors of virological failure (p = 0.360 for blip 50-≤1000, p = 0.309 for blip 50-≤400 and p = 0.300 for blip 50-≤200). 209 of 866 (24%) patients were switched to an alternate regimen in the setting of a blip. Despite a lower proportion of blips occurring in low/middle-income settings, no significant difference was found between settings. Nonetheless, a substantial number of participants were switched to alternative regimens in the setting of blips.

Integrating Genetic, Neuropsychological and Neuroimaging Data to Model Early-Onset Obsessive Compulsive Disorder Severity

PubMed Central

Mas, Sergi; Gassó, Patricia; Morer, Astrid; Calvo, Anna; Bargalló, Nuria; Lafuente, Amalia; Lázaro, Luisa

2016-01-01

We propose an integrative approach that combines structural magnetic resonance imaging data (MRI), diffusion tensor imaging data (DTI), neuropsychological data, and genetic data to predict early-onset obsessive compulsive disorder (OCD) severity. From a cohort of 87 patients, 56 with complete information were used in the present analysis. First, we performed a multivariate genetic association analysis of OCD severity with 266 genetic polymorphisms. This association analysis was used to select and prioritize the SNPs that would be included in the model. Second, we split the sample into a training set (N = 38) and a validation set (N = 18). Third, entropy-based measures of information gain were used for feature selection with the training subset. Fourth, the selected features were fed into two supervised methods of class prediction based on machine learning, using the leave-one-out procedure with the training set. Finally, the resulting model was validated with the validation set. Nine variables were used for the creation of the OCD severity predictor, including six genetic polymorphisms and three variables from the neuropsychological data. The developed model classified child and adolescent patients with OCD by disease severity with an accuracy of 0.90 in the testing set and 0.70 in the validation sample. Above its clinical applicability, the combination of particular neuropsychological, neuroimaging, and genetic characteristics could enhance our understanding of the neurobiological basis of the disorder. PMID:27093171

Integrated pathway analysis of nasopharyngeal carcinoma implicates the axonemal dynein complex in the Malaysian cohort.

PubMed

Chin, Yoon-Ming; Tan, Lu Ping; Abdul Aziz, Norazlin; Mushiroda, Taisei; Kubo, Michiaki; Mohd Kornain, Noor Kaslina; Tan, Geok Wee; Khoo, Alan Soo-Beng; Krishnan, Gopala; Pua, Kin-Choo; Yap, Yoke-Yeow; Teo, Soo-Hwang; Lim, Paul Vey-Hong; Nakamura, Yusuke; Lum, Chee Lun; Ng, Ching-Ching

2016-10-15

Nasopharyngeal carcinoma (NPC) is an epithelial squamous cell carcinoma on the mucosal lining of the nasopharynx. The etiology of NPC remains elusive despite many reported studies. Most studies employ a single platform approach, neglecting the cumulative influence of both the genome and transcriptome toward NPC development. We aim to employ an integrated pathway approach to identify dysregulated pathways linked to NPC. Our approach combines imputation NPC GWAS data from a Malaysian cohort as well as published expression data GSE12452 from both NPC and non-NPC nasopharynx tissues. Pathway association for GWAS data was performed using MAGENTA while for expression data, GSA-SNP was used with gene p values derived from differential expression values from GEO2R. Our study identified NPC association in the gene ontology (GO) axonemal dynein complex pathway (pGWAS-GSEA  = 1.98 × 10(-2) ; pExpr-GSEA  = 1.27 × 10(-24) ; pBonf-Combined  = 4.15 × 10(-21) ). This association was replicated in a separate cohort using gene expression data from NPC and non-NPC nasopharynx tissues (pAmpliSeq-GSEA  = 6.56 × 10(-4) ). Loss of function in the axonemal dynein complex causes impaired cilia function, leading to poor mucociliary clearance and subsequently upper or lower respiratory tract infection, the former of which includes the nasopharynx. Our approach illustrates the potential use of integrated pathway analysis in detecting gene sets involved in the development of NPC in the Malaysian cohort. © 2016 UICC.

Creatinine generation is reduced in patients requiring continuous venovenous hemodialysis and independently predicts mortality

PubMed Central

Wilson, Francis P.; Sheehan, Jessica M.; Mariani, Laura H.; Berns, Jeffrey S.

2012-01-01

Background Existing systems for grading severity of acute kidney injury (AKI) rely on a change of serum creatinine concentration over a defined time interval. The rate of change in serum creatinine increases by degree of reduction in glomerular filtration rate, but is mitigated by low creatinine generation rate (CGR). Failure to appreciate variation in CGR may lead to erroneous conclusions regarding severity of AKI and distorted predictions regarding patient outcomes based on AKI severity. Methods Cohort study of 103 patients who received continuous venovenous hemodialysis (CVVHD) over a 2-year period in a tertiary care hospital setting. Study participants entered the cohort when they were anuric, receiving a stable and uninterrupted dose of CVVHD with serum creatinine in steady state. They were followed until hospital discharge. CGR was measured based on dialyzate effluent volume and effluent creatinine concentration (prospective cohort) and via effluent volume and serum creatinine concentration (retrospective cohort). Results CGR (mean 10.5, range 1.7–22.4 mg/kg/day) was substantially lower in this patient population than what would be predicted from existing equations. Correlates of CGR in multivariable analysis included the length of hospitalization prior to measurement and presence of an oncologic diagnosis. Lower CGR was independently associated with in-hospital mortality in unadjusted analysis and after multivariable adjustment for measures of severity of illness. Conclusions Grading systems for severity of AKI fail to account for variation in CGR, limiting their ability to predict relevant outcomes. Calculation of CGR is superior to other risk metrics in predicting hospital mortality in this population. PMID:22273668

Machine Learning Meta-analysis of Large Metagenomic Datasets: Tools and Biological Insights.

PubMed

Pasolli, Edoardo; Truong, Duy Tin; Malik, Faizan; Waldron, Levi; Segata, Nicola

2016-07-01

Shotgun metagenomic analysis of the human associated microbiome provides a rich set of microbial features for prediction and biomarker discovery in the context of human diseases and health conditions. However, the use of such high-resolution microbial features presents new challenges, and validated computational tools for learning tasks are lacking. Moreover, classification rules have scarcely been validated in independent studies, posing questions about the generality and generalization of disease-predictive models across cohorts. In this paper, we comprehensively assess approaches to metagenomics-based prediction tasks and for quantitative assessment of the strength of potential microbiome-phenotype associations. We develop a computational framework for prediction tasks using quantitative microbiome profiles, including species-level relative abundances and presence of strain-specific markers. A comprehensive meta-analysis, with particular emphasis on generalization across cohorts, was performed in a collection of 2424 publicly available metagenomic samples from eight large-scale studies. Cross-validation revealed good disease-prediction capabilities, which were in general improved by feature selection and use of strain-specific markers instead of species-level taxonomic abundance. In cross-study analysis, models transferred between studies were in some cases less accurate than models tested by within-study cross-validation. Interestingly, the addition of healthy (control) samples from other studies to training sets improved disease prediction capabilities. Some microbial species (most notably Streptococcus anginosus) seem to characterize general dysbiotic states of the microbiome rather than connections with a specific disease. Our results in modelling features of the "healthy" microbiome can be considered a first step toward defining general microbial dysbiosis. The software framework, microbiome profiles, and metadata for thousands of samples are publicly available at http://segatalab.cibio.unitn.it/tools/metaml.

Mammography Among Women With Severe Mental Illness: Exploring Disparities Through a Large Retrospective Cohort Study.

PubMed

Thomas, Melanie; James, Monique; Vittinghoff, Eric; Creasman, Jennifer M; Schillinger, Dean; Mangurian, Christina

2018-01-01

This study examined mammogram screening rates among women with severe mental illness by using a socioecological framework. Because it has been shown that people with severe mental illness receive less preventive health care overall, the analysis included psychosocial predictors of mammogram screening rates in a cohort of women with severe mental illness. This retrospective cohort study (N=14,651) used existing statewide data for women ages 48-67 in California with Medicaid insurance who received treatment in the specialty mental health care system. The primary outcome of interest was evidence of breast cancer screening via mammogram. The associations of each predictor of interest with mammogram screening were evaluated by using Poisson models with robust standard errors. Across all demographic and diagnostic categories, rates of breast cancer screening in this cohort of women with severe mental illness fell below the national average. Only 26.3% (3,859/14,651) of women in the cohort received breast cancer screening in the past year. This study replicated previous findings that women with schizophrenia spectrum disorder and those with a comorbid substance use disorder are less likely to receive screening than those with other types of mental illness. In this cohort of women with severe mental illness, evidence of nonpsychiatric health care utilization was strongly associated with breast cancer screening (adjusted risk ratio=3.30, 95% confidence interval=2.61-4.16, p<.001). The findings can inform efforts to improve breast cancer screening among women with severe mental illness, such as targeted outreach to population subsets and colocation of primary care services in mental health treatment settings.

Interpretation of clinical relevance of X-chromosome copy number variations identified in a large cohort of individuals with cognitive disorders and/or congenital anomalies.

PubMed

Willemsen, Marjolein H; de Leeuw, Nicole; de Brouwer, Arjan P M; Pfundt, Rolph; Hehir-Kwa, Jayne Y; Yntema, Helger G; Nillesen, Willy M; de Vries, Bert B A; van Bokhoven, Hans; Kleefstra, Tjitske

2012-11-01

Genome-wide array studies are now routinely being used in the evaluation of patients with cognitive disorders (CD) and/or congenital anomalies (CA). Therefore, inevitably each clinician is confronted with the challenging task of the interpretation of copy number variations detected by genome-wide array platforms in a diagnostic setting. Clinical interpretation of autosomal copy number variations is already challenging, but assessment of the clinical relevance of copy number variations of the X-chromosome is even more complex. This study provides an overview of the X-Chromosome copy number variations that we have identified by genome-wide array analysis in a large cohort of 4407 male and female patients. We have made an interpretation of the clinical relevance of each of these copy number variations based on well-defined criteria and previous reports in literature and databases. The prevalence of X-chromosome copy number variations in this cohort was 57/4407 (∼1.3%), of which 15 (0.3%) were interpreted as (likely) pathogenic. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Single cell analysis of innate cytokine responses to pattern recognition receptor stimulation in children across four continents

PubMed Central

Smolen, Kinga K; Cai, Bing; Fortuno, Edgardo S; Gelinas, Laura; Larsen, Martin; Speert, David P; Chamekh, Mustapha; Kollmann, Tobias R

2014-01-01

Innate immunity instructs adaptive immunity, and suppression of innate immunity is associated with increased risk for infection. We had previously shown that whole blood cellular components from a cohort of South African children secreted significantly lower levels of most cytokines following stimulation of pattern recognition receptors (PRR) as compared to whole blood from cohorts of Ecuadorian, Belgian, or Canadian children. To begin dissecting the responsible molecular mechanisms, we now set out to identify the relevant cellular source of these differences. Across the four cohorts represented in our study, we identified significant variation in the cellular composition of whole blood; however, significant reduction of the intracellular cytokine production on the single cell level was only detected in South African childrens’ monocytes, cDC, and pDC. We also uncovered a marked reduction in polyfunctionality for each of these cellular compartments in South African children as compared to children from other continents. Together our data identify differences in cell composition as well as profoundly lower functional responses of innate cells in our cohort of South African children. A possible link between altered innate immunity and increased risk for infection or lower response to vaccines in South African infants needs to be explored. PMID:25135829

Meta-analytic framework for sparse K-means to identify disease subtypes in multiple transcriptomic studies

PubMed Central

Huo, Zhiguang; Ding, Ying; Liu, Silvia; Oesterreich, Steffi; Tseng, George

2016-01-01

Disease phenotyping by omics data has become a popular approach that potentially can lead to better personalized treatment. Identifying disease subtypes via unsupervised machine learning is the first step towards this goal. In this paper, we extend a sparse K-means method towards a meta-analytic framework to identify novel disease subtypes when expression profiles of multiple cohorts are available. The lasso regularization and meta-analysis identify a unique set of gene features for subtype characterization. An additional pattern matching reward function guarantees consistent subtype signatures across studies. The method was evaluated by simulations and leukemia and breast cancer data sets. The identified disease subtypes from meta-analysis were characterized with improved accuracy and stability compared to single study analysis. The breast cancer model was applied to an independent METABRIC dataset and generated improved survival difference between subtypes. These results provide a basis for diagnosis and development of targeted treatments for disease subgroups. PMID:27330233

Meta-analytic framework for sparse K-means to identify disease subtypes in multiple transcriptomic studies.

PubMed

Huo, Zhiguang; Ding, Ying; Liu, Silvia; Oesterreich, Steffi; Tseng, George

Disease phenotyping by omics data has become a popular approach that potentially can lead to better personalized treatment. Identifying disease subtypes via unsupervised machine learning is the first step towards this goal. In this paper, we extend a sparse K -means method towards a meta-analytic framework to identify novel disease subtypes when expression profiles of multiple cohorts are available. The lasso regularization and meta-analysis identify a unique set of gene features for subtype characterization. An additional pattern matching reward function guarantees consistent subtype signatures across studies. The method was evaluated by simulations and leukemia and breast cancer data sets. The identified disease subtypes from meta-analysis were characterized with improved accuracy and stability compared to single study analysis. The breast cancer model was applied to an independent METABRIC dataset and generated improved survival difference between subtypes. These results provide a basis for diagnosis and development of targeted treatments for disease subgroups.

2016 American College of Rheumatology/European League Against Rheumatism Criteria for Minimal, Moderate, and Major Clinical Response in Adult Dermatomyositis and Polymyositis: An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative.

PubMed

Aggarwal, Rohit; Rider, Lisa G; Ruperto, Nicolino; Bayat, Nastaran; Erman, Brian; Feldman, Brian M; Oddis, Chester V; Amato, Anthony A; Chinoy, Hector; Cooper, Robert G; Dastmalchi, Maryam; Fiorentino, David; Isenberg, David; Katz, James D; Mammen, Andrew; de Visser, Marianne; Ytterberg, Steven R; Lundberg, Ingrid E; Chung, Lorinda; Danko, Katalin; García-De la Torre, Ignacio; Song, Yeong Wook; Villa, Luca; Rinaldi, Mariangela; Rockette, Howard; Lachenbruch, Peter A; Miller, Frederick W; Vencovsky, Jiri

2017-05-01

To develop response criteria for adult dermatomyositis (DM) and polymyositis (PM). Expert surveys, logistic regression, and conjoint analysis were used to develop 287 definitions using core set measures. Myositis experts rated greater improvement among multiple pairwise scenarios in conjoint analysis surveys, where different levels of improvement in 2 core set measures were presented. The PAPRIKA (Potentially All Pairwise Rankings of All Possible Alternatives) method determined the relative weights of core set measures and conjoint analysis definitions. The performance characteristics of the definitions were evaluated on patient profiles using expert consensus (gold standard) and were validated using data from a clinical trial. The nominal group technique was used to reach consensus. Consensus was reached for a conjoint analysis-based continuous model using absolute percent change in core set measures (physician, patient, and extramuscular global activity, muscle strength, Health Assessment Questionnaire, and muscle enzyme levels). A total improvement score (range 0-100), determined by summing scores for each core set measure, was based on improvement in and relative weight of each core set measure. Thresholds for minimal, moderate, and major improvement were ≥20, ≥40, and ≥60 points in the total improvement score. The same criteria were chosen for juvenile DM, with different improvement thresholds. Sensitivity and specificity in DM/PM patient cohorts were 85% and 92%, 90% and 96%, and 92% and 98% for minimal, moderate, and major improvement, respectively. Definitions were validated in the clinical trial analysis for differentiating the physician rating of improvement (P < 0.001). The response criteria for adult DM/PM consisted of the conjoint analysis model based on absolute percent change in 6 core set measures, with thresholds for minimal, moderate, and major improvement. © 2017, American College of Rheumatology.

metaCCA: summary statistics-based multivariate meta-analysis of genome-wide association studies using canonical correlation analysis.

PubMed

Cichonska, Anna; Rousu, Juho; Marttinen, Pekka; Kangas, Antti J; Soininen, Pasi; Lehtimäki, Terho; Raitakari, Olli T; Järvelin, Marjo-Riitta; Salomaa, Veikko; Ala-Korpela, Mika; Ripatti, Samuli; Pirinen, Matti

2016-07-01

A dominant approach to genetic association studies is to perform univariate tests between genotype-phenotype pairs. However, analyzing related traits together increases statistical power, and certain complex associations become detectable only when several variants are tested jointly. Currently, modest sample sizes of individual cohorts, and restricted availability of individual-level genotype-phenotype data across the cohorts limit conducting multivariate tests. We introduce metaCCA, a computational framework for summary statistics-based analysis of a single or multiple studies that allows multivariate representation of both genotype and phenotype. It extends the statistical technique of canonical correlation analysis to the setting where original individual-level records are not available, and employs a covariance shrinkage algorithm to achieve robustness.Multivariate meta-analysis of two Finnish studies of nuclear magnetic resonance metabolomics by metaCCA, using standard univariate output from the program SNPTEST, shows an excellent agreement with the pooled individual-level analysis of original data. Motivated by strong multivariate signals in the lipid genes tested, we envision that multivariate association testing using metaCCA has a great potential to provide novel insights from already published summary statistics from high-throughput phenotyping technologies. Code is available at https://github.com/aalto-ics-kepaco anna.cichonska@helsinki.fi or matti.pirinen@helsinki.fi Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press.

metaCCA: summary statistics-based multivariate meta-analysis of genome-wide association studies using canonical correlation analysis

PubMed Central

Cichonska, Anna; Rousu, Juho; Marttinen, Pekka; Kangas, Antti J.; Soininen, Pasi; Lehtimäki, Terho; Raitakari, Olli T.; Järvelin, Marjo-Riitta; Salomaa, Veikko; Ala-Korpela, Mika; Ripatti, Samuli; Pirinen, Matti

2016-01-01

Motivation: A dominant approach to genetic association studies is to perform univariate tests between genotype-phenotype pairs. However, analyzing related traits together increases statistical power, and certain complex associations become detectable only when several variants are tested jointly. Currently, modest sample sizes of individual cohorts, and restricted availability of individual-level genotype-phenotype data across the cohorts limit conducting multivariate tests. Results: We introduce metaCCA, a computational framework for summary statistics-based analysis of a single or multiple studies that allows multivariate representation of both genotype and phenotype. It extends the statistical technique of canonical correlation analysis to the setting where original individual-level records are not available, and employs a covariance shrinkage algorithm to achieve robustness. Multivariate meta-analysis of two Finnish studies of nuclear magnetic resonance metabolomics by metaCCA, using standard univariate output from the program SNPTEST, shows an excellent agreement with the pooled individual-level analysis of original data. Motivated by strong multivariate signals in the lipid genes tested, we envision that multivariate association testing using metaCCA has a great potential to provide novel insights from already published summary statistics from high-throughput phenotyping technologies. Availability and implementation: Code is available at https://github.com/aalto-ics-kepaco Contacts: anna.cichonska@helsinki.fi or matti.pirinen@helsinki.fi Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27153689

Integrated analysis of epigenomic and genomic changes by DNA methylation dependent mechanisms provides potential novel biomarkers for prostate cancer.

PubMed

White-Al Habeeb, Nicole M A; Ho, Linh T; Olkhov-Mitsel, Ekaterina; Kron, Ken; Pethe, Vaijayanti; Lehman, Melanie; Jovanovic, Lidija; Fleshner, Neil; van der Kwast, Theodorus; Nelson, Colleen C; Bapat, Bharati

2014-09-15

Epigenetic silencing mediated by CpG methylation is a common feature of many cancers. Characterizing aberrant DNA methylation changes associated with tumor progression may identify potential prognostic markers for prostate cancer (PCa). We treated two PCa cell lines, 22Rv1 and DU-145 with the demethylating agent 5-Aza 2'-deoxycitidine (DAC) and global methylation status was analyzed by performing methylation-sensitive restriction enzyme based differential methylation hybridization strategy followed by genome-wide CpG methylation array profiling. In addition, we examined gene expression changes using a custom microarray. Gene Set Enrichment Analysis (GSEA) identified the most significantly dysregulated pathways. In addition, we assessed methylation status of candidate genes that showed reduced CpG methylation and increased gene expression after DAC treatment, in Gleason score (GS) 8 vs. GS6 patients using three independent cohorts of patients; the publically available The Cancer Genome Atlas (TCGA) dataset, and two separate patient cohorts. Our analysis, by integrating methylation and gene expression in PCa cell lines, combined with patient tumor data, identified novel potential biomarkers for PCa patients. These markers may help elucidate the pathogenesis of PCa and represent potential prognostic markers for PCa patients.

Frequency of debridements and time to heal: a retrospective cohort study of 312 744 wounds.

PubMed

Wilcox, James R; Carter, Marissa J; Covington, Scott

2013-09-01

Chronic wounds usually get trapped in the inflammatory stage of wound healing; however, aggressive debridement transforms chronic wounds to acute wounds and therefore complete healing. To investigate healing outcomes and debridement frequency in a large wound data set. Retrospective cohort study. Data collected from 525 wound care centers from June 1, 2008, through June 31, 2012, using a web-based clinical management system. Referred sample of 154 644 patients with 312 744 wounds of all causes (of an initial data set of 364 534 wounds) participated. A total of 47.1% were male. Median age was 69 years (age range, 19-112 years), with 59.2% having one wound. Eligibility criteria included age older than 18 years, receiving at least 1 debridement, and having been discharged from the system. Advanced therapeutic treatment was ineligible. Because of incomplete, questionable, or ineligible data, 57 190 wounds were not included. Most wounds were diabetic foot ulcers (19.0%), venous leg ulcers (26.1%), and pressure ulcers (16.2%). Debridement (removal of necrotic tissue and foreign bodies from the wound) at different frequencies. Wound healing (completely epithelialized with dimensions at 0 × 0 × 0 cm). A total of 70.8% of wounds healed. The median number of debridements was 2 (range, 1-138). Frequent debridement healed more wounds in a shorter time (P <  .001). In regression analysis, significant variables included male sex, physician category, wound type, increased patient age, and increased wound age, area, and depth. The odds ratio varied considerably for each variable. The more frequent the debridements, the better the healing outcome. Although limited by retrospective data, this study's strength was the analysis of the largest wound data set to date.

Hepatitis C in HIV-infected individuals: a systematic review and meta-analysis of estimated prevalence in Africa.

PubMed

Azevedo, Tiago Castro Lopes; Zwahlen, Marcel; Rauch, Andri; Egger, Matthias; Wandeler, Gilles

2016-01-01

Although hepatitis C virus (HCV) screening is recommended for all HIV-infected patients initiating antiretroviral therapy, data on epidemiologic characteristics of HCV infection in resource-limited settings are scarce. We searched PubMed and EMBASE for studies assessing the prevalence of HCV infection among HIV-infected individuals in Africa and extracted data on laboratory methods used. Prevalence estimates from individual studies were combined for each country using random-effects meta-analysis. The importance of study design, population and setting as well as type of test (anti-HCV antibody tests and polymerase chain reactions) was examined with meta-regression. Three randomized controlled trials, 28 cohort studies and 121 cross-sectional analyses with 108,180 HIV-infected individuals from 35 countries were included. The majority of data came from outpatient populations (55%), followed by blood donors (15%) and pregnant women (14%). Based on estimates from 159 study populations, anti-HCV positivity prevalence ranged between 3.3% (95% confidence interval (CI) 1.8-4.7) in Southern Africa and 42.3% (95% CI 4.1-80.5) in North Africa. Study design, type of setting and age distribution did not influence this prevalence significantly. The prevalence of replicating HCV infection, estimated from data of 29 cohorts, was 2.0% (95% CI 1.5-2.6). Ten studies from nine countries reported the HCV genotype of 74 samples, 53% were genotype 1, 24% genotype 2, 14% genotype 4 and 9% genotypes 3, 5 or 6. The prevalence of anti-HCV antibodies is high in HIV-infected patients in Africa, but replicating HCV infection is rare and varies widely across countries.

Molecular Classification Substitutes for the Prognostic Variables Stage, Age, and MYCN Status in Neuroblastoma Risk Assessment.

PubMed

Rosswog, Carolina; Schmidt, Rene; Oberthuer, André; Juraeva, Dilafruz; Brors, Benedikt; Engesser, Anne; Kahlert, Yvonne; Volland, Ruth; Bartenhagen, Christoph; Simon, Thorsten; Berthold, Frank; Hero, Barbara; Faldum, Andreas; Fischer, Matthias

2017-12-01

Current risk stratification systems for neuroblastoma patients consider clinical, histopathological, and genetic variables, and additional prognostic markers have been proposed in recent years. We here sought to select highly informative covariates in a multistep strategy based on consecutive Cox regression models, resulting in a risk score that integrates hazard ratios of prognostic variables. A cohort of 695 neuroblastoma patients was divided into a discovery set (n=75) for multigene predictor generation, a training set (n=411) for risk score development, and a validation set (n=209). Relevant prognostic variables were identified by stepwise multivariable L1-penalized least absolute shrinkage and selection operator (LASSO) Cox regression, followed by backward selection in multivariable Cox regression, and then integrated into a novel risk score. The variables stage, age, MYCN status, and two multigene predictors, NB-th24 and NB-th44, were selected as independent prognostic markers by LASSO Cox regression analysis. Following backward selection, only the multigene predictors were retained in the final model. Integration of these classifiers in a risk scoring system distinguished three patient subgroups that differed substantially in their outcome. The scoring system discriminated patients with diverging outcome in the validation cohort (5-year event-free survival, 84.9±3.4 vs 63.6±14.5 vs 31.0±5.4; P<.001), and its prognostic value was validated by multivariable analysis. We here propose a translational strategy for developing risk assessment systems based on hazard ratios of relevant prognostic variables. Our final neuroblastoma risk score comprised two multigene predictors only, supporting the notion that molecular properties of the tumor cells strongly impact clinical courses of neuroblastoma patients. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Plasma Biomarkers Discriminate Clinical Forms of Multiple Sclerosis

PubMed Central

Tejera-Alhambra, Marta; Casrouge, Armanda; de Andrés, Clara; Seyfferth, Ansgar; Ramos-Medina, Rocío; Alonso, Bárbara; Vega, Janet; Fernández-Paredes, Lidia; Albert, Matthew L.; Sánchez-Ramón, Silvia

2015-01-01

Multiple sclerosis, the most common cause of neurological disability in young population after trauma, represents a significant public health burden. Current challenges associated with management of multiple sclerosis (MS) patients stem from the lack of biomarkers that might enable stratification of the different clinical forms of MS and thus prompt treatment for those patients with progressive MS, for whom there is currently no therapy available. In the present work we analyzed a set of thirty different plasma cytokines, chemokines and growth factors present in circulation of 129 MS patients with different clinical forms (relapsing remitting, secondary progressive and primary progressive MS) and 53 healthy controls, across two independent cohorts. The set of plasma analytes was quantified with Luminex xMAP technology and their predictive power regarding clinical outcome was evaluated both individually using ROC curves and in combination using logistic regression analysis. Our results from two independent cohorts of MS patients demonstrate that the divergent clinical and histology-based MS forms are associated with distinct profiles of circulating plasma protein biomarkers, with distinct signatures being composed of chemokines and growth/angiogenic factors. With this work, we propose that an evaluation of a set of 4 circulating biomarkers (HGF, Eotaxin/CCL11, EGF and MIP-1β/CCL4) in MS patients might serve as an effective tool in the diagnosis and more personalized therapeutic targeting of MS patients. PMID:26039252

A comparative study of the risk profile of hemodialysis patients in a for profit network and in two regional registries of the Italian Society of Nephrology.

PubMed

Postorino, Maurizio; Amato, Claudia; Mancini, Elena; Carioni, Paola; D'Arrigo, Graziella; Di Benedetto, Attilio; Cerino, Fabrizio; Marino, Carmela; Vilasi, Antonio; Tripepi, Giovanni; Stuard, Stefano; Capasso, Giovanbattista; Santoro, Antonio; Zoccali, Carmine

2018-02-01

In 2013, the Italian Society of Nephrology joined forces with Nephrocare-Italy to create a clinical research cohort of patients on file in the data-rich clinical management system (EUCLID) of this organization for the performance of observational studies in the hemodialysis (HD) population. To see whether patients in EUCLID are representative of the HD population in Italy, we set out to compare the whole EUCLID population with patients included in the regional HD registries in Emilia-Romagna (Northern Italy) and in Calabria (Southern Italy), the sole regions in Italy which have systematically collected an enlarged clinical data set allowing comparison with the data-rich EUCLID system. An analysis of prevalent and incident patients in 2010 and 2011 showed that EUCLID patients had a lower prevalence of coronary heart disease, peripheral vascular disease, heart failure, valvular heart disease, liver disease, peptic ulcer and other comorbidities and risk factors and a higher fractional urea clearance (Kt/V) than those in the Emilia Romagna and Calabria registries. Accordingly, survival analysis showed a lower mortality risk in the EUCLID 2010 and 2011 cohorts than in the combined two regional registries in the corresponding years: for 2010, hazard ratio (HR) EUCLID vs. Regional registries: 0.80 [95% confidence interval: 0.71-0.90]; for 2011, HR: 0.76 [0.65-0.90]. However, this difference was nullified by statistical adjustment for the difference in comorbidities and risk factors, indicating that the longer survival in the EUCLID database was attributable to the lower risk profile of patients included in that database. This preliminary analysis sets the stage for future observational studies and indicates that appropriate adjustment for difference in comorbidities and risk factors is needed to generalize to the Italian HD population analyses based on the data-rich EUCLID database.

The prevalence of patellofemoral osteoarthritis: a systematic review and meta-analysis.

PubMed

Kobayashi, S; Pappas, E; Fransen, M; Refshauge, K; Simic, M

2016-10-01

To determine the prevalence of radiographic patellofemoral osteoarthritis (OA) from population- and symptom-based cohorts and to evaluate if knee pain, physical function and quality of life (QOL) differ between people with isolated patellofemoral OA, isolated tibiofemoral OA and combined patellofemoral and tibiofemoral OA. Terms associated with "patellofemoral OA", "prevalence" and "clinical features" were used to search Medline, EMBASE, CINAHL, SCOPUS, AMED and Web of Science databases with no language restriction' from inception to August 2014. Two independent reviewers screened papers for eligibility. Studies were included if they reported prevalence of compartmental patterns of radiographic knee OA in population- or symptom-based cohorts. Studies were excluded if they evaluated a targeted sample (e.g., occupation-specific participants) or repeated already reported data from the same cohorts. Point prevalence estimates of patellofemoral OA were extracted from eligible studies, pooled and quantitatively analysed. A critical appraisal tool was used to evaluate methodological quality. The search yielded 1891 records. The inclusion criteria were met by 32 studies. The crude prevalence of patellofemoral OA was 25% in the population-based cohorts (aged >20 years) and 39% in the symptom-based cohorts (aged >30 years). Eight studies reported knee pain, physical function and QOL in people with different compartmental disease; however no significant differences were found. These findings confirm the substantial prevalence of patellofemoral OA, demonstrating the need to specifically consider the patellofemoral joint in knee OA research and clinical settings. Copyright © 2016. Published by Elsevier Ltd.

Development of quantitative exposure data for a pooled exposure-response analysis of 10 silica cohorts.

PubMed

Mannetje, Andrea 't; Steenland, Kyle; Checkoway, Harvey; Koskela, Riitta-Sisko; Koponen, Matti; Attfield, Michael; Chen, Jingqiong; Hnizdo, Eva; DeKlerk, Nicholas; Dosemeci, Mustafa

2002-08-01

Comprehensive quantitative silica exposure estimates over time, measured in the same units across a number of cohorts, would make possible a pooled exposure-response analysis for lung cancer. Such an analysis would help clarify the continuing controversy regarding whether silica causes lung cancer. Existing quantitative exposure data for 10 silica-exposed cohorts were retrieved from the original investigators. Occupation- and time-specific exposure estimates were either adopted/adapted or developed for each cohort, and converted to milligram per cubic meter (mg/m(3)) respirable crystalline silica. Quantitative exposure assignments were typically based on a large number (thousands) of raw measurements, or otherwise consisted of exposure estimates by experts (for two cohorts). Median exposure level of the cohorts ranged between 0.04 and 0.59 mg/m(3) respirable crystalline silica. Exposure estimates were partially validated via their successful prediction of silicosis in these cohorts. Existing data were successfully adopted or modified to create comparable quantitative exposure estimates over time for 10 silica-exposed cohorts, permitting a pooled exposure-response analysis. The difficulties encountered in deriving common exposure estimates across cohorts are discussed. Copyright 2002 Wiley-Liss, Inc.

Symptom dimensions and subgroups in childhood-onset schizophrenia.

PubMed

Craddock, Kirsten E S; Zhou, Xueping; Liu, Siyuan; Gochman, Peter; Dickinson, Dwight; Rapoport, Judith L

2017-11-13

This study investigated symptom dimensions and subgroups in the National Institute of Mental Health (NIMH) childhood-onset schizophrenia (COS) cohort and their similarities to adult-onset schizophrenia (AOS) literature. Scores from the Scales for the Assessment of Positive and Negative Symptoms (SAPS & SANS) from 125 COS patients were assessed for fit with previously established symptom dimensions from AOS literature using confirmatory factor analysis (CFA). K-means cluster analysis of each individual's scores on the best fitting set of dimensions was used to form patient clusters, which were then compared using demographic and clinical data. CFA showed the SAPS & SANS data was well suited to a 2-dimension solution, including positive and negative dimensions, out of five well established models. Cluster analysis identified three patient groups characterized by different dimension scores: (1) low scores on both dimensions, (2) high negative, low positive scores, and (3) high scores on both dimensions. These groups had different Full scale IQ, Children's Global Assessment Scale (CGAS) scores, ages of onset, and prevalence of some co-morbid behavior disorders (all p<3.57E-03). Our analysis found distinct symptom-based subgroups within the NIMH COS cohort using an established AOS symptom structure. These findings confirm the heterogeneity of COS and were generally consistent with AOS literature. Published by Elsevier B.V.

Detergent protease exposure and respiratory disease: case-referent analysis of a retrospective cohort.

PubMed

Brant, A; Upchurch, S; van Tongeren, M; Zekveld, C; Helm, J; Barnes, F; Newman Taylor, A J; Cullinan, P

2009-11-01

To examine the relationship between protease exposure and respiratory disease in a cohort of detergent enzyme manufacturers. Case-referent analysis of a cohort of employees working in a European detergent factory between 1989 and 2002. Cases with new lower or upper respiratory disease were ascertained by examination of occupational health records and matched to referents on date of first employment. Personal exposures to airborne detergent protease were estimated, using a job exposure matrix, from >12,000 measurements taken in the factory during the period of study. We found clear, monotonic relationships between estimated protease exposure and both lower and upper respiratory disease. After control for age, sex and smoking, the odds ratio of lower respiratory disease was significantly elevated (1.98, 95% CI 1.04 to 3.79) in those employees working in jobs in the highest quartile of protease exposure (geometric mean 7.9 ng x m(-3)). For employees with upper respiratory disease, the risk was significantly elevated at a lower level of estimated protease exposure (geometric mean 2.3 ng x m(-3)). These findings provide strong evidence of an association between detergent enzyme exposure and the development of respiratory disease in an occupational setting. Using the routinely collected information on specific sensitisation and the close attention to workplace exposures that are characteristic of this industry, it should be possible to derive meaningful occupational exposure standards for most detergent enzymes.

Daily diaries of respiratory symptoms and air pollution: Methodological issues and results

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

Schwartz, J.; Wypij, D.; Dockery D.

1991-01-01

Daily diaries of respiratory symptoms are a powerful technique for detecting acute effects of air pollution exposure. While conceptually simple, these diary studies can be difficult to analyze. The daily symptom rates are highly correlated, even after adjustment for covariates, and this lack of independence must be considered in the analysis. Possible approaches include the use of incidence instead of prevalence rates and autoregressive models. Heterogeneity among subjects also induces dependencies in the data. These can be addressed by stratification and by two-stage models such as those developed by Korn and Whittemore. These approaches have been applied to two datamore » sets: a cohort of school children participating in the Harvard Six Cities Study and a cohort of student nurses in Los Angeles. Both data sets provide evidence of autocorrelation and heterogeneity. Controlling for autocorrelation corrects the precision estimates, and because diary data are usually positively autocorrelated, this leads to larger variance estimates. Controlling for heterogeneity among subjects appears to increase the effect sizes for air pollution exposure. Preliminary results indicate associations between sulfur dioxide and cough incidence in children and between nitrogen dioxide and phlegm incidence in student nurses.« less

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

PubMed

Cordell, Heather J; Han, Younghun; Mells, George F; Li, Yafang; Hirschfield, Gideon M; Greene, Casey S; Xie, Gang; Juran, Brian D; Zhu, Dakai; Qian, David C; Floyd, James A B; Morley, Katherine I; Prati, Daniele; Lleo, Ana; Cusi, Daniele; Gershwin, M Eric; Anderson, Carl A; Lazaridis, Konstantinos N; Invernizzi, Pietro; Seldin, Michael F; Sandford, Richard N; Amos, Christopher I; Siminovitch, Katherine A

2015-09-22

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

Multi-Omics Factor Analysis-a framework for unsupervised integration of multi-omics data sets.

PubMed

Argelaguet, Ricard; Velten, Britta; Arnol, Damien; Dietrich, Sascha; Zenz, Thorsten; Marioni, John C; Buettner, Florian; Huber, Wolfgang; Stegle, Oliver

2018-06-20

Multi-omics studies promise the improved characterization of biological processes across molecular layers. However, methods for the unsupervised integration of the resulting heterogeneous data sets are lacking. We present Multi-Omics Factor Analysis (MOFA), a computational method for discovering the principal sources of variation in multi-omics data sets. MOFA infers a set of (hidden) factors that capture biological and technical sources of variability. It disentangles axes of heterogeneity that are shared across multiple modalities and those specific to individual data modalities. The learnt factors enable a variety of downstream analyses, including identification of sample subgroups, data imputation and the detection of outlier samples. We applied MOFA to a cohort of 200 patient samples of chronic lymphocytic leukaemia, profiled for somatic mutations, RNA expression, DNA methylation and ex vivo drug responses. MOFA identified major dimensions of disease heterogeneity, including immunoglobulin heavy-chain variable region status, trisomy of chromosome 12 and previously underappreciated drivers, such as response to oxidative stress. In a second application, we used MOFA to analyse single-cell multi-omics data, identifying coordinated transcriptional and epigenetic changes along cell differentiation. © 2018 The Authors. Published under the terms of the CC BY 4.0 license.

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

Differentials and income-related inequalities in maternal depression during the first two years after childbirth: birth cohort studies from Brazil and the UK.

PubMed

Matijasevich, Alicia; Golding, Jean; Smith, George Davey; Santos, Iná S; Barros, Aluísio Jd; Victora, Cesar G

2009-06-05

Depression is a prevalent health problem among women during the childbearing years. To obtain a more accurate global picture of maternal postnatal depression, studies that explore maternal depression with comparable measurements are needed. The aims of the study are: (1) to compare the prevalence of maternal depression in the first and second year postpartum between a UK and Brazilian birth cohort study; (2) to explore the extent to which variations in the rates were explained by maternal and infant characteristics, and (3) to investigate income-related inequalities in maternal depression after childbirth in both settings. Population-based birth cohort studies were carried out in Avon, UK in 1991 (ALSPAC) and in the city of Pelotas, Brazil in 2004, where 13 798 and 4109 women were analysed, respectively. Self-completion questionnaires were used in the ALSPAC study while questionnaires completed by interviewers were used in the Pelotas cohort study. Three repeated measures of maternal depression were obtained using the Edinburgh Postnatal Depression Scale in the first and second year after delivery in each cohort. Unadjusted and adjusted analyses were carried out. The Relative index of Inequality was used for the analysis of income-relate inequalities so that results were comparable between cohorts. At both the second and third time assessments, the likelihood of being depressed was higher among women from the Pelotas cohort study. These differences were not completely explained by differences in maternal and infant characteristics. Income-related inequalities in maternal depression after childbirth were high and of similar magnitude in both cohort studies at the three time assessments. The burden of maternal depression after childbirth varies between and within populations. Strategies to reduce income-related inequalities in maternal depression should be targeted to low-income women in both developed and developing countries.

Understanding the Disease Course and Therapeutic Benefit of Tafamidis Across Real-World Studies of Hereditary Transthyretin Amyloidosis with Polyneuropathy: A Proof of Concept for Integrative Data Analytic Approaches.

PubMed

Serrano, Daniel; Atzinger, Christopher B; Botteman, Marc F

2018-06-01

Hereditary transthyretin (TTR) amyloidosis with polyneuropathy (hATTR-PN) is a rare, autosomal dominant amyloidosis characterized primarily by progressive ascending sensorimotor neuropathy often associated with  autonomic involvement. hATTR-PN is caused by a mutation in the TTR gene leading to protein misfolding and amyloid accumulation in peripheral nerves and vital organs. The latest global prevalence estimates point to 10,000 cases worldwide, with an upper end of about 40,000. Tafamidis has been approved in over 40 countries for delaying neurologic disease progression in early-stage hATTR-PN. Multiple observational studies have examined clinical outcomes in hATTR-PN patients treated with tafamidis in the routine clinical setting. Integrative data analysis (IDA) is a technique for optimally constructing synthetic treatment and control cohorts from multiple independent studies, which allows meta-analysis of patient-level data. Herein, we provide a proof of concept for the application of IDA to real-world and natural history hATTR-PN data. IDA permits increased understanding of outcomes in tafamidis-treated and untreated persons with hATTR-PN by optimally pooling all available information. Summary statistics corresponding to the Neuropathy Impairment Score-Lower Limb (NIS-LL) from five published studies were pooled, converted to change from baseline means and variances, and analyzed using IDA. IDA-based synthetic cohorts were generated by averaging across studies stratified on treatment versus control cohort. Trends in change from baseline in each study and the corresponding synthetic cohorts were plotted. Patient-level data were simulated from the synthetic cohort trends in a Monte Carlo simulation to highlight the ability to contrast synthetic cohort trends using the mixed model for repeated measures (MMRM). The average sample size among the five studies was 71 (37-128) patients. The average NIS-LL trends indicated that tafamidis-treated patients experienced slower progression in neuropathy compared to untreated patients. Synthetic cohort trends reflected the trends observed in the contributing studies, while simultaneously shrinking the width of corresponding confidence bands. Monte Carlo simulation results demonstrated precise recovery of the synthetic cohort and time-dependent simulated NIS-LL means by the MMRM. This proof of concept demonstrates the utility of IDA-based synthetic cohorts for increased precision in characterizing and testing hypotheses about treatment outcomes and prognosis in hATTR-PN. Pfizer. Plain language summary available for this article.

Team-based simulations for new surgeons: Does early and often make a difference?

PubMed

AbdelFattah, Kareem R; Spalding, M Chance; Leshikar, David; Gardner, Aimee K

2018-04-01

Current work hour restrictions and the expansion of requirements for surgery residents has led to decreased time on high-acuity rotations such as trauma and acute care surgery. In an effort to improve resident competency, we examined the efficacy of a new team-based trauma curriculum for postgraduate year 1 (PGY1) residents. After completing required Advanced Trauma Life Support certification, PGY1s participated in a series of trauma simulations in 3-person teams from June to August. Scenarios were created to develop skills related to trauma management, teamwork, and communication. Each simulation was followed by video-based debriefing with a faculty facilitator. Clinical performance on a 1-month trauma rotation during the year was assessed by trauma faculty using a 24-item evaluation assessing management of acutely ill patients, leadership, communication, cooperation, and professionalism on a 1 (poor) to 5 (very effective) scale. Performance metrics of this intern class were compared with 2 years of previous cohorts who had not participated in any trauma-focused simulation curricula. One-way analysis of variance was used to examine differences in performance ratings across groups. The 2015 intern class (n = 30) each participated in 6 scenarios during their first 2 months in residency. Trauma as intended specialty and performance on preinternship Advanced Trauma Life Support course were similar across 2013, 2014, and 2015 cohorts. Average performance on the trauma rotation was 3.55 ± 0.56 for the 2013 cohort (n = 11), 3.50 ± 0.57 for the 2014 cohort (n = 11), and 4.35 ± 0.68 for the 2015 cohort (n = 12). Post hoc analyses indicated no difference between means of the 2013 and 2014 cohort. However, the mean of the 2015 cohort was statistically significantly better than both the 2013 cohort (P < .01) and the 2014 cohort (P < .01). Trauma-focused simulation improved PGY1 faculty ratings of performance in the clinical setting compared with previous cohorts with no such simulation experience. Adoption of these curricula is both feasible and beneficial. Copyright © 2017 Elsevier Inc. All rights reserved.

Questionnaire layout and wording influence prevalence and risk estimates of respiratory symptoms in a population cohort

PubMed Central

Ekerljung, Linda; Rönmark, Eva; Lötvall, Jan; Wennergren, Göran; Torén, Kjell; Lundbäck, Bo

2013-01-01

Objective Results of epidemiological studies are greatly influenced by the chosen methodology. The study aims to investigate how two frequently used questionnaires (Qs), with partly different layout, influence the prevalence of respiratory symptoms. Study Design and Setting A booklet containing two Qs, the Global Allergy and Asthma European Network Q and the Obstructive Lung Disease in Northern Sweden Q, was mailed to 30 000 subjects aged 16–75 years in West Sweden; 62% responded. Sixteen questions were included in the analysis: seven identical between the Qs, four different in set-up and five with the same layout but different wording. Comparisons were made using differences in proportions, observed agreement and Kappa statistics. Results Identical questions yielded similar prevalences with high observed agreement and kappa values. Questions with different set-up or differences in wording resulted in significantly different prevalences with lower observed agreement and kappa values. In general, the use of follow-up questions, excluding subjects answering no to the initial question, resulted in 2.9–6.7% units lower prevalence. Conclusion The question set-up has great influences on epidemiological results, and specifically questions that are set up to be excluded based on a previous no answer leads to lower prevalence compared with detached questions. Therefore, Q layout and exact wording of questions has to be carefully considered when comparing studies. Please cite this paper as: Ekerljung L, Rönmark E, Lötvall J, Wennergren G, Torén K and Lundbäck B. Questionnaire layout and wording influence prevalence and risk estimates of respiratory symptoms in a population cohort. Clin Respir J 2013; 7: 53–63. PMID:22243692

Comprehensive profiling of DNA repair defects in breast cancer identifies a novel class of endocrine therapy resistance drivers.

PubMed

Anurag, Meenakshi; Punturi, Nindo; Hoog, Jeremy; Bainbridge, Matthew N; Ellis, Matthew J; Haricharan, Svasti

2018-05-23

This study was undertaken to conduct a comprehensive investigation of the role of DNA damage repair (DDR) defects in poor outcome ER+ disease. Expression and mutational status of DDR genes in ER+ breast tumors were correlated with proliferative response in neoadjuvant aromatase inhibitor therapy trials (discovery data set), with outcomes in METABRIC, TCGA and Loi data sets (validation data sets), and in patient derived xenografts. A causal relationship between candidate DDR genes and endocrine treatment response, and the underlying mechanism, was then tested in ER+ breast cancer cell lines. Correlations between loss of expression of three genes: CETN2 (p<0.001) and ERCC1 (p=0.01) from the nucleotide excision repair (NER) and NEIL2 (p=0.04) from the base excision repair (BER) pathways were associated with endocrine treatment resistance in discovery data sets, and subsequently validated in independent patient cohorts. Complementary mutation analysis supported associations between mutations in NER and BER pathways and reduced endocrine treatment response. A causal role for CETN2, NEIL2 and ERCC1 loss in intrinsic endocrine resistance was experimentally validated in ER+ breast cancer cell lines, and in ER+ patient-derived xenograft models. Loss of CETN2, NEIL2 or ERCC1 induced endocrine treatment response by dysregulating G1/S transition, and therefore, increased sensitivity to CDK4/6 inhibitors. A combined DDR signature score was developed that predicted poor outcome in multiple patient cohorts. This report identifies DDR defects as a new class of endocrine treatment resistance drivers and indicates new avenues for predicting efficacy of CDK4/6 inhibition in the adjuvant treatment setting. Copyright ©2018, American Association for Cancer Research.

Epidemiology of Hepatitis C Virus in Pennsylvania State Prisons, 2004–2012: Limitations of 1945–1965 Birth Cohort Screening in Correctional Settings

PubMed Central

Mahowald, Madeline K.; Scharff, Nicholas; Flanigan, Timothy P.; Beckwith, Curt G.; Zaller, Nickolas D.

2014-01-01

Objectives. We described hepatitis C virus antibody (anti-HCV) prevalence in a state prison system and retrospectively evaluated the case-finding performance of targeted testing of the 1945 to 1965 birth cohort in this population. Methods. We used observational data from universal testing of Pennsylvania state prison entrants (June 2004–December 2012) to determine anti-HCV prevalence by birth cohort. We compared anti-HCV prevalence and the burden of anti-HCV in the 1945 to 1965 birth cohort with that in all other birth years. Results. Anti-HCV prevalence among 101 727 adults entering prison was 18.1%. Prevalence was highest among those born from 1945 to 1965, but most anti-HCV cases were in people born after 1965. Targeted testing of the 1945 to 1965 birth cohort would have identified a decreasing proportion of cases with time. Conclusions. HCV is endemic in correctional populations. Targeted testing of the 1945 to 1965 birth cohort would produce a high yield of positive test results but would identify only a minority of cases. We recommend universal anti-HCV screening in correctional settings to allow for maximum case identification, secondary prevention, and treatment of affected prisoners. PMID:24825235

Assessment of Gene-by-Sex Interaction Effect on Bone Mineral Density

PubMed Central

Liu, Ching-Ti; Estrada, Karol; Yerges-Armstrong, Laura M.; Amin, Najaf; Evangelou, Evangelos; Li, Guo; Minster, Ryan L.; Carless, Melanie A.; Kammerer, Candace M.; Oei, Ling; Zhou, Yanhua; Alonso, Nerea; Dailiana, Zoe; Eriksson, Joel; García-Giralt, Natalia; Giroux, Sylvie; Husted, Lise Bjerre; Khusainova, Rita I.; Koromila, Theodora; Kung, Annie WaiChee; Lewis, Joshua R.; Masi, Laura; Mencej-Bedrac, Simona; Nogues, Xavier; Patel, Millan S.; Prezelj, Janez; Richards, J Brent; Sham, Pak Chung; Spector, Timothy; Vandenput, Liesbeth; Xiao, Su-Mei; Zheng, Hou-Feng; Zhu, Kun; Balcells, Susana; Brandi, Maria Luisa; Frost, Morten; Goltzman, David; González-Macías, Jesús; Karlsson, Magnus; Khusnutdinova, Elza K.; Kollia, Panagoula; Langdahl, Bente Lomholt; Ljunggren, Östen; Lorentzon, Mattias; Marc, Janja; Mellström, Dan; Ohlsson, Claes; Olmos, José M.; Ralston, Stuart H.; Riancho, José A.; Rousseau, François; Urreizti, Roser; Van Hul, Wim; Zarrabeitia, María T.; Castano-Betancourt, Martha; Demissie, Serkalem; Grundberg, Elin; Herrera, Lizbeth; Kwan, Tony; Medina-Gómez, Carolina; Pastinen, Tomi; Sigurdsson, Gunnar; Thorleifsson, Gudmar; vanMeurs, Joyce B.J.; Blangero, John; Hofman, Albert; Liu, Yongmei; Mitchell, Braxton D.; O’Connell, Jeffrey R.; Oostra, Ben A.; Rotter, Jerome I; Stefansson, Kari; Streeten, Elizabeth A.; Styrkarsdottir, Unnur; Thorsteinsdottir, Unnur; Tylavsky, Frances A.; Uitterlinden, Andre; Cauley, Jane A.; Harris, Tamara B.; Ioannidis, John P.A.; Psaty, Bruce M.; Robbins, John A; Zillikens, M. Carola; vanDuijn, Cornelia M.; Prince, Richard L.; Karasik, David; Rivadeneira, Fernando; Kiel, Douglas P.; Cupples, L. Adrienne; Hsu, Yi-Hsiang

2012-01-01

Background Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed eQTL analysis and bioinformatics network analysis. Methods We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS-) and femoral neck (FN-) BMD, in 25,353 individuals from eight cohorts. In a second stage, we followed up the 12 top SNPs (P<1×10−5) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. Results We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 & p-value = 3.0×10−5; female effect = −0.007 & p-value=3.3×10−2) and eleven suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (P<5×10−8) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Conclusion Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found influencing BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP. PMID:22692763

Physical Examination-Indicated Cerclage: A Systematic Review and Meta-analysis.

PubMed

Ehsanipoor, Robert M; Seligman, Neil S; Saccone, Gabriele; Szymanski, Linda M; Wissinger, Christina; Werner, Erika F; Berghella, Vincenzo

2015-07-01

To estimate the effectiveness of physical examination-indicated cerclage in the setting of second-trimester cervical dilatation by systematic review and meta-analysis of published studies. We searched MEDLINE, EMBASE, Scopus, ClinicalTrials.gov, Web of Science, and the Cochrane Library for studies published between 1966 and 2014 that evaluated cervical cerclage for the treatment of cervical insufficiency. The search yielded 6,314 citations. We included cohort studies and randomized controlled trials comparing cerclage placement with expectant management of women with cervical dilatation between 14 and 27 weeks of gestation. Two investigators independently reviewed each citation for inclusion or exclusion and discordant decisions were arbitrated by a third reviewer. Summary estimates were reported as the mean difference and 95% confidence interval (CI) for continuous variables or relative risk and with 95% CI for dichotomous outcomes. Fixed- and random-effects meta-analysis was used, depending on heterogeneity. Ten studies met inclusion criteria and were included in the final analysis. One was a randomized controlled trial, two were prospective cohort studies, and the remaining seven were retrospective cohort studies. Of the 757 women, 485 (64%) underwent physical examination-indicated cerclage placement and 272 (36%) were expectantly managed. Cerclage was associated with increased neonatal survival (71% compared with 43%; relative risk 1.65, 95% CI 1.19-2.28) and prolongation of pregnancy (mean difference 33.98 days, 95% CI 17.88-50.08). Physical examination-indicated cerclage is associated with a significant increase in neonatal survival and prolongation of pregnancy of approximately 1 month when compared with no such cerclage. The strength of this conclusion is limited by the potential for bias in the included studies.

Association of genome-wide variation with the risk of incident heart failure in adults of European and African ancestry: a prospective meta-analysis from the cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium.

PubMed

Smith, Nicholas L; Felix, Janine F; Morrison, Alanna C; Demissie, Serkalem; Glazer, Nicole L; Loehr, Laura R; Cupples, L Adrienne; Dehghan, Abbas; Lumley, Thomas; Rosamond, Wayne D; Lieb, Wolfgang; Rivadeneira, Fernando; Bis, Joshua C; Folsom, Aaron R; Benjamin, Emelia; Aulchenko, Yurii S; Haritunians, Talin; Couper, David; Murabito, Joanne; Wang, Ying A; Stricker, Bruno H; Gottdiener, John S; Chang, Patricia P; Wang, Thomas J; Rice, Kenneth M; Hofman, Albert; Heckbert, Susan R; Fox, Ervin R; O'Donnell, Christopher J; Uitterlinden, Andre G; Rotter, Jerome I; Willerson, James T; Levy, Daniel; van Duijn, Cornelia M; Psaty, Bruce M; Witteman, Jacqueline C M; Boerwinkle, Eric; Vasan, Ramachandran S

2010-06-01

Although genetic factors contribute to the onset of heart failure (HF), no large-scale genome-wide investigation of HF risk has been published to date. We have investigated the association of 2,478,304 single-nucleotide polymorphisms with incident HF by meta-analyzing data from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. Eligible participants for these analyses were of European or African ancestry and free of clinical HF at baseline. Each study independently conducted genome-wide scans and imputed data to the approximately 2.5 million single-nucleotide polymorphisms in HapMap. Within each study, Cox proportional hazards regression models provided age- and sex-adjusted estimates of the association between each variant and time to incident HF. Fixed-effect meta-analyses combined results for each single-nucleotide polymorphism from the 4 cohorts to produce an overall association estimate and P value. A genome-wide significance P value threshold was set a priori at 5.0x10(-7). During a mean follow-up of 11.5 years, 2526 incident HF events (12%) occurred in 20 926 European-ancestry participants. The meta-analysis identified a genome-wide significant locus at chromosomal position 15q22 (1.4x10(-8)), which was 58.8 kb from USP3. Among 2895 African-ancestry participants, 466 incident HF events (16%) occurred during a mean follow-up of 13.7 years. One genome-wide significant locus was identified at 12q14 (6.7x10(-8)), which was 6.3 kb from LRIG3. We identified 2 loci that were associated with incident HF and exceeded genome-wide significance. The findings merit replication in other community-based settings of incident HF.

Analysis of the North Carolina long-term care polypharmacy initiative: a multiple-cohort approach using propensity-score matching for both evaluation and targeting.

PubMed

Trygstad, Troy K; Christensen, Dale B; Wegner, Steve E; Sullivan, Rob; Garmise, Jennifer M

2009-09-01

The high cost and undesirable consequences of polypharmacy are well-recognized problems among elderly long-term care (LTC) residents. Despite the implementation of the 1987 Omnibus Budget Reconciliation Act, which requires pharmacist review of drug regimens in this setting, medical and drug costs for LTC residents have continued to increase. This study evaluates the North Carolina Long-Term Care Polypharmacy Initiative, a large-scale medication therapy management program (MTMP) that combined drug utilization review activities with drug regimen review techniques. This was a prospective records-based study that used a difference-in-difference model with both historical and nonintervention group controls. To ensure equivalence among subjects, propensity scoring was used to match study subjects from participating LTC facilities with comparison subjects from nonparticipating facilities. Residents with interventions were grouped for analysis by intervention type-retrospective only, prospective only, or dual type (residents with both prospective and retrospective interventions)-and by intervention stage-review, recommendation, and drug change-plus an all-inclusive "all types" grouping that aggregated groups by intervention type, for a total of 10 total cohorts. In the overall population of 5255 study subjects identified, a US $21.63 per member per month drug-cost savings was observed. Although only 1 of 10 cohorts had a change in the number of drug fills, substantial reductions in 2 of 5 types of drug alerts were observed in all 10 cohorts. A reduction in the relative risk for hospitalization (0.84 [95% CI, 0.71-1.00]) was observed in the cohort of residents receiving a retrospective review. This Initiative suggests that an MTMP can be quickly launched in a large number of LTC facility residents to produce monetary drug-cost savings and improved health outcomes. Additionally, the evaluation of this program illustrates the utility of using propensity scoring techniques to target future intervention groups in a cost-effective manner.

Pooled exposure-response analyses and risk assessment for lung cancer in 10 cohorts of silica-exposed workers: an IARC multicentre study.

PubMed

Steenland, K; Mannetje, A; Boffetta, P; Stayner, L; Attfield, M; Chen, J; Dosemeci, M; DeKlerk, N; Hnizdo, E; Koskela, R; Checkoway, H

2001-11-01

Silica is one of the most common occupational exposures worldwide. In 1997 the International Agency for Research on Cancer (IARC) classified inhaled crystalline silica as a human carcinogen (group 1), but acknowledged limitations in the epidemiologic data, including inconsistencies across studies and the lack of extensive exposure-response data. We have conducted a pooled exposure-response analysis of 10 silica-exposed cohorts to investigate lung cancer. The pooled cohort included 65,980 workers (44,160 miners, 21,820 nominees), and 1,072 lung cancer deaths (663 miners, 409 nonminers). Follow-up has been extended for five of these cohorts beyond published data. Quantitative exposure estimates by job and calendar time were adopted, modified, or developed to permit common analyses by respirable silica (mg/m3) across cohorts. The log of cumulative exposure, with a 15-year lag, was a strong predictor of lung cancer (p = 0.0001), with consistency across studies (test for heterogeneity, p = 0.34). Results for the log of cumulative exposure were consistent between underground mines and other facilities. Categorical analyses by quintile of cumulative exposure resulted in a monotonic trend with odds ratios of 1.0. 1.0, 1.3, 1.5, 1.6. Analyses using a spline curve also showed a monotonic increase in risk with increasing exposure. The estimated excess lifetime risk (through age 75) of lung cancer for a worker exposed from age 20 to 65 at 0.1 mg/m3 respirable crystalline silica (the permissible level in many countries) was 1.1-1.7%, above background risks of 3-6%. Our results support the decision by the IARC to classify inhaled silica in occupational settings as a carcinogen, and suggest that the current exposure limits in many countries may be inadequate. These data represent the first quantitative exposure-response analysis and risk assessment for silica using data from multiple studies.

Cross-sectional associations between air pollution and chronic bronchitis: an ESCAPE meta-analysis across five cohorts.

PubMed

Cai, Yutong; Schikowski, Tamara; Adam, Martin; Buschka, Anna; Carsin, Anne-Elie; Jacquemin, Benedicte; Marcon, Alessandro; Sanchez, Margaux; Vierkötter, Andrea; Al-Kanaani, Zaina; Beelen, Rob; Birk, Matthias; Brunekreef, Bert; Cirach, Marta; Clavel-Chapelon, Françoise; Declercq, Christophe; de Hoogh, Kees; de Nazelle, Audrey; Ducret-Stich, Regina E; Valeria Ferretti, Virginia; Forsberg, Bertil; Gerbase, Margaret W; Hardy, Rebecca; Heinrich, Joachim; Hoek, Gerard; Jarvis, Debbie; Keidel, Dirk; Kuh, Diana; Nieuwenhuijsen, Mark J; Ragettli, Martina S; Ranzi, Andrea; Rochat, Thierry; Schindler, Christian; Sugiri, Dorothea; Temam, Sofia; Tsai, Ming-Yi; Varraso, Raphaëlle; Kauffmann, Francine; Krämer, Ursula; Sunyer, Jordi; Künzli, Nino; Probst-Hensch, Nicole; Hansell, Anna L

2014-11-01

This study aimed to assess associations of outdoor air pollution on prevalence of chronic bronchitis symptoms in adults in five cohort studies (Asthma-E3N, ECRHS, NSHD, SALIA, SAPALDIA) participating in the European Study of Cohorts for Air Pollution Effects (ESCAPE) project. Annual average particulate matter (PM(10), PM(2.5), PM(absorbance), PM(coarse)), NO(2), nitrogen oxides (NO(x)) and road traffic measures modelled from ESCAPE measurement campaigns 2008-2011 were assigned to home address at most recent assessments (1998-2011). Symptoms examined were chronic bronchitis (cough and phlegm for ≥3 months of the year for ≥2 years), chronic cough (with/without phlegm) and chronic phlegm (with/without cough). Cohort-specific cross-sectional multivariable logistic regression analyses were conducted using common confounder sets (age, sex, smoking, interview season, education), followed by meta-analysis. 15 279 and 10 537 participants respectively were included in the main NO(2) and PM analyses at assessments in 1998-2011. Overall, there were no statistically significant associations with any air pollutant or traffic exposure. Sensitivity analyses including in asthmatics only, females only or using back-extrapolated NO(2) and PM10 for assessments in 1985-2002 (ECRHS, NSHD, SALIA, SAPALDIA) did not alter conclusions. In never-smokers, all associations were positive, but reached statistical significance only for chronic phlegm with PM(coarse) OR 1.31 (1.05 to 1.64) per 5 µg/m(3) increase and PM(10) with similar effect size. Sensitivity analyses of older cohorts showed increased risk of chronic cough with PM(2.5abs) (black carbon) exposures. Results do not show consistent associations between chronic bronchitis symptoms and current traffic-related air pollution in adult European populations. 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.

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

Meta-analysis of gene expression profiles associated with histological classification and survival in 829 ovarian cancer samples.

PubMed

Fekete, Tibor; Rásó, Erzsébet; Pete, Imre; Tegze, Bálint; Liko, István; Munkácsy, Gyöngyi; Sipos, Norbert; Rigó, János; Györffy, Balázs

2012-07-01

Transcriptomic analysis of global gene expression in ovarian carcinoma can identify dysregulated genes capable to serve as molecular markers for histology subtypes and survival. The aim of our study was to validate previous candidate signatures in an independent setting and to identify single genes capable to serve as biomarkers for ovarian cancer progression. As several datasets are available in the GEO today, we were able to perform a true meta-analysis. First, 829 samples (11 datasets) were downloaded, and the predictive power of 16 previously published gene sets was assessed. Of these, eight were capable to discriminate histology subtypes, and none was capable to predict survival. To overcome the differences in previous studies, we used the 829 samples to identify new predictors. Then, we collected 64 ovarian cancer samples (median relapse-free survival 24.5 months) and performed TaqMan Real Time Polimerase Chain Reaction (RT-PCR) analysis for the best 40 genes associated with histology subtypes and survival. Over 90% of subtype-associated genes were confirmed. Overall survival was effectively predicted by hormone receptors (PGR and ESR2) and by TSPAN8. Relapse-free survival was predicted by MAPT and SNCG. In summary, we successfully validated several gene sets in a meta-analysis in large datasets of ovarian samples. Additionally, several individual genes identified were validated in a clinical cohort. Copyright © 2011 UICC.

Assessing the accuracy of blood RNA profiles to identify patients with post-concussion syndrome: A pilot study in a military patient population.

PubMed

Hardy, Jimmaline J; Mooney, Scott R; Pearson, Andrea N; McGuire, Dawn; Correa, Daniel J; Simon, Roger P; Meller, Robert

2017-01-01

Mild traumatic brain injury (mTBI) is a complex, neurophysiological condition that can have detrimental outcomes. Yet, to date, no objective method of diagnosis exists. Physical damage to the blood-brain-barrier and normal waste clearance via the lymphatic system may enable the detection of biomarkers of mTBI in peripheral circulation. Here we evaluate the accuracy of whole transcriptome analysis of blood to predict the clinical diagnosis of post-concussion syndrome (PCS) in a military cohort. Sixty patients with clinically diagnosed chronic concussion and controls (no history of concussion) were recruited (retrospective study design). Male patients (46) were split into a training set comprised of 20 long-term concussed (> 6 months and symptomatic) and 12 controls (no documented history of concussion). Models were validated in a testing set (control = 9, concussed = 5). RNA_Seq libraries were prepared from whole blood samples for sequencing using a SOLiD5500XL sequencer and aligned to hg19 reference genome. Patterns of differential exon expression were used for diagnostic modeling using support vector machine classification, and then validated in a second patient cohort. The accuracy of RNA profiles to predict the clinical diagnosis of post-concussion syndrome patients from controls was 86% (sensitivity 80%; specificity 89%). In addition, RNA profiles reveal duration of concussion. This pilot study shows the potential utility of whole transcriptome analysis to establish the clinical diagnosis of chronic concussion syndrome.

Using individual patient anatomy to predict protocol compliance for prostate intensity-modulated radiotherapy

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

Caine, Hannah; Whalley, Deborah; Kneebone, Andrew

If a prostate intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT) plan has protocol violations, it is often a challenge knowing whether this is due to unfavorable anatomy or suboptimal planning. This study aimed to create a model to predict protocol violations based on patient anatomical variables and their potential relationship to target and organ at risk (OAR) end points in the setting of definitive, dose-escalated IMRT/VMAT prostate planning. Radiotherapy plans from 200 consecutive patients treated with definitive radiation for prostate cancer using IMRT or VMAT were analyzed. The first 100 patient plans (hypothesis-generating cohort) were examined to identifymore » anatomical variables that predict for dosimetric outcome, in particular OAR end points. Variables that scored significance were further assessed for their ability to predict protocol violations using a Classification and Regression Tree (CART) analysis. These results were then validated in a second group of 100 patients (validation cohort). In the initial analysis of the hypothesis-generating cohort, percentage of rectum overlap in the planning target volume (PTV) (%OR) and percentage of bladder overlap in the PTV (%OB) were highlighted as significant predictors of rectal and bladder dosimetry. Lymph node treatment was also significant for bladder outcomes. For the validation cohort, CART analysis showed that %OR of < 6%, 6% to 9% and > 9% predicted a 13%, 63%, and 100% rate of rectal protocol violations respectively. For the bladder, %OB of < 9% vs > 9% is associated with 13% vs 88% rate of bladder constraint violations when lymph nodes were not treated. If nodal irradiation was delivered, plans with a %OB of < 9% had a 59% risk of violations. Percentage of rectum and bladder within the PTV can be used to identify individual plan potential to achieve dose-volume histogram (DVH) constraints. A model based on these factors could be used to reduce planning time, improve work flow, and strengthen plan quality and consistency.« less

Effect of direct and indirect transfer status on trauma mortality in sub Saharan Africa.

PubMed

Boschini, Laura P; Lu-Myers, Yemeng; Msiska, Nelson; Cairns, Bruce; Charles, Anthony G

2016-05-01

Traumatic injuries account for the greatest portion of global surgical burden particularly in low- and middle-income countries (LMICs). To assess effectiveness of a developing trauma system, we hypothesize that there are survival differences between direct and indirect transfer of trauma patients to a tertiary hospital in sub Saharan Africa. Retrospective analysis of 51,361 trauma patients within the Kamuzu Central Hospital (KCH) trauma registry from 2008 to 2012 was performed. Analysis of patient characteristics and logistic regression modelling for in-hospital mortality was performed. The primary study outcome is in hospital mortality in the direct and indirect transfer groups. There were 50,059 trauma patients were included in this study. 6578 patients transferred from referring facilities and 43,481 patients transported from the scene. The indirect and direct transfer cohorts were similar in age and sex. The mechanism of injury for transferred patients was 78.1% blunt, 14.5% penetrating, and 7.4% other, whereas for the scene group it was 70.7% blunt, 24.0% penetrating, and 5.2% other. Median times to presentation were 13 (4-30) and 3 (1-14)h for transferred and scene patients, respectively. Mortality rate was 4.2% and 1.6% for indirect and direct transfer cohorts, respectively. A total of 8816 patients were admitted of which 3636 and 5963 were in the transfer and scene cohort, respectively. After logistic regression analysis, the adjusted in-hospital mortality odds ratio was 2.09 (1.24-3.54); P=0.006 for indirect transfer versus direct transfer cohort, after controlling for significant covariates. Direct transfer of trauma patients from the scene to the tertiary care centre is associated with a survival benefit. Our findings suggest that trauma education and efforts directed at regionalization of trauma care, strengthening pre-hospital care and timely transfer from district hospitals could mitigate trauma-related mortality in a resource-poor setting. Copyright © 2016 Elsevier Ltd. All rights reserved.

Fruit and vegetable intake and the risk of overall cancer in Japanese: A pooled analysis of population-based cohort studies.

PubMed

Takachi, Ribeka; Inoue, Manami; Sugawara, Yumi; Tsuji, Ichiro; Tsugane, Shoichiro; Ito, Hidemi; Matsuo, Keitaro; Tanaka, Keitaro; Tamakoshi, Akiko; Mizoue, Tetsuya; Wakai, Kenji; Nagata, Chisato; Sasazuki, Shizuka

2017-04-01

A series of recent reports from large-scale cohort studies involving more than 100,000 subjects reported no or only very small inverse associations between fruit and vegetable intake and overall cancer incidence, despite having sufficient power to do so. To date, however, no such data have been reported for Asian populations. To provide some indication of the net impact of fruit and vegetable consumption on overall cancer prevention, we examined these associations in a pooled analysis of large-scale cohort studies in Japanese populations. We analyzed original data from four cohort studies that measured fruit and vegetable consumption using validated questionnaires at baseline. Hazard ratios (HRs) in the individual studies were calculated, with adjustment for a common set of variables, and combined using a random-effects model. During 2,318,927 person-years of follow-up for a total of 191,519 subjects, 17,681 cases of overall cancers were identified. Consumption of fruit or vegetables was not associated with decreased risk of overall cancers: corresponding HRs for the highest versus lowest quartiles of intake for men and women were 1.03 (95% CI, 0.97-1.10; trend p = 1.00) and 1.03 (95% CI, 0.95-1.11; trend p = 0.97), respectively, for fruit and 1.07 (95% CI, 1.01-1.14; trend p = 0.18) and 0.98 (95% CI, 0.91-1.06; trend p = 0.99), respectively, for vegetables, even in analyses stratified by smoking status and alcohol drinking. The results of this pooled analysis do not support inverse associations of fruit and vegetable consumption with overall cancers in the Japanese population. Copyright © 2016 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Progress towards zero, an international comparison: Improvements in traffic fatality from 1990 to 2010 for different age groups in the USA and 15 of its peers.

PubMed

Ahangari, Hamed; Atkinson-Palombo, Carol; Garrick, Norman W

2016-06-01

In January 2015, the United States Department of Transportation (USDOT) announced that the official target of the federal government transportation safety policy was zero deaths. Having a better understanding of traffic fatality trends of various age cohorts-and to what extent the US is lagging other countries-is a crucial first step to identifying policies that may help the USDOT achieve its goal. In this paper we analyze fatality rates for different age cohorts in developed countries to better understand how road traffic fatality patterns vary across countries by age cohort. Using benchmarking analysis and comparative index analysis based on panel data modelling and data for selected years between 1990 and 2010, we compare changes in the rate of road traffic fatality over time, as well as the absolute level of road traffic fatality for six age groups in the US, with 15 other developed countries. Our findings illustrate tremendous variations in road fatality rates (both in terms of the absolute values and the rates of improvement over time) among different age cohorts in all of the 16 countries. Looking specifically at the US, our analysis shows that safety improvements for Youngsters (15-17 years old) was much better than for other age groups, and closely tracked peer countries. In sharp contrast, Children (0-14 years old) and Seniors (+65 years old) in the US, fare very poorly when compared to peer countries. For example, in 2010, Children in the US were a stunning five times more likely to experience a road traffic fatality than Children in the UK. This startling statistic suggests an immediate need to explore further the causes and potential solutions to these disparities. This is especially important if countries, including the US, are to achieve the ambitious goals set out in Zero Vision initiatives. Copyright © 2016 Elsevier Ltd and National Safety Council. All rights reserved.

Safety of the two-step tuberculin skin test in Indian health care workers.

PubMed

Christopher, Devasahayam J; Shankar, Deepa; Datey, Ashima; Zwerling, Alice; Pai, Madhukar

2014-12-01

Health care workers (HCW) in low and middle income countries are at high risk of nosocomial tuberculosis infection. Periodic screening of health workers for both TB disease and infection can play a critical role in TB infection control. Occupational health programs that implement serial tuberculin skin testing (TST) are advised to use a two-step baseline TST. This helps to ensure that boosting of waned immune response is not mistaken as new TB infection (i.e. conversion). However, there are no data on safety of the two-step TST in the Indian context where HCWs are repeatedly exposed. Nursing students were recruited from 2007 to 2009 at the Christian Medical College and Hospital, Vellore, India. Consenting nursing students were screened with a baseline two-step TST at the time of recruitment. From 2007 to 2008 adverse events were recorded when reported during the TST reading (Cohort A). Nurses recruited in the final study year (2009) answered an investigator administered questionnaire assessing all likely side-effects Cohort B). This information was extracted from the case report forms and analysed. Between 2007 and 09, 800 trainees consented to participate in the annual TB screening study and 779 did not have a past history of TB or recall a positive TST and were selected to administer TST. Of these, 755 returned for reading the result and had complete data and were included for the final analysis - 623 subjects in (cohort A) and 132 in (cohort B). These were included for the final analysis. In cohort A only 1.3% reported adverse events. In cohort B, as per the investigator administered questionnaire; 25% reported minor side effects. Itching and local pain were the most common side effects encountered. There were no major adverse events reported. In particular, the adverse events were similar in the second step of the test and not more severe. Screening of HCWs with two-step TST for LTBI is simple and safe, and hence suitable for wide scale implementation in high-burden settings such as India. Copyright © 2014 Asian-African Society for Mycobacteriology. Published by Elsevier Ltd. All rights reserved.

The development of a simulation model of primary prevention strategies for coronary heart disease.

PubMed

Babad, Hannah; Sanderson, Colin; Naidoo, Bhash; White, Ian; Wang, Duolao

2002-11-01

This paper describes the present state of development of a discrete-event micro-simulation model for coronary heart disease prevention. The model is intended to support health policy makers in assessing the impacts on health care resources of different primary prevention strategies. For each person, a set of times to disease events, conditional on the individual's risk factor profile, is sampled from a set of probability distributions that are derived from a new analysis of the Framingham cohort study on coronary heart disease. Methods used to model changes in behavioural and physiological risk factors are discussed and a description of the simulation logic is given. The model incorporates POST (Patient Oriented Simulation Technique) simulation routines.

An epigenome-wide study of body mass index and DNA methylation in blood using participants from the Sister Study cohort.

PubMed

Wilson, L E; Harlid, S; Xu, Z; Sandler, D P; Taylor, J A

2017-01-01

The relationship between obesity and chronic disease risk is well-established; the underlying biological mechanisms driving this risk increase may include obesity-related epigenetic modifications. To explore this hypothesis, we conducted a genome-wide analysis of DNA methylation and body mass index (BMI) using data from a subset of women in the Sister Study. The Sister Study is a cohort of 50 884 US women who had a sister with breast cancer but were free of breast cancer themselves at enrollment. Study participants completed examinations which included measurements of height and weight, and provided blood samples. Blood DNA methylation data generated with the Illumina Infinium HumanMethylation27 BeadChip array covering 27,589 CpG sites was available for 871 women from a prior study of breast cancer and DNA methylation. To identify differentially methylated CpG sites associated with BMI, we analyzed this methylation data using robust linear regression with adjustment for age and case status. For those CpGs passing the false discovery rate significance level, we examined the association in a replication set comprised of a non-overlapping group of 187 women from the Sister Study who had DNA methylation data generated using the Infinium HumanMethylation450 BeadChip array. Analysis of this expanded 450 K array identified additional BMI-associated sites which were investigated with targeted pyrosequencing. Four CpG sites reached genome-wide significance (false discovery rate (FDR) q<0.05) in the discovery set and associations for all four were significant at strict Bonferroni correction in the replication set. An additional 23 sites passed FDR in the replication set and five were replicated by pyrosequencing in the discovery set. Several of the genes identified including ANGPT4, RORC, SOCS3, FSD2, XYLT1, ABCG1, STK39, ASB2 and CRHR2 have been linked to obesity and obesity-related chronic diseases. Our findings support the hypothesis that obesity-related epigenetic differences are detectable in blood and may be related to risk of chronic disease.

Assessing the Effects of the 2003 Resident Duty Hours Reform on Internal Medicine Board Scores

PubMed Central

Romano, Patrick S.; Itani, Kamal M.F.; Rosen, Amy K.; Small, Dylan; Lipner, Rebecca S.; Bosk, Charles L.; Wang, Yanli; Halenar, Michael J.; Korovaichuk, Sophia; Even-Shoshan, Orit; Volpp, Kevin G.

2014-01-01

Purpose To determine whether the 2003 Accreditation Council for Graduate Medical Education (ACGME) duty hours reform affected medical knowledge as reflected by written board scores for internal medicine (IM) residents. Method The authors conducted a retrospective cohort analysis of postgraduate year 1 (PGY-1) Internal Medicine residents who started training before and after the 2003 duty hour reform using a merged data set of American Board of Internal Medicine (ABIM) Board examination and the National Board of Medical Examiners (NMBE) United States Medical Licensing Examination (USMLE) Step 2 Clinical Knowledge test scores. Specifically, using four regression models, the authors compared IM residents beginning PGY-1 training in 2000 and completing training unexposed to the 2003 duty hours reform (PGY-1 2000 cohort, n = 5,475) to PGY-1 cohorts starting in 2001 through 2005 (n = 28,008), all with some exposure to the reform. Results The mean ABIM board score for the unexposed PGY-1 2000 cohort (n = 5,475) was 491, SD = 85. Adjusting for demographics, program, and USMLE Step 2 exam score, the mean differences (95% CI) in ABIM board scores between the PGY-1 2001, 2002, 2003, 2004 and 2005 cohorts minus the PGY-1 2000 cohort were −5.43 (−7.63, −3.23), −3.44 (−5.65, −1.24), 2.58 (0.36, 4.79), 11.10 (8.88, 13.33) and 11.28 (8.98, 13.58) points respectively. None of these differences exceeded one-fifth of an SD in ABIM board scores. Conclusions The duty hours reforms of 2003 did not meaningfully affect medical knowledge as measured by scores on the ABIM board examinations. PMID:24556772

Assessing the effects of the 2003 resident duty hours reform on internal medicine board scores.

PubMed

Silber, Jeffrey H; Romano, Patrick S; Itani, Kamal M F; Rosen, Amy K; Small, Dylan; Lipner, Rebecca S; Bosk, Charles L; Wang, Yanli; Halenar, Michael J; Korovaichuk, Sophia; Even-Shoshan, Orit; Volpp, Kevin G

2014-04-01

To determine whether the 2003 Accreditation Council for Graduate Medical Education (ACGME) duty hours reform affected medical knowledge as reflected by written board scores for internal medicine (IM) residents. The authors conducted a retrospective cohort analysis of postgraduate year 1 (PGY-1) Internal Medicine residents who started training before and after the 2003 duty hour reform using a merged data set of American Board of Internal Medicine (ABIM) Board examination and the National Board of Medical Examiners (NMBE) United States Medical Licensing Examination (USMLE) Step 2 Clinical Knowledge test scores. Specifically, using four regression models, the authors compared IM residents beginning PGY-1 training in 2000 and completing training unexposed to the 2003 duty hours reform (PGY-1 2000 cohort, n = 5,475) to PGY-1 cohorts starting in 2001 through 2005 (n = 28,008), all with some exposure to the reform. The mean ABIM board score for the unexposed PGY-1 2000 cohort (n = 5,475) was 491, SD = 85. Adjusting for demographics, program, and USMLE Step 2 exam score, the mean differences (95% CI) in ABIM board scores between the PGY-1 2001, 2002, 2003, 2004 and 2005 cohorts minus the PGY-1 2000 cohort were -5.43 (-7.63, -3.23), -3.44 (-5.65, -1.24), 2.58 (0.36, 4.79), 11.10 (8.88, 13.33) and 11.28 (8.98, 13.58) points respectively. None of these differences exceeded one-fifth of an SD in ABIM board scores. The duty hours reforms of 2003 did not meaningfully affect medical knowledge as measured by scores on the ABIM board examinations.

Serum microRNAs as biomarkers for recurrence in melanoma

PubMed Central

2012-01-01

Background Identification of melanoma patients at high risk for recurrence and monitoring for recurrence are critical for informed management decisions. We hypothesized that serum microRNAs (miRNAs) could provide prognostic information at the time of diagnosis unaccounted for by the current staging system and could be useful in detecting recurrence after resection. Methods We screened 355 miRNAs in sera from 80 melanoma patients at primary diagnosis (discovery cohort) using a unique quantitative reverse transcription-PCR (qRT-PCR) panel. Cox proportional hazard models and Kaplan-Meier recurrence-free survival (RFS) curves were used to identify a miRNA signature with prognostic potential adjusting for stage. We then tested the miRNA signature in an independent cohort of 50 primary melanoma patients (validation cohort). Logistic regression analysis was performed to determine if the miRNA signature can determine risk of recurrence in both cohorts. Selected miRNAs were measured longitudinally in subsets of patients pre-/post-operatively and pre-/post-recurrence. Results A signature of 5 miRNAs successfully classified melanoma patients into high and low recurrence risk groups with significant separation of RFS in both discovery and validation cohorts (p = 0.0036, p = 0.0093, respectively). Significant separation of RFS was maintained when a logistic model containing the same signature set was used to predict recurrence risk in both discovery and validation cohorts (p < 0.0001, p = 0.033, respectively). Longitudinal expression of 4 miRNAs in a subset of patients was dynamic, suggesting miRNAs can be associated with tumor burden. Conclusion Our data demonstrate that serum miRNAs can improve accuracy in identifying primary melanoma patients with high recurrence risk and in monitoring melanoma tumor burden over time. PMID:22857597

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

The impact of confounder selection in propensity scores when applied to prospective cohort studies in pregnancy.

PubMed

Xu, Ronghui; Hou, Jue; Chambers, Christina D

2018-06-01

Our work was motivated by small cohort studies on the risk of birth defects in infants born to pregnant women exposed to medications. We controlled for confounding using propensity scores (PS). The extremely rare events setting renders the matching or stratification infeasible. In addition, the PS itself may be formed via different approaches to select confounders from a relatively long list of potential confounders. We carried out simulation experiments to compare different combinations of approaches: IPW or regression adjustment, with 1) including all potential confounders without selection, 2) selection based on univariate association between the candidate variable and the outcome, 3) selection based on change in effects (CIE). The simulation showed that IPW without selection leads to extremely large variances in the estimated odds ratio, which help to explain the empirical data analysis results that we had observed. Copyright © 2018 Elsevier Inc. All rights reserved.

Economic crisis and smoking behaviour: prospective cohort study in Iceland

PubMed Central

McClure, Christopher Bruce; Valdimarsdóttir, Unnur A; Hauksdóttir, Arna; Kawachi, Ichiro

2012-01-01

Objective To examine the associations between the 2008 economic collapse in Iceland and smoking behaviour at the national and individual levels. Design A population-based, prospective cohort study based on a mail survey (Health and Wellbeing in Iceland) assessed in 2007 and 2009. Setting National mail survey. Participants Representative cohort (n=3755) of Icelandic adults. Main outcome measure Smoking status. Results A significant reduction in the prevalence of smoking was observed from 2007 (pre-economic collapse) to 2009 (postcollapse) in both males (17.4–14.8%; p 0.01) and females (20.0–17.5%; p 0.01) in the cohort (n=3755). At the individual level of analysis, male former smokers experiencing a reduction in income during the same period were less likely to relapse (OR 0.37; 95% CI 0.16 to 0.85). Female smokers were less likely to quit over time compared to males (OR 0.65; 95% CI 0.45 to 0.93). Among male former smokers who experienced an increase in income between 2007 and 2009, we observed an elevated risk of smoking relapse (OR 4.02; 95% CI 1.15 to 14.00). Conclusions The national prevalence of smoking in Iceland declined following the 2008 economic crisis. This could be due to the procyclical relationship between macro-economic conditions and smoking behaviour (ie, hard times lead to less smoking because of lower affordability), or it may simply reflect a continuation of trends already in place prior to the crisis. In individual-level analysis, we find that former smokers who experienced a decline in income were less likely to relapse; and conversely, an increase in income raises the risk. However, caution is warranted since these findings are based on small numbers. PMID:23048059

Localization patterns of the ganglioside GM1 in human sperm are indicative of male fertility and independent of traditional semen measures

PubMed Central

Cardona, Cristina; Neri, Queenie V.; Simpson, Alana J.; Moody, Melissa A.; Ostermeier, G. Charles; Seaman, Eric K.; Paniza, Theodore; Rosenwaks, Zev; Palermo, Gianpiero D.

2017-01-01

Semen analysis lacks a functional component and best identifies extreme cases of infertility. The ganglioside GM1 is known to have functional roles during capacitation and acrosome exocytosis. Here, we assessed whether GM1 localization patterns (Cap‐Score™) correspond with male fertility in different settings: Study 1 involved couples pursuing assisted reproduction in a tertiary care fertility clinic, while Study 2 involved men with known fertility versus those questioning their fertility at a local urology center. In Study 1, we examined various thresholds versus clinical history for 42 patients; 13 had Cap‐Scores ≥39.5%, with 12 of these (92.3%) achieving clinical pregnancy by natural conception or ≤3 intrauterine insemination cycles. Of the 29 patients scoring <39.5%, only six (20.7%) attained clinical pregnancy by natural conception or ≤3 intrauterine insemination cycles. In Study 2, Cap‐Scores were obtained from 76 fertile men (Cohort 1, pregnant partner or recent father) and compared to 122 men seeking fertility assessment (Cohort 2). Cap‐Score values were normally distributed in Cohort 1, with 13.2% having Cap‐Scores more than one standard deviation below the mean (35.3 ± 7.7%). Significantly, more men in Cohort 2 had Cap‐Scores greater than one standard deviation below the normal mean (33.6%; p = 0.001). Minimal/no relationship was found between Cap‐Score and sperm concentration, morphology, or motility. Together, these data demonstrate that Cap‐Score provides novel, clinically relevant insights into sperm function and male fertility that complement traditional semen analysis. Furthermore, the data provide normal reference ranges for fertile men that can help clinicians counsel couples toward the most appropriate fertility treatment. PMID:28418610

Risk Matrix for Prediction of Disease Progression in a Referral Cohort of Patients with Crohn's Disease.

PubMed

Lakatos, Peter L; Sipeki, Nora; Kovacs, Gyorgy; Palyu, Eszter; Norman, Gary L; Shums, Zakera; Golovics, Petra A; Lovasz, Barbara D; Antal-Szalmas, Peter; Papp, Maria

2015-10-01

Early identification of patients with Crohn's disease (CD) at risk of subsequent complications is essential for adapting the treatment strategy. We aimed to develop a prediction model including clinical and serological markers for assessing the probability of developing advanced disease in a prospective referral CD cohort. Two hundred and seventy-one consecutive CD patients (42.4% males, median follow-up 108 months) were included and followed up prospectively. Anti-Saccharomyces cerevisiae antibodies (ASCA IgA/IgG) were determined by enzyme-linked immunosorbent assay. The final analysis was limited to patients with inflammatory disease behaviour at diagnosis. The final definition of advanced disease outcome was having intestinal resection or disease behaviour progression. Antibody (ASCA IgA and/or IgG) status, disease location and need for early azathioprine were included in a 3-, 5- and 7-year prediction matrix. The probability of advanced disease after 5 years varied from 6.2 to 55% depending on the combination of predictors. Similar findings were obtained in Kaplan-Meier analysis; the combination of ASCA, location and early use of azathioprine was associated with the probability of developing advanced disease (p < 0.001, log rank test). Our prediction models identified substantial differences in the probability of developing advanced disease in the early disease course of CD. Markers identified in this referral cohort were different from those previously published in a population-based cohort, suggesting that different prediction models should be used in the referral setting. Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Cotrimoxazole prophylactic treatment prevents malaria in children in sub-Saharan Africa: systematic review and meta-analysis.

PubMed

Mbeye, Nyanyiwe M; ter Kuile, Feiko O; Davies, Mary-Ann; Phiri, Kamija S; Egger, Matthias; Wandeler, Gilles

2014-09-01

Cotrimoxazole prophylactic treatment (CPT) prevents opportunistic infections in HIV-infected or HIV-exposed children, but estimates of the effectiveness in preventing malaria vary. We reviewed studies that examined the effect of CPT on incidence of malaria in children in sub-Saharan Africa. We searched PubMed and EMBASE for randomised controlled trials (RCTs) and cohort studies on the effect of CPT on incidence of malaria and mortality in children and extracted data on the prevalence of sulphadoxine-pyrimethamine resistance-conferring point mutations. Incidence rate ratios (IRR) from individual studies were combined using random effects meta-analysis; confounder-adjusted estimates were used for cohort studies. The importance of resistance was examined in meta-regression analyses. Three RCTs and four cohort studies with 5039 children (1692 HIV-exposed; 2800 HIV-uninfected; 1486 HIV-infected) were included. Children on CPT were less likely to develop clinical malaria episodes than those without prophylaxis (combined IRR 0.37, 95% confidence interval: 0.21-0.66), but there was substantial between-study heterogeneity (I-squared = 94%, P < 0.001). The protective efficacy of CPT was highest in an RCT from Mali, where the prevalence of antifolate resistant plasmodia was low. In meta-regression analyses, there was some evidence that the efficacy of CPT declined with increasing levels of resistance. Mortality was reduced with CPT in an RCT from Zambia, but not in a cohort study from Côte d'Ivoire. Cotrimoxazole prophylactic treatment reduces incidence of malaria and mortality in children in sub-Saharan Africa, but study designs, settings and results were heterogeneous. CPT appears to be beneficial for HIV-infected and HIV-exposed as well as HIV-uninfected children. © 2014 John Wiley & Sons Ltd.

Trends in U.S., Past-Year Marijuana Use from 1985–2009; An Age-Period-Cohort Analysis

PubMed Central

Miech, Richard; Koester, Stephen

2014-01-01

Background We present a formal age-period-cohort analysis to examine if the recent increase in past-year marijuana use among the young is specific to the younger generation or if, instead, it is part of a general increase present across cohorts of all ages. This is the first age-period-cohort analysis of past-year marijuana use that includes adult trends from 2001–09. Methods Data come from the National Survey on Drug Use and Health, a series of annual, nationally-representative, cross-sectional surveys of the U.S. civilian, non-institutionalized population. The analysis focuses on the 25 year time span from 1985–2009 and uses the recently developed ‘intrinsic estimator’ algorithm to estimate independent effects of age, period, and cohort. Results The recent increase in past-year marijuana use is not unique to the youngest birth cohorts. An independent, positive influence of cohort membership on past-year marijuana use, net of historical period and age effects, is smaller for today’s youngest cohorts than it was for the cohorts that came immediately before, and, in fact, is at its lowest level in three decades. The recent increase in marijuana use among the young is more consistent with a historical period effect that has acted across all cohorts. Period and cohort trends differ substantially for Hispanics. Conclusions The major forces that drive trends in past-year marijuana use are moving away from cohort-specific factors and toward broad-based influences that affect cohorts of all ages. Strategic public health and policy efforts aimed at countering the recent increase in past-year marijuana use should do the same. PMID:22361212

The pediatric resuscitative thoracotomy during combat operations in Iraq and Afghanistan - A retrospective cohort study.

PubMed

Schauer, Steven G; Hill, Guyon J; Connor, Richard E; Oh, John S; April, Michael D

2018-05-01

Combat zone trauma poses a unique set of challenges and injury patterns not seen in the civilian setting. The role of the pediatric resuscitative thoracotomy in combat zones remains unclear given a paucity of data regarding procedure outcomes in this setting. We compare outcomes among children in traumatic arrest undergoing resuscitative thoracotomy versus cardiopulmonary (CPR) resuscitation only. We queried the Department of Defense Trauma Registry (DODTR) from 2007 to 2016 for all pediatric subjects that underwent a resuscitative thoracotomy or CPR in the prehospital or emergency department setting during operations in Iraq or Afghanistan. We removed CPR subjects with mechanisms of injury not matched in the thoracotomy cohort. During the study period, there were 3439 pediatric encounters. We identified 13 subjects who underwent a resuscitative thoracotomy and 66 subjects who underwent CPR without thoracotomy with matching mechanisms of injury. When comparing the two cohorts those in the thoracotomy group had higher median thorax body region scores (median 3 versus 0, p = .001), but a trend towards higher rates of survival to discharge (31% versus 9%, p = .108). The youngest survivor in the thoracotomy cohort was less than 1 year old. We observed a trend towards higher survival among subjects that underwent a resuscitative thoracotomy survived to hospital discharge compared to subjects undergoing CPR without thoracotomy. The literature will benefit from further data to confirm an association between this procedure and a survival benefit among pediatric subjects in the resource limited setting. Furthermore, improvements in documentation will guide equipping and training providers expected to care for pediatric trauma patients. Published by Elsevier Ltd.

A Comparative Analysis of Collaborative Leadership Skills Employed by Graduates of Cohort Based and Non-Cohort Based Doctoral Programs in Eduational Leadership

ERIC Educational Resources Information Center

Breton Caminos, Michelle Evangeline

2015-01-01

This qualitative comparative case analysis investigates the leadership approaches of the graduates of two educational leadership doctoral programs in Upstate New York--one a cohort-modeled program, the other a non-cohort program--with specific attention to collaboration. Responses from participants indicate key differences in Engaging Communities,…

Effectiveness of N95 respirators versus surgical masks in protecting health care workers from acute respiratory infection: a systematic review and meta-analysis

PubMed Central

Smith, Jeffrey D.; MacDougall, Colin C.; Johnstone, Jennie; Copes, Ray A.; Schwartz, Brian; Garber, Gary E.

2016-01-01

Background: Conflicting recommendations exist related to which facial protection should be used by health care workers to prevent transmission of acute respiratory infections, including pandemic influenza. We performed a systematic review of both clinical and surrogate exposure data comparing N95 respirators and surgical masks for the prevention of transmissible acute respiratory infections. Methods: We searched various electronic databases and the grey literature for relevant studies published from January 1990 to December 2014. Randomized controlled trials (RCTs), cohort studies and case–control studies that included data on health care workers wearing N95 respirators and surgical masks to prevent acute respiratory infections were included in the meta-analysis. Surrogate exposure studies comparing N95 respirators and surgical masks using manikins or adult volunteers under simulated conditions were summarized separately. Outcomes from clinical studies were laboratory-confirmed respiratory infection, influenza-like illness and workplace absenteeism. Outcomes from surrogate exposure studies were filter penetration, face-seal leakage and total inward leakage. Results: We identified 6 clinical studies (3 RCTs, 1 cohort study and 2 case–control studies) and 23 surrogate exposure studies. In the meta-analysis of the clinical studies, we found no significant difference between N95 respirators and surgical masks in associated risk of (a) laboratory-confirmed respiratory infection (RCTs: odds ratio [OR] 0.89, 95% confidence interval [CI] 0.64–1.24; cohort study: OR 0.43, 95% CI 0.03–6.41; case–control studies: OR 0.91, 95% CI 0.25–3.36); (b) influenza-like illness (RCTs: OR 0.51, 95% CI 0.19–1.41); or (c) reported workplace absenteeism (RCT: OR 0.92, 95% CI 0.57–1.50). In the surrogate exposure studies, N95 respirators were associated with less filter penetration, less face-seal leakage and less total inward leakage under laboratory experimental conditions, compared with surgical masks. Interpretation: Although N95 respirators appeared to have a protective advantage over surgical masks in laboratory settings, our meta-analysis showed that there were insufficient data to determine definitively whether N95 respirators are superior to surgical masks in protecting health care workers against transmissible acute respiratory infections in clinical settings. PMID:26952529

Effectiveness of N95 respirators versus surgical masks in protecting health care workers from acute respiratory infection: a systematic review and meta-analysis.

PubMed

Smith, Jeffrey D; MacDougall, Colin C; Johnstone, Jennie; Copes, Ray A; Schwartz, Brian; Garber, Gary E

2016-05-17

Conflicting recommendations exist related to which facial protection should be used by health care workers to prevent transmission of acute respiratory infections, including pandemic influenza. We performed a systematic review of both clinical and surrogate exposure data comparing N95 respirators and surgical masks for the prevention of transmissible acute respiratory infections. We searched various electronic databases and the grey literature for relevant studies published from January 1990 to December 2014. Randomized controlled trials (RCTs), cohort studies and case-control studies that included data on health care workers wearing N95 respirators and surgical masks to prevent acute respiratory infections were included in the meta-analysis. Surrogate exposure studies comparing N95 respirators and surgical masks using manikins or adult volunteers under simulated conditions were summarized separately. Outcomes from clinical studies were laboratory-confirmed respiratory infection, influenza-like illness and workplace absenteeism. Outcomes from surrogate exposure studies were filter penetration, face-seal leakage and total inward leakage. We identified 6 clinical studies (3 RCTs, 1 cohort study and 2 case-control studies) and 23 surrogate exposure studies. In the meta-analysis of the clinical studies, we found no significant difference between N95 respirators and surgical masks in associated risk of (a) laboratory-confirmed respiratory infection (RCTs: odds ratio [OR] 0.89, 95% confidence interval [CI] 0.64-1.24; cohort study: OR 0.43, 95% CI 0.03-6.41; case-control studies: OR 0.91, 95% CI 0.25-3.36); (b) influenza-like illness (RCTs: OR 0.51, 95% CI 0.19-1.41); or (c) reported workplace absenteeism (RCT: OR 0.92, 95% CI 0.57-1.50). In the surrogate exposure studies, N95 respirators were associated with less filter penetration, less face-seal leakage and less total inward leakage under laboratory experimental conditions, compared with surgical masks. Although N95 respirators appeared to have a protective advantage over surgical masks in laboratory settings, our meta-analysis showed that there were insufficient data to determine definitively whether N95 respirators are superior to surgical masks in protecting health care workers against transmissible acute respiratory infections in clinical settings. © 2016 Canadian Medical Association or its licensors.

Characterizing longitudinal health state transitions among heroin, cocaine, and methamphetamine users

PubMed Central

Nosyk, B; Li, L; Evans, E; Huang, D; Min, J; Kerr, T; Brecht, ML; Hser, YI

2014-01-01

Aims Characterize longitudinal patterns of drug use careers and identify determinants of drug use frequency across cohorts of primary heroin, methamphetamine (MA) and cocaine users. Design Pooled analysis of prospective cohort studies. Settings Illicit drug users recruited from community, criminal justice and drug treatment settings in California, USA. Participants We used longitudinal data on from five observational cohort studies featuring primary users of heroin (N=629), cocaine (N=694) and methamphetamine (N=474). The mean duration of follow-up was 20.9 years. Measurements Monthly longitudinal data was arranged according to five health states (incarceration, drug treatment, abstinence, non-daily and daily use). We fitted proportional hazards (PH) frailty models to determine independent differences in successive episode durations. We then executed multi-state Markov (MSM) models to estimate probabilities of transitioning between health states, and the determinants of these transitions. Findings Across primary drug use types, PH frailty models demonstrated durations of daily use diminished in successive episodes over time. MSM models revealed primary stimulant users had more erratic longitudinal patterns of drug use, transitioning more rapidly between periods of treatment, abstinence, non-daily and daily use. MA users exhibited relatively longer durations of high-frequency use. Criminal engagement had a destabilizing effect on health state durations across drug types. Longer incarceration histories were associated with delayed transitions towards cessation. Conclusions PH frailty and MSM modeling techniques provided complementary information on longitudinal patterns of drug abuse. This information can inform clinical practice and policy, and otherwise be used in health economic simulation models, designed to inform resource allocation decisions. PMID:24837584

The maternal and neonatal outcomes for an urban Indigenous population compared with their non-Indigenous counterparts and a trend analysis over four triennia.

PubMed

Kildea, Sue; Stapleton, Helen; Murphy, Rebecca; Kosiak, Machellee; Gibbons, Kristen

2013-08-30

Indigenous Australians experience significantly disproportionate poorer health outcomes compared to their non-Indigenous counterparts. Despite the recognised importance of maternal infant health (MIH), there is surprisingly little empirical research to guide service redesign that successfully addresses the disparities. This paper reports on a service evaluation that also compared key MIH indicators for Indigenous and non-Indigenous mothers and babies over a 12-year period 1998-2009. Trend analysis with logistic regression, using the independent variables of ethnicity and triennia, explored changes over time (1998-2009) between two cohorts: 1,523 births to Indigenous mothers and 43,693 births to non-Indigenous mothers. We included bivariate and multivariate analysis on key indicators (e.g. teenage births, preterm birth, low birth weight, smoking) and report odds ratios (ORs), 95% CIs and logistic regression adjusting for important confounders. We excluded transfers in from other areas which are identified within the database. Bivariate analysis revealed Indigenous women were statistically more likely to have spontaneous onset of labour and a non-instrumental vaginal birth. They were less likely to take epidurals for pain relief in labour, have assisted births, caesarean sections or perineal trauma. Despite better labour outcomes, Indigenous babies were more likely to be born preterm (< 37 weeks) and be low birth weight (< 2500 g); these differences remained significant in multivariate analysis. The trend analysis revealed relatively stable rates for teenage pregnancy, small for gestational age, low birth weight babies, and perinatal mortality for both cohorts, with the gap between cohorts consistent over time. A statistical widening of the gap in preterm birth and smoking rates was found with preterm birth demonstrating a relative increase of 51% over this period. The comprehensive database from a large urban hospital allowed a thorough examination of outcomes and contributing factors. The gap between both cohorts remains static in several areas but in some cases worsened. Alternative models for delivering care to Indigenous women and their babies have shown improved outcomes, including preterm birth, though not all have been sustained over time and none are available Australia-wide. New models of care, which recognise the heterogeneity of Indigenous communities, incorporate a multiagency approach, and are set within a research framework, are urgently needed.

Assessing self-efficacy of frontline providers to perform newborn resuscitation in a low-resource setting.

PubMed

Olson, Kristian R; Caldwell, Aya; Sihombing, Melva; Guarino, A J; Nelson, Brett D; Petersen, Rebecca

2015-04-01

Newborn deaths comprise an alarming proportion of under-five mortality globally. In this retrospective cohort study, we investigated the effectiveness of focused newborn resuscitation training and delivery of a positive-pressure device in a rural midwife population in a low-resource setting. The present research attempts to better understand the extent to which knowledge and self-efficacy contribute to resuscitation attempts by birth attendants in practice. A one-year retrospective cohort analysis was undertaken in Aceh, Indonesia of two groups of community-based midwives, one having received formal training and a positive-pressure resuscitative device and the other receiving usual educational resources and management. A path analysis was undertaken to evaluate relative determinants of actual resuscitation attempts. 348 community-based midwives participated in the evaluation and had attended 3116 births during the preceding year. Path analysis indicated that formal training in resuscitation and delivery of a positive-pressure device were significantly related to both increased knowledge (β=0.55, p=0.001) and increased self-efficacy (β=0.52, p=0.001) in performing neonatal resuscitations with a positive-pressure device. However, training impacted actual resuscitation attempts only indirectly through a relationship with self-efficacy and with knowledge. Combined across groups, self-efficacy was significantly associated with positive pressure ventilation attempts (β=0.26, p<0.01) whereas knowledge was not (β=-0.05, p=0.39). Although, to date, evaluations of newborn resuscitation programs have primarily focused on training and has reported process indicators, these results indicate that in order to improve intrapartum-related hypoxic events ("birth asphyxia"), increased emphasis should be placed on participant self-efficacy and mastery of newborn resuscitation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

SPATIAL PATTERNS OF ARRESTS, POLICE ASSAULT, AND ADDICTION TREATMENT CENTER LOCATIONS IN TIJUANA, MEXICO

PubMed Central

Werb, D; Strathdee, SA; Vera, A; Arredondo, J; Beletsky, L; Gonzalez-Zuniga, P; Gaines, T

2016-01-01

Aims In the context of a public health-oriented drug policy reform in Mexico, we assessed the spatial distribution of police encounters among people who inject drugs (PWID) in Tijuana; determined the association between these encounters and the location of addiction treatment centers; and explored the association between police encounters and treatment access. Design Geographically weighted regression (GWR) and logistic regression analysis using prospective spatial data from a community-recruited cohort of PWID in Tijuana and official geographic arrest data from the Tijuana Municipal Police Department. Setting Tijuana, Mexico. Participants 608 participants (median age 37; 28.4% female) in the prospective Proyecto El Cuete cohort study recruited between January and December 2011. Measurements We compared the mean distance of police encounters and a randomly distributed set of events to treatment centers. GWR was undertaken to model the spatial relationship between police interactions and treatment centers. Logistic regression analysis was used to investigate factors associated with reporting police interactions. Findings During the study period, 27.5% of police encounters occurred within 500 meters of treatment centers. The GWR model suggested spatial correlation between encounters and treatment centers (Global R2 = 0.53). Reporting a need for addiction treatment was associated with reporting arrest and police assault (Adjusted Odds Ratio = 2.74, 95% Confidence Interval [CI]: 1.25–6.02, p = 0.012). Conclusions A geospatial analysis suggests that in Mexico, people who inject drugs are at greater risk of being a victim of police violence if they consider themselves in need of addiction treatment, and their interactions with police appear to be more frequent around treatment centres. PMID:26879179

Discriminative ability and predictive validity of the timed up and go test in identifying older people who fall: systematic review and meta-analysis.

PubMed

Schoene, Daniel; Wu, Sandy M-S; Mikolaizak, A Stefanie; Menant, Jasmine C; Smith, Stuart T; Delbaere, Kim; Lord, Stephen R

2013-02-01

To investigate the discriminative ability and diagnostic accuracy of the Timed Up and Go Test (TUG) as a clinical screening instrument for identifying older people at risk of falling. Systematic literature review and meta-analysis. People aged 60 and older living independently or in institutional settings. Studies were identified with searches of the PubMed, EMBASE, CINAHL, and Cochrane CENTRAL data bases. Retrospective and prospective cohort studies comparing times to complete any version of the TUG of fallers and non-fallers were included. Fifty-three studies with 12,832 participants met the inclusion criteria. The pooled mean difference between fallers and non-fallers depended on the functional status of the cohort investigated: 0.63 seconds (95% confidence (CI) = 0.14-1.12 seconds) for high-functioning to 3.59 seconds (95% CI = 2.18-4.99 seconds) for those in institutional settings. The majority of studies did not retain TUG scores in multivariate analysis. Derived cut-points varied greatly between studies, and with the exception of a few small studies, diagnostic accuracy was poor to moderate. The findings suggest that the TUG is not useful for discriminating fallers from non-fallers in healthy, high-functioning older people but is of more value in less-healthy, lower-functioning older people. Overall, the predictive ability and diagnostic accuracy of the TUG are at best moderate. No cut-point can be recommended. Quick, multifactorial fall risk screens should be considered to provide additional information for identifying older people at risk of falls. © 2013, Copyright the Authors Journal compilation © 2013, The American Geriatrics Society.

Methodology Series Module 3: Cross-sectional Studies.

PubMed

Setia, Maninder Singh

2016-01-01

Cross-sectional study design is a type of observational study design. In a cross-sectional study, the investigator measures the outcome and the exposures in the study participants at the same time. Unlike in case-control studies (participants selected based on the outcome status) or cohort studies (participants selected based on the exposure status), the participants in a cross-sectional study are just selected based on the inclusion and exclusion criteria set for the study. Once the participants have been selected for the study, the investigator follows the study to assess the exposure and the outcomes. Cross-sectional designs are used for population-based surveys and to assess the prevalence of diseases in clinic-based samples. These studies can usually be conducted relatively faster and are inexpensive. They may be conducted either before planning a cohort study or a baseline in a cohort study. These types of designs will give us information about the prevalence of outcomes or exposures; this information will be useful for designing the cohort study. However, since this is a 1-time measurement of exposure and outcome, it is difficult to derive causal relationships from cross-sectional analysis. We can estimate the prevalence of disease in cross-sectional studies. Furthermore, we will also be able to estimate the odds ratios to study the association between exposure and the outcomes in this design.

Methodology Series Module 3: Cross-sectional Studies

PubMed Central

Setia, Maninder Singh

2016-01-01

Cross-sectional study design is a type of observational study design. In a cross-sectional study, the investigator measures the outcome and the exposures in the study participants at the same time. Unlike in case–control studies (participants selected based on the outcome status) or cohort studies (participants selected based on the exposure status), the participants in a cross-sectional study are just selected based on the inclusion and exclusion criteria set for the study. Once the participants have been selected for the study, the investigator follows the study to assess the exposure and the outcomes. Cross-sectional designs are used for population-based surveys and to assess the prevalence of diseases in clinic-based samples. These studies can usually be conducted relatively faster and are inexpensive. They may be conducted either before planning a cohort study or a baseline in a cohort study. These types of designs will give us information about the prevalence of outcomes or exposures; this information will be useful for designing the cohort study. However, since this is a 1-time measurement of exposure and outcome, it is difficult to derive causal relationships from cross-sectional analysis. We can estimate the prevalence of disease in cross-sectional studies. Furthermore, we will also be able to estimate the odds ratios to study the association between exposure and the outcomes in this design. PMID:27293245

Identifying genetic variants that affect viability in large cohorts

PubMed Central

Berisa, Tomaz; Day, Felix R.; Perry, John R. B.

2017-01-01

A number of open questions in human evolutionary genetics would become tractable if we were able to directly measure evolutionary fitness. As a step towards this goal, we developed a method to examine whether individual genetic variants, or sets of genetic variants, currently influence viability. The approach consists in testing whether the frequency of an allele varies across ages, accounting for variation in ancestry. We applied it to the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort and to the parents of participants in the UK Biobank. Across the genome, we found only a few common variants with large effects on age-specific mortality: tagging the APOE ε4 allele and near CHRNA3. These results suggest that when large, even late-onset effects are kept at low frequency by purifying selection. Testing viability effects of sets of genetic variants that jointly influence 1 of 42 traits, we detected a number of strong signals. In participants of the UK Biobank of British ancestry, we found that variants that delay puberty timing are associated with a longer parental life span (P~6.2 × 10−6 for fathers and P~2.0 × 10−3 for mothers), consistent with epidemiological studies. Similarly, variants associated with later age at first birth are associated with a longer maternal life span (P~1.4 × 10−3). Signals are also observed for variants influencing cholesterol levels, risk of coronary artery disease (CAD), body mass index, as well as risk of asthma. These signals exhibit consistent effects in the GERA cohort and among participants of the UK Biobank of non-British ancestry. We also found marked differences between males and females, most notably at the CHRNA3 locus, and variants associated with risk of CAD and cholesterol levels. Beyond our findings, the analysis serves as a proof of principle for how upcoming biomedical data sets can be used to learn about selection effects in contemporary humans. PMID:28873088

Clinical outcomes, health resource use, and cost in patients with early versus late dual or triple anti-platelet treatment for acute coronary syndrome.

PubMed

Friedman, Howard; Mollon, Patrick; Lian, Jean; Navaratnam, Prakash

2013-08-01

Acute coronary syndrome (ACS) guidelines recommend early dual anti-platelet therapy (thienopyridines + acetylsalicylic acid [aspirin]). However, triple therapy (thienopyridines + aspirin + glycoprotein IIb/IIIa receptor inhibitors [GRIs]) has shown benefit in clinical trials. This study assessed real-world ACS treatment patterns and outcomes in the acute care setting. A retrospective analysis of patients admitted to hospital with ACS (index event) from January 2007 to December 2009 was conducted (Thomson's MarketScan Hospital Drug Database). Eligible patients were ≥18 years of age, of either sex, and had primary admission and discharge diagnoses of ACS. Cohorts were defined by anti-platelet treatment and then by the timing of treatment initiation (early initiation: within ≤2 days of admission; late initiation: ≥2 days post-admission). Patient characteristics, clinical outcomes, resource utilization, and costs were assessed using descriptive statistics. A total of 249,907 eligible patients were placed into four treatment cohorts (aspirin assumed for all patients): aspirin only; clopidogrel only (dual therapy); GRI only (dual therapy); and clopidogrel + GRI (triple therapy). Patients in the 'clopidogrel-only' cohort were more likely to be older, female, and have more co-morbidities than those in other cohorts; stroke (6.2 %) and re-hospitalization (15.4 %) rates were higher than in the 'GRI-only' and 'triple therapy' cohorts. The GRI-only cohort had higher major bleeding rates (3.3 %), mortality (7.6 %), and costs ($US21,975 [year 2010 values]) than the clopidogrel-only and triple-therapy cohorts. Late initiation cohorts were more likely to be older, female, and have more co-morbidities than early initiation cohorts. Major bleeding was more likely with GRI-only patients (regardless of initiation timing) than with other cohorts. Late-treated clopidogrel-only patients had higher rates of stroke (6.9 %), ACS-related re-admissions (6.1 %), and all-cause re-admissions (15.9 %) than other cohorts. Late treatment was associated with longer length of stay and significantly higher costs. Real-world anti-platelet treatment patterns are consistent with ACS guidelines recommending early initiation and selective GRI use. In contrast to recommendations, some outcomes were improved with triple therapy compared with dual therapy.

Cost-effectiveness of supervised exercise therapy compared with endovascular revascularization for intermittent claudication.

PubMed

van den Houten, M M L; Lauret, G J; Fakhry, F; Fokkenrood, H J P; van Asselt, A D I; Hunink, M G M; Teijink, J A W

2016-11-01

Current guidelines recommend supervised exercise therapy (SET) as the preferred initial treatment for patients with intermittent claudication. The availability of SET programmes is, however, limited and such programmes are often not reimbursed. Evidence for the long-term cost-effectiveness of SET compared with endovascular revascularization (ER) as primary treatment for intermittent claudication might aid widespread adoption in clinical practice. A Markov model was constructed to determine the incremental costs, incremental quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio of SET versus ER for a hypothetical cohort of patients with newly diagnosed intermittent claudication, from the Dutch healthcare payer's perspective. In the event of primary treatment failure, possible secondary interventions were repeat ER, open revascularization or major amputation. Data sources for model parameters included original data from two RCTs, as well as evidence from the medical literature. The robustness of the results was tested with probabilistic and one-way sensitivity analysis. Considering a 5-year time horizon, probabilistic sensitivity analysis revealed that SET was associated with cost savings compared with ER (-€6412, 95 per cent credibility interval (CrI) -€11 874 to -€1939). The mean difference in effectiveness was -0·07 (95 per cent CrI -0·27 to 0·16) QALYs. ER was associated with an additional €91 600 per QALY gained compared with SET. One-way sensitivity analysis indicated more favourable cost-effectiveness for ER in subsets of patients with low quality-of-life scores at baseline. SET is a more cost-effective primary treatment for intermittent claudication than ER. These results support implementation of supervised exercise programmes in clinical practice. © 2016 BJS Society Ltd Published by John Wiley & Sons Ltd.

Preparing Generation Z for the Teaching Profession

ERIC Educational Resources Information Center

Carter, Tim

2018-01-01

Generation Z, also known as the Homeland Generation, is the most recent generational cohort to enter the university setting. As with other generational cohorts, various shaping factors have impacted this group contributing to its unique and defining characteristics. When carefully considered, these characteristics may provide insight into how to…

A brief dietary assessment predicts executive dysfunction in an elderly cohort: results from the Einstein Aging Study

USDA-ARS?s Scientific Manuscript database

Objectives: To examine the association between diet and executive function, episodic memory and global verbal cognition in the Einstein Aging Study (EAS) cohort and determine whether race modifies this relationship. Design: Cross-sectional. Setting: Community. Participants: EAS participants without ...

A Phenomenological Study of an Indonesian Cohort Group's Transformative Learning

ERIC Educational Resources Information Center

Budiraharjo, Markus

2013-01-01

This study was set to investigate how a cohort of ten Indonesian teachers experienced transformations in their teaching professionalism upon receiving an assignment of instructional leadership training to other school leaders. These ten teachers, who came from three different Indonesian Jesuit high schools and one archdiocese-based educational…

Quasi-Experiments in Schools: The Case for Historical Cohort Control Groups

ERIC Educational Resources Information Center

Walser, Tamara M.

2014-01-01

There is increased emphasis on using experimental and quasi-experimental methods to evaluate educational programs; however, educational evaluators and school leaders are often faced with challenges when implementing such designs in educational settings. Use of a historical cohort control group design provides a viable option for conducting…

Self rated health as a predictor of coronary heart disease in Copenhagen, Denmark.

PubMed Central

Møller, L; Kristensen, T S; Hollnagel, H

1996-01-01

STUDY OBJECTIVE: To analyse the association between self rated health and the incidence of fatal and non-fatal coronary heart disease (CHD) in a Danish cohort followed up over 16 years. DESIGN: This was a prospective epidemiological follow up study. SETTING: A cohort from the County of Copenhagen, Denmark. PARTICIPANTS: The study included 1052 men and women born in 1936. During the 16 years' follow up 50 cases of CHD were registered in either the Danish register of deaths or the register of hospital admissions. MAIN RESULTS: Univariate analysis showed the following relative risks of CHD in the four self rated health groups: 'extremely good': 1.0, 'good': 4.0, 'poor': 5.8, 'miserable': 12.1 (p = 0.02). After control for the conventional CHD risk factors and a substantial number of other potential confounders the relative risks were: 1.0, 4.2, 6.5, and 18.6 (p = 0.02) respectively. CONCLUSIONS: Self rated health was an independent predictor of CHD in the present cohort. If confirmed, the association between self rated health and CHD may lead to new insight into psychosocial processes leading to this disease. Images PMID:8882226

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.

Foreign-born Peers and Academic Performance.

PubMed

Conger, Dylan

2015-04-01

The academic performance of foreign-born youth in the United States is well studied, yet little is known about whether and how foreign-born students influence their classmates. In this article, I develop a set of expectations regarding the potential consequences of immigrant integration across schools, with a distinction between the effects of sharing schools with immigrants who are designated as English language learners (ELL) and those who are not. I then use administrative data on multiple cohorts of Florida public high school students to estimate the effect of immigrant shares on immigrant and native-born students' academic performance. The identification strategy pays careful attention to the selection problem by estimating the effect of foreign-born peers from deviations in the share foreign-born across cohorts of students attending the same school in different years. The assumption underlying this approach is that students choose schools based on the composition of the entire school, not on the composition of each entering cohort. The results of the analysis, which hold under several robustness checks, indicate that foreign-born peers (both those who are ELL and those who are non-ELL) have no effect on their high school classmates' academic performance.

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.

Comparison of Estimates between Cohort and Case-Control Studies in Meta-Analyses of Therapeutic Interventions: A Meta-Epidemiological Study.

PubMed

Lanza, Amy; Ravaud, Philippe; Riveros, Carolina; Dechartres, Agnes

2016-01-01

Observational studies are increasingly being used for assessing therapeutic interventions. Case-control studies are generally considered to have greater risk of bias than cohort studies, but we lack evidence of differences in effect estimates between the 2 study types. We aimed to compare estimates between cohort and case-control studies in meta-analyses of observational studies of therapeutic interventions by using a meta-epidemiological study. We used a random sample of meta-analyses of therapeutic interventions published in 2013 that included both cohort and case-control studies assessing a binary outcome. For each meta-analysis, the ratio of estimates (RE) was calculated by comparing the estimate in case-control studies to that in cohort studies. Then, we used random-effects meta-analysis to estimate a combined RE across meta-analyses. An RE < 1 indicated that case-control studies yielded larger estimates than cohort studies. The final analysis included 23 meta-analyses: 138 cohort and 133 case-control studies. Treatment effect estimates did not significantly differ between case-control and cohort studies (combined RE 0.97 [95% CI 0.86-1.09]). Heterogeneity was low, with between-meta-analysis variance τ2 = 0.0049. Estimates did not differ between case-control and prospective or retrospective cohort studies (RE = 1.05 [95% CI 0.96-1.15] and RE = 0.99 [95% CI, 0.83-1.19], respectively). Sensitivity analysis of studies reporting adjusted estimates also revealed no significant difference (RE = 1.03 [95% CI 0.91-1.16]). Heterogeneity was also low for these analyses. We found no significant difference in treatment effect estimates between case-control and cohort studies assessing therapeutic interventions.

Mortality among people who inject drugs: a systematic review and meta-analysis

PubMed Central

Degenhardt, Louisa; Bucello, Chiara; Lemon, James; Wiessing, Lucas; Hickman, Mathew

2013-01-01

Abstract Objective To systematically review cohort studies of mortality among people who inject drugs, examine mortality rates and causes of death in this group, and identify participant- and study-level variables associated with a higher risk of death. Methods Tailored search strings were used to search EMBASE, Medline and PsycINFO. The grey literature was identified through online grey literature databases. Experts were consulted to obtain additional studies and data. Random effects meta-analyses were performed to estimate pooled crude mortality rates (CMRs) and standardized mortality ratios (SMRs). Findings Sixty-seven cohorts of people who inject drugs were identified, 14 of them from low- and middle-income countries. The pooled CMR was 2.35 deaths per 100 person–years (95% confidence interval, CI: 2.12–2.58). SMRs were reported for 32 cohorts; the pooled SMR was 14.68 (95% CI: 13.01–16.35). Comparison of CMRs and the calculation of CMR ratios revealed mortality to be higher in low- and middle-income country cohorts, males and people who injected drugs that were positive for human immunodeficiency virus (HIV). It was also higher during off-treatment periods. Drug overdose and acquired immunodeficiency syndrome (AIDS) were the primary causes of death across cohorts. Conclusion Compared with the general population, people who inject drugs have an elevated risk of death, although mortality rates vary across different settings. Any comprehensive approach to improving health outcomes in this group must include efforts to reduce HIV infection as well as other causes of death, particularly drug overdose. PMID:23554523

Radiation exposure due to local fallout from Soviet atmospheric nuclear weapons testing in Kazakhstan: solid cancer mortality in the Semipalatinsk historical cohort, 1960-1999.

PubMed

Bauer, Susanne; Gusev, Boris I; Pivina, Ludmila M; Apsalikov, Kazbek N; Grosche, Bernd

2005-10-01

Little information is available on the health effects of exposures to fallout from Soviet nuclear weapons testing and on the combined external and internal environmental exposures that have resulted from these tests. This paper reports the first analysis of the Semipalatinsk historical cohort exposed in the vicinity of the Semipalatinsk nuclear test site, Kazakhstan. The cohort study, which includes 19,545 inhabitants of exposed and comparison villages of the Semipalatinsk region, was set up in the 1960s and comprises 582,750 person-years of follow-up between 1960 and 1999. Cumulative effective radiation dose estimates in this cohort range from 20 mSv to approximately 4 Sv. Rates of mortality and cancer mortality in the exposed group substantially exceeded those of the comparison group. Dose-response analyses within the exposed group confirmed a significant trend with dose for all solid cancers (P < 0.0001) and for digestive and respiratory cancers (P = 0.0255 and P < 0.0001), whereas no consistent dose-response trend was found for all causes of death (P = 0.4296). Regarding specific cancer sites, a significant trend with dose was observed for lung cancer (P = 0.0001), stomach cancer (P = 0.0050), and female breast cancer (P = 0.0040) as well as for esophagus cancer in women (P = 0.0030). The excess relative risk per sievert for all solid cancers combined was 1.77 (1.35; 2.27) based on the total cohort data, yet a selection bias regarding the comparison group could not be entirely ruled out. The excess relative risk per sievert based on the cohort's exposed group was 0.81 (0.46; 1.33) for all solid cancers combined and thus still exceeds current risk estimates from the Life Span Study. Future epidemiological assessments based on this cohort will benefit from extension of follow-up and ongoing validation of dosimetric data.

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.

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

Development and validation of a casemix classification to predict costs of specialist palliative care provision across inpatient hospice, hospital and community settings in the UK: a study protocol

PubMed Central

Guo, Ping; Dzingina, Mendwas; Firth, Alice M; Davies, Joanna M; Douiri, Abdel; O’Brien, Suzanne M; Pinto, Cathryn; Pask, Sophie; Higginson, Irene J; Eagar, Kathy; Murtagh, Fliss E M

2018-01-01

Introduction Provision of palliative care is inequitable with wide variations across conditions and settings in the UK. Lack of a standard way to classify by case complexity is one of the principle obstacles to addressing this. We aim to develop and validate a casemix classification to support the prediction of costs of specialist palliative care provision. Methods and analysis Phase I: A cohort study to determine the variables and potential classes to be included in a casemix classification. Data are collected from clinicians in palliative care services across inpatient hospice, hospital and community settings on: patient demographics, potential complexity/casemix criteria and patient-level resource use. Cost predictors are derived using multivariate regression and then incorporated into a classification using classification and regression trees. Internal validation will be conducted by bootstrapping to quantify any optimism in the predictive performance (calibration and discrimination) of the developed classification. Phase II: A mixed-methods cohort study across settings for external validation of the classification developed in phase I. Patient and family caregiver data will be collected longitudinally on demographics, potential complexity/casemix criteria and patient-level resource use. This will be triangulated with data collected from clinicians on potential complexity/casemix criteria and patient-level resource use, and with qualitative interviews with patients and caregivers about care provision across difference settings. The classification will be refined on the basis of its performance in the validation data set. Ethics and dissemination The study has been approved by the National Health Service Health Research Authority Research Ethics Committee. The results are expected to be disseminated in 2018 through papers for publication in major palliative care journals; policy briefs for clinicians, commissioning leads and policy makers; and lay summaries for patients and public. Trial registration number ISRCTN90752212. PMID:29550781

Stochastic models to demonstrate the effect of motivated testing on HIV incidence estimates using the serological testing algorithm for recent HIV seroconversion (STARHS).

PubMed

White, Edward W; Lumley, Thomas; Goodreau, Steven M; Goldbaum, Gary; Hawes, Stephen E

2010-12-01

To produce valid seroincidence estimates, the serological testing algorithm for recent HIV seroconversion (STARHS) assumes independence between infection and testing, which may be absent in clinical data. STARHS estimates are generally greater than cohort-based estimates of incidence from observable person-time and diagnosis dates. The authors constructed a series of partial stochastic models to examine whether testing motivated by suspicion of infection could bias STARHS. One thousand Monte Carlo simulations of 10,000 men who have sex with men were generated using parameters for HIV incidence and testing frequency from data from a clinical testing population in Seattle. In one set of simulations, infection and testing dates were independent. In another set, some intertest intervals were abbreviated to reflect the distribution of intervals between suspected HIV exposure and testing in a group of Seattle men who have sex with men recently diagnosed as having HIV. Both estimation methods were applied to the simulated datasets. Both cohort-based and STARHS incidence estimates were calculated using the simulated data and compared with previously calculated, empirical cohort-based and STARHS seroincidence estimates from the clinical testing population. Under simulated independence between infection and testing, cohort-based and STARHS incidence estimates resembled cohort estimates from the clinical dataset. Under simulated motivated testing, cohort-based estimates remained unchanged, but STARHS estimates were inflated similar to empirical STARHS estimates. Varying motivation parameters appreciably affected STARHS incidence estimates, but not cohort-based estimates. Cohort-based incidence estimates are robust against dependence between testing and acquisition of infection, whereas STARHS incidence estimates are not.

Sleep Disordered Breathing in Four Resource-Limited Settings in Peru: Prevalence, Risk Factors, and Association with Chronic Diseases

PubMed Central

Schwartz, Noah G.; Rattner, Adi; Schwartz, Alan R.; Mokhlesi, Babak; Gilman, Robert H.; Bernabe-Ortiz, Antonio; Miranda, J. Jaime; Checkley, William

2015-01-01

Study Objectives: Sleep disordered breathing (SDB) is a highly prevalent condition in high-income countries, with major consequences for cardiopulmonary health, public safety, healthcare utilization, and mortality. However, its prevalence and effect in low- and middle-income countries are less well known. We sought to determine the prevalence, risk factors, and comorbidities of SDB symptoms in four resource-limited settings. Design: Cross-sectional analysis of the CRONICAS Cohort, a population-based age- and sex-stratified sample. Setting: Four resource-limited settings in Peru varying in altitude, urbanization, and air pollution. Participants: There were 2,682 adults aged 35 to 92 y. Measurements and Results: Self-reported SDB symptoms (habitual snoring, observed apneas, Epworth Sleepiness Scale), sociodemographics, medical history, anthropometrics, spirometry, blood biomarkers were reported. We found a high prevalence of habitual snoring (30.2%, 95% confidence interval [CI] 28.5–32.0%), observed apneas (20.9%, 95% CI 19.4–22.5%) and excessive daytime sleepiness (18.6%, 95% CI 17.1–20.1%). SDB symptoms varied across sites; prevalence and adjusted odds for habitual snoring were greatest at sea level, whereas those for observed apneas were greatest at high altitude. In multivariable analysis, habitual snoring was associated with older age, male sex, body mass index (BMI), and higher socioeconomic status; observed apneas were associated with BMI; and excessive daytime sleepiness was associated with older age, female sex, and medium socioeconomic status. Adjusted odds of cardiovascular disease, depression, and hypertension and total chronic disease burden increased progressively with the number of SDB symptoms. A threefold increase in the odds of having an additional chronic comorbid disease (adjusted odds ratio 3.57, 95% CI 2.18–5.84) was observed in those with all three versus no SDB symptoms. Conclusions: Sleep disordered breathing symptoms were highly prevalent, varied widely across four resource-limited settings in Peru, and exhibited strong independent associations with chronic diseases. Citation: Schwartz NG, Rattner A, Schwartz AR, Mokhlesi B, Gilman RH, Bernabe-Ortiz A, Miranda JJ, Checkley W, CRONICAS Cohort Study Group. Sleep disordered breathing in four resource-limited settings in Peru: prevalence, risk factors, and association with chronic diseases. SLEEP 2015;38(9):1451–1459. PMID:25845694

The Significance of HIV ‘Blips’ in Resource-Limited Settings: Is It the Same? Analysis of the Treat Asia HIV Observational Database (TAHOD) and the Australian HIV Observational Database (AHOD)

PubMed Central

Kanapathipillai, Rupa; McManus, Hamish; Kamarulzaman, Adeeba; Lim, Poh Lian; Templeton, David J.; Law, Matthew; Woolley, Ian

2014-01-01

Introduction Magnitude and frequency of HIV viral load blips in resource-limited settings, has not previously been assessed. This study was undertaken in a cohort from a high income country (Australia) known as AHOD (Australian HIV Observational Database) and another cohort from a mixture of Asian countries of varying national income per capita, TAHOD (TREAT Asia HIV Observational Database). Methods Blips were defined as detectable VL (≥ 50 copies/mL) preceded and followed by undetectable VL (<50 copies/mL). Virological failure (VF) was defined as two consecutive VL ≥50 copies/ml. Cox proportional hazard models of time to first VF after entry, were developed. Results 5040 patients (AHOD n = 2597 and TAHOD n = 2521) were included; 910 (18%) of patients experienced blips. 744 (21%) and 166 (11%) of high- and middle/low-income participants, respectively, experienced blips ever. 711 (14%) experienced blips prior to virological failure. 559 (16%) and 152 (10%) of high- and middle/low-income participants, respectively, experienced blips prior to virological failure. VL testing occurred at a median frequency of 175 and 91 days in middle/low- and high-income sites, respectively. Longer time to VF occurred in middle/low income sites, compared with high-income sites (adjusted hazards ratio (AHR) 0.41; p<0.001), adjusted for year of first cART, Hepatitis C co-infection, cART regimen, and prior blips. Prior blips were not a significant predictor of VF in univariate analysis (AHR 0.97, p = 0.82). Differing magnitudes of blips were not significant in univariate analyses as predictors of virological failure (p = 0.360 for blip 50–≤1000, p = 0.309 for blip 50–≤400 and p = 0.300 for blip 50–≤200). 209 of 866 (24%) patients were switched to an alternate regimen in the setting of a blip. Conclusion Despite a lower proportion of blips occurring in low/middle-income settings, no significant difference was found between settings. Nonetheless, a substantial number of participants were switched to alternative regimens in the setting of blips. PMID:24516527

Blinatumomab vs historical standard therapy of adult relapsed/refractory acute lymphoblastic leukemia.

PubMed

Gökbuget, N; Kelsh, M; Chia, V; Advani, A; Bassan, R; Dombret, H; Doubek, M; Fielding, A K; Giebel, S; Haddad, V; Hoelzer, D; Holland, C; Ifrah, N; Katz, A; Maniar, T; Martinelli, G; Morgades, M; O'Brien, S; Ribera, J-M; Rowe, J M; Stein, A; Topp, M; Wadleigh, M; Kantarjian, H

2016-09-23

We compared outcomes from a single-arm study of blinatumomab in adult patients with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia (R/R ALL) with a historical data set from Europe and the United States. Estimates of complete remission (CR) and overall survival (OS) were weighted by the frequency distribution of prognostic factors in the blinatumomab trial. Outcomes were also compared between the trial and historical data using propensity score methods. The historical cohort included 694 patients with CR data and 1112 patients with OS data compared with 189 patients with CR and survival data in the blinatumomab trial. The weighted analysis revealed a CR rate of 24% (95% CI: 20-27%) and a median OS of 3.3 months (95% CI: 2.8-3.6) in the historical cohort compared with a CR/CRh rate of 43% (95% CI: 36-50%) and a median OS of 6.1 months (95% CI: 4.2-7.5) in the blinatumomab trial. Propensity score analysis estimated increased odds of CR/CRh (OR=2.68, 95% CI: 1.67-4.31) and improved OS (HR=0.536, 95% CI: 0.394-0.730) with blinatumomab. The analysis demonstrates the application of different study designs and statistical methods to compare novel therapies for R/R ALL with historical data.

Quantitative Tissue Proteomics Analysis Reveals Versican as Potential Biomarker for Early-Stage Hepatocellular Carcinoma.

PubMed

Naboulsi, Wael; Megger, Dominik A; Bracht, Thilo; Kohl, Michael; Turewicz, Michael; Eisenacher, Martin; Voss, Don Marvin; Schlaak, Jörg F; Hoffmann, Andreas-Claudius; Weber, Frank; Baba, Hideo A; Meyer, Helmut E; Sitek, Barbara

2016-01-04

Hepatocellular carcinoma (HCC) is one of the most aggressive tumors, and the treatment outcome of this disease is improved when the cancer is diagnosed at an early stage. This requires biomarkers allowing an accurate and early tumor diagnosis. To identify potential markers for such applications, we analyzed a patient cohort consisting of 50 patients (50 HCC and 50 adjacent nontumorous tissue samples as controls) using two independent proteomics approaches. We performed label-free discovery analysis on 19 HCC and corresponding tissue samples. The data were analyzed considering events known to take place in early events of HCC development, such as abnormal regulation of Wnt/b-catenin and activation of receptor tyrosine kinases (RTKs). 31 proteins were selected for verification experiments. For this analysis, the second set of the patient cohort (31 HCC and corresponding tissue samples) was analyzed using selected (multiple) reaction monitoring (SRM/MRM). We present the overexpression of ATP-dependent RNA helicase (DDX39), Fibulin-5 (FBLN5), myristoylated alanine-rich C-kinase substrate (MARCKS), and Serpin H1 (SERPINH1) in HCC for the first time. We demonstrate Versican core protein (VCAN) to be significantly associated with well differentiated and low-stage HCC. We revealed for the first time the evidence of VCAN as a potential biomarker for early-HCC diagnosis.

A genome-wide association study of corneal astigmatism: The CREAM Consortium

PubMed Central

Shah, Rupal L.; Li, Qing; Zhao, Wanting; Tedja, Milly S.; Tideman, J. Willem L.; Khawaja, Anthony P.; Fan, Qiao; Yazar, Seyhan; Williams, Katie M.; Verhoeven, Virginie J.M.; Xie, Jing; Wang, Ya Xing; Hess, Moritz; Nickels, Stefan; Lackner, Karl J.; Pärssinen, Olavi; Wedenoja, Juho; Biino, Ginevra; Concas, Maria Pina; Uitterlinden, André; Rivadeneira, Fernando; Jaddoe, Vincent W.V.; Hysi, Pirro G.; Sim, Xueling; Tan, Nicholas; Tham, Yih-Chung; Sensaki, Sonoko; Hofman, Albert; Vingerling, Johannes R.; Jonas, Jost B.; Mitchell, Paul; Hammond, Christopher J.; Höhn, René; Baird, Paul N.; Wong, Tien-Yin; Cheng, Chinfsg-Yu; Teo, Yik Ying; Mackey, David A.; Williams, Cathy; Saw, Seang-Mei; Klaver, Caroline C.W.; Bailey-Wilson, Joan E.

2018-01-01

Purpose To identify genes and genetic markers associated with corneal astigmatism. Methods A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression. Results The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha (PDGFRA) gene: top SNP: rs7673984, odds ratio=1.12 (95% CI:1.08–1.16), p=5.55×10−9. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans—claudin-7 (CLDN7), acid phosphatase 2, lysosomal (ACP2), and TNF alpha-induced protein 8 like 3 (TNFAIP8L3). Conclusions In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, gene-based analysis identified three novel candidate genes, CLDN7, ACP2, and TNFAIP8L3, that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism. PMID:29422769

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.

Atlas-based analysis of cardiac shape and function: correction of regional shape bias due to imaging protocol for population studies.

PubMed

Medrano-Gracia, Pau; Cowan, Brett R; Bluemke, David A; Finn, J Paul; Kadish, Alan H; Lee, Daniel C; Lima, Joao A C; Suinesiaputra, Avan; Young, Alistair A

2013-09-13

Cardiovascular imaging studies generate a wealth of data which is typically used only for individual study endpoints. By pooling data from multiple sources, quantitative comparisons can be made of regional wall motion abnormalities between different cohorts, enabling reuse of valuable data. Atlas-based analysis provides precise quantification of shape and motion differences between disease groups and normal subjects. However, subtle shape differences may arise due to differences in imaging protocol between studies. A mathematical model describing regional wall motion and shape was used to establish a coordinate system registered to the cardiac anatomy. The atlas was applied to data contributed to the Cardiac Atlas Project from two independent studies which used different imaging protocols: steady state free precession (SSFP) and gradient recalled echo (GRE) cardiovascular magnetic resonance (CMR). Shape bias due to imaging protocol was corrected using an atlas-based transformation which was generated from a set of 46 volunteers who were imaged with both protocols. Shape bias between GRE and SSFP was regionally variable, and was effectively removed using the atlas-based transformation. Global mass and volume bias was also corrected by this method. Regional shape differences between cohorts were more statistically significant after removing regional artifacts due to imaging protocol bias. Bias arising from imaging protocol can be both global and regional in nature, and is effectively corrected using an atlas-based transformation, enabling direct comparison of regional wall motion abnormalities between cohorts acquired in separate studies.

Downregulated CDKN1C/p57kip2 drives tumorigenesis and associates with poor overall survival in breast cancer.

PubMed

Qiu, Zhu; Li, Yunhai; Zeng, Beilei; Guan, Xiaoqin; Li, Hongzhong

2018-02-26

CDKN1C, also known as p57 kip2 , is considered to be a potential tumor suppressor implicated in several kinds of human cancers. However, the current knowledge of CDKN1C in breast cancer remains obscure. In the present study, we demonstrated that CDKN1C was dramatically downregulated in breast cancer compared with normal tissues by using real-time quantitative polymerase chain reaction, western blot and two public data portals: The Cancer Genome Atlas (TCGA) and Oncomine datasets. Moreover, the expression of CDKN1C was correlated with age and tumor size in the TCGA cohort containing 708 cases of breast cancer. Low expression of CDKN1C was significantly associated with poor overall survival (OS) in the TCGA cohort and validated cohort composed of 1402 patients. Multivariate Cox regression analysis indicated that CDKN1C was an independent prognostic factor for worse OS (HR = 1.78, 95% CI: 1.09-2.89, p = 0.020). Furthermore, gene set enrichment analysis (GSEA) revealed that CDKN1C was significantly correlated with gene signatures involving DNA repair, cell cycle, glycolysis, adipogenesis, and two critical signaling pathways mTORC1 and PI3K/Akt/mTOR. In conclusion, our data suggested an essential role of CDKN1C in the tumorgenesis of breast cancer. Targeting CDKN1C may be a promising strategy for anticancer therapeutics. Copyright © 2018 Elsevier Inc. All rights reserved.

Neuroanatomical basis of paroxysmal sympathetic hyperactivity: A diffusion tensor imaging analysis

PubMed Central

Hinson, Holly E.; Puybasset, Louis; Weiss, Nicolas; Perlbarg, Vincent; Benali, Habib; Galanaud, Damien; Lasarev, Mike; Stevens, Robert D.

2015-01-01

Primary objective Paroxysmal sympathetic hyperactivity (PSH) is observed in a sub-set of patients with moderate-to-severe traumatic brain injury (TBI). The neuroanatomical basis of PSH is poorly understood. It is hypothesized that PSH is linked to changes in connectivity within the central autonomic network. Research design Retrospective analysis in a sub-set of patients from a multi-centre, prospective cohort study Methods and procedures Adult patients who were <3 weeks after severe TBI were enrolled and screened for PSH using a standard definition. Patients underwent multimodal MRI, which included quantitative diffusion tensor imaging. Main outcomes and results Principal component analysis (PCA) was used to resolve the set of tracts into components. Ability to predict PSH was evaluated via area under the receiver operating characteristic (AUROC) and tree-based classification analyses. Among 102 enrolled patients, 16 met criteria for PSH. The first principle component was significantly associated (p = 0.024, AUROC = 0.867) with PSH status even after controlling for age and admission GCS. In a classification tree analysis, age, GCS and decreased FA in the splenium of the corpus callosum and in the right posterior limb of the internal capsule discriminated PSH vs no PSH with an AUROC of 0.933. Conclusions Disconnection involving the posterior corpus callosum and of the posterior limb of the internal capsule may play a role in the pathogenesis or expression of PSH. PMID:25565392

2016 American College of Rheumatology/European League Against Rheumatism criteria for minimal, moderate, and major clinical response in adult dermatomyositis and polymyositis: An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative.

PubMed

Aggarwal, Rohit; Rider, Lisa G; Ruperto, Nicolino; Bayat, Nastaran; Erman, Brian; Feldman, Brian M; Oddis, Chester V; Amato, Anthony A; Chinoy, Hector; Cooper, Robert G; Dastmalchi, Maryam; Fiorentino, David; Isenberg, David; Katz, James D; Mammen, Andrew; de Visser, Marianne; Ytterberg, Steven R; Lundberg, Ingrid E; Chung, Lorinda; Danko, Katalin; García-De la Torre, Ignacio; Song, Yeong Wook; Villa, Luca; Rinaldi, Mariangela; Rockette, Howard; Lachenbruch, Peter A; Miller, Frederick W; Vencovsky, Jiri

2017-05-01

To develop response criteria for adult dermatomyositis (DM) and polymyositis (PM). Expert surveys, logistic regression, and conjoint analysis were used to develop 287 definitions using core set measures. Myositis experts rated greater improvement among multiple pairwise scenarios in conjoint analysis surveys, where different levels of improvement in 2 core set measures were presented. The PAPRIKA (Potentially All Pairwise Rankings of All Possible Alternatives) method determined the relative weights of core set measures and conjoint analysis definitions. The performance characteristics of the definitions were evaluated on patient profiles using expert consensus (gold standard) and were validated using data from a clinical trial. The nominal group technique was used to reach consensus. Consensus was reached for a conjoint analysis-based continuous model using absolute per cent change in core set measures (physician, patient, and extramuscular global activity, muscle strength, Health Assessment Questionnaire, and muscle enzyme levels). A total improvement score (range 0-100), determined by summing scores for each core set measure, was based on improvement in and relative weight of each core set measure. Thresholds for minimal, moderate, and major improvement were ≥20, ≥40, and ≥60 points in the total improvement score. The same criteria were chosen for juvenile DM, with different improvement thresholds. Sensitivity and specificity in DM/PM patient cohorts were 85% and 92%, 90% and 96%, and 92% and 98% for minimal, moderate, and major improvement, respectively. Definitions were validated in the clinical trial analysis for differentiating the physician rating of improvement (p<0.001). The response criteria for adult DM/PM consisted of the conjoint analysis model based on absolute per cent change in 6 core set measures, with thresholds for minimal, moderate, and major improvement. 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/.

Genome-Wide Gene Expression in relation to Age in Large Laboratory Cohorts of Drosophila melanogaster

PubMed Central

Carlson, Kimberly A.; Gardner, Kylee; Pashaj, Anjeza; Carlson, Darby J.; Yu, Fang; Eudy, James D.; Zhang, Chi; Harshman, Lawrence G.

2015-01-01

Aging is a complex process characterized by a steady decline in an organism's ability to perform life-sustaining tasks. In the present study, two cages of approximately 12,000 mated Drosophila melanogaster females were used as a source of RNA from individuals sampled frequently as a function of age. A linear model for microarray data method was used for the microarray analysis to adjust for the box effect; it identified 1,581 candidate aging genes. Cluster analyses using a self-organizing map algorithm on the 1,581 significant genes identified gene expression patterns across different ages. Genes involved in immune system function and regulation, chorion assembly and function, and metabolism were all significantly differentially expressed as a function of age. The temporal pattern of data indicated that gene expression related to aging is affected relatively early in life span. In addition, the temporal variance in gene expression in immune function genes was compared to a random set of genes. There was an increase in the variance of gene expression within each cohort, which was not observed in the set of random genes. This observation is compatible with the hypothesis that D. melanogaster immune function genes lose control of gene expression as flies age. PMID:26090231

Longitudinal Surveys of Australian Youth (LSAY) 2009 Cohort: Wave 2 (2010)-- Questionnaire. Technical Report 71A

ERIC Educational Resources Information Center

National Centre for Vocational Education Research (NCVER), 2012

2012-01-01

The Longitudinal Surveys of Australian Youth (LSAY) program studies the progress of several groups of young Australians as they move from school into post-secondary education and work. This technical paper contains the questionnaire for the LSAY 2009 cohort Wave 2 (2010) data set.

Longitudinal Surveys of Australian Youth (LSAY) 2009 Cohort: Wave 3 (2011)--Questionnaire. Technical Report 72A

ERIC Educational Resources Information Center

National Centre for Vocational Education Research (NCVER), 2012

2012-01-01

The Longitudinal Surveys of Australian Youth (LSAY) program studies the progress of several groups of young Australians as they move from school into post-secondary education and work. This technical paper contains the questionnaire for the LSAY 2009 cohort Wave 3 (2011) data set.

Longitudinal Surveys of Australian Youth (LSAY) 2009 Cohort: Wave 2 (2010)--Frequency Tables. Technical Report 71B

ERIC Educational Resources Information Center

National Centre for Vocational Education Research (NCVER), 2012

2012-01-01

The Longitudinal Surveys of Australian Youth (LSAY) program studies the progress of several groups of young Australians as they move from school into post-secondary education and work. This technical paper contains the frequency tables for the LSAY 2009 cohort Wave 2 (2010) data set.

Genome-wide scan of job-related exhaustion with three replication studies implicate a susceptibility variant at the UST gene locus

PubMed Central

Sulkava, Sonja; Ollila, Hanna M.; Ahola, Kirsi; Partonen, Timo; Viitasalo, Katriina; Kettunen, Johannes; Lappalainen, Maarit; Kivimäki, Mika; Vahtera, Jussi; Lindström, Jaana; Härmä, Mikko; Puttonen, Sampsa; Salomaa, Veikko; Paunio, Tiina

2013-01-01

Job-related exhaustion is the core dimension of burnout, a work-related stress syndrome that has several negative health consequences. In this study, we explored the molecular genetic background of job-related exhaustion. A genome-wide analysis of job-related exhaustion was performed in the GENMETS subcohort (n = 1256) of the Finnish population-based Health 2000 study. Replication analyses included an analysis of the strongest associations in the rest of the Health 2000 sample (n = 1660 workers) and in three independent populations (the FINRISK population cohort, n = 10 753; two occupational cohorts, total n = 1451). Job-related exhaustion was ascertained using a standard self-administered questionnaire (the Maslach Burnout Inventory (MBI)-GS exhaustion scale in the Health 2000 sample and the occupational cohorts) or a single question (FINRISK). A variant located in an intron of UST, uronyl-2-sulfotransferase (rs13219957), gave the strongest statistical evidence in the initial genome-wide study (P = 1.55 × 10−7), and was associated with job-related exhaustion in all the replication sets (P < 0.05; P = 6.75 × 10−7 from the meta-analysis). Consistent with studies of mood disorders, individual common genetic variants did not have any strong effect on job-related exhaustion. However, the nominally significant signals from the allelic variant of UST in four separate samples suggest that this variant might be a weak risk factor for job-related exhaustion. Together with the previously reported associations of other dermatan/chondroitin sulfate genes with mood disorders, these results indicate a potential molecular pathway for stress-related traits and mark a candidate region for further studies of job-related and general exhaustion. PMID:23620144

Lung cancer incidence trends in Uruguay 1990-2014: An age-period-cohort analysis.

PubMed

Alonso, Rafael; Piñeros, Marion; Laversanne, Mathieu; Musetti, Carina; Garau, Mariela; Barrios, Enrique; Bray, Freddie

2018-05-11

Uruguay, a country with one of the highest lung cancer rates worldwide, initiated a series of comprehensive anti-smoking measures in 2005. We assess the tobacco control policies in the context of cohort-driven lung cancer incidence trends over a 25-year period, providing baseline predictions to 2035. Using data from the National Cancer Registry of Uruguay, an age-period-cohort analysis of trends 1990-2014 was performed. The NORDPRED package was used to predict the annual number of new cases of lung cancer and incidence rates up to 2035. In men, age-standardised (world) rates declined from a peak of 165.6 in 1995 to 103.1 by 2014, translating to a 70% reduction in the risk of lung cancer in men born in 1970 relative to the early-1940s. In females, rates increased steadily from 18.3 in 1991 to 30.0 by 2014, with successive increases in risk among generations of women born 1940-1960. There is however evidence of a decline in observed rates in women born recently. Extrapolations of the trends indicate an 8% reduction in the mean number of new lung cancer cases in men by 2035, but a 69% increase in women. Despite observed and predicted reductions in lung cancer incidence in Uruguayan men, rates among women are set to continue to increase, with a large rise in the annual number of female lung cancer diagnoses expected before 2035. There are signals of a diminishing risk among recent generations of women born after 1960. The current analysis provides important baseline information in assessing the future impact of the recent tobacco control initiatives in Uruguay. Copyright © 2018 Elsevier Ltd. All rights reserved.

Perceptions and practices of commensality and solo-eating among Korean and Japanese university students: A cross-cultural analysis.

PubMed

Cho, Wookyoun; Takeda, Wakako; Oh, Yujin; Aiba, Naomi; Lee, Youngmee

2015-10-01

Commensality, eating together with others, is a major representation of human sociality. In recent time, environments around commensality have changed significantly due to rapid social changes, and the decline of commensality is perceived as a serious concern in many modern societies. This study employs a cross-cultural analysis of university students in two East Asian countries, and examines cross-cultural variations of perceptions and actual practices of commensality and solo-eating. The analysis was drawn from a free-list survey and a self-administrative questionnaires of university students in urban Korea and Japan. The free-listing survey was conducted with a small cohort to explore common images and meanings of commensality and solo-eating. The self-administrative questionnaire was developed based on the result of the free-list survey, and conducted with a larger cohort to examine reasons and problems of practices and associated behaviors and food intake. We found that Korean subjects tended to show stronger associations between solo-eating and negative emotions while the Japanese subjects expressed mixed emotions towards the practice of solo-eating. In the questionnaire, more Korean students reported they prefer commensality and tend to eat more quantities when they eat commensally. In contrast, more Japanese reported that they do not have preference on commensality and there is no notable difference in food quantities when they eat commensally and alone. Compared to the general Korean cohort finding, more proportion of overweight and obese groups of Korean subjects reported that they tend to eat more when they are alone than normal and underweight groups. This difference was not found in the overweight Japanese subjects. Our study revealed cross-cultural variations of perceptions and practices of commensality and solo-eating in a non-western setting.

Segmenting a general practitioner market to improve recruitment outcomes.

PubMed

Hemphill, Elizabeth; Kulik, Carol T

2011-05-01

Recruitment is an ongoing challenge in the health industry with general practitioner (GP) shortages in many areas beyond rural and Indigenous communities. This paper suggests a marketing solution that identifies different segments of the GP market for recruitment strategy development. In February 2008, 96 GPs in Australia responded to a mail questionnaire (of which 85 questionnaires were useable). A total of 350 GPs were sent the questionnaire. Respondents considered small sets of attributes in the decision to accept a new job at a general practice and selected the most and least important attribute from each set. We identified latent class clusters (cohorts) of GPs from the most-least important data. Three cohorts were found in the GP market, distinguishing practitioners who emphasised job, family or practice attributes in their decision to join a practice. Few significant demographic differences exist between the cohorts. A segmented GP market suggests two alternative recruitment strategies. One option is for general practices to target members of a single cohort (family-, job-, or practice-focussed GPs). The other option is for general practices to diversify their recruitment strategies to target all three cohorts (family-, job- and practice-focussed GPs). A single brand (practice) can have multiple advertising strategies with each strategy involving advertising activities targeting a particular consumer segment.

Association of prescription of oral sodium polystyrene sulfonate with sorbitol in an inpatient setting with colonic necrosis: a retrospective cohort study.

PubMed

Watson, Maura A; Baker, Thomas P; Nguyen, Annie; Sebastianelli, Mary E; Stewart, Heather L; Oliver, David K; Abbott, Kevin C; Yuan, Christina M

2012-09-01

Colonic necrosis has been reported after sodium polystyrene sulfonate (SPS)/sorbitol use, but the incidence and relative risk (RR) are not established. Retrospective cohort study. 123,391 adult inpatients at a tertiary medical center. Receipt of SPS prescriptions (exposed) or a prescription other than SPS (unexposed internal comparison group) between September 1, 2001, and October 31, 2010. The main outcome measure was tissue-confirmed diagnosis of colonic necrosis, considered SPS-associated if SPS was prescribed 30 or fewer days before tissue accession date. Demographics, serum chemistry test results, hospital location, and International Classification of Diseases, Ninth Revision diagnostic codes. SPS was prescribed to 2,194 inpatients. 82 inpatient colonic necrosis cases were identified. 3 received oral SPS (1 gram per 4 milliliters of 33% sorbitol) 30 or fewer days before the colonic necrosis accession date (3.7% of inpatient colonic necrosis cases). The data were linked with 123,391 individuals who received inpatient prescriptions between the same dates. Colonic necrosis incidence was 0.14% (95% CI, 0.03%-0.40%) in those prescribed SPS versus 0.07% (95% CI, 0.05-0.08%) in those not prescribed SPS (RR, 2.10; 95% CI, 0.68-6.48; P = 0.2). The number needed to harm was 1,395 (95% CI, 298-5,100). Subgroup analysis (age >65 years; estimated glomerular filtration rate, <30 mL/min/1.73 m(2), intensive care unit admission, or surgical ward status) did not show significant associations. Sample-size analysis indicated that 4,974 SPS-treated individuals older than 65 years and a comparison group 10 times larger would be required for rigorous multivariate analysis of SPS-associated colonic necrosis risk. Individuals with colonic necrosis admitted to non-Department of Defense hospitals would not have been ascertained. Only individuals who had colonic biopsy or surgical tissue submitted for pathologic review could be ascertained as having colonic necrosis. SPS-associated colonic necrosis is rare, and inpatient SPS/sorbitol prescription was not associated significantly with an increased RR of colonic necrosis in this retrospective cohort analysis. Multivariate analysis would require retrospective clinical cohorts from larger or more than one hospital system(s). Published by Elsevier Inc.

Prediction of Dementia in Primary Care Patients

PubMed Central

Jessen, Frank; Wiese, Birgitt; Bickel, Horst; Eiffländer-Gorfer, Sandra; Fuchs, Angela; Kaduszkiewicz, Hanna; Köhler, Mirjam; Luck, Tobias; Mösch, Edelgard; Pentzek, Michael; Riedel-Heller, Steffi G.; Wagner, Michael; Weyerer, Siegfried; Maier, Wolfgang; van den Bussche, Hendrik

2011-01-01

Background Current approaches for AD prediction are based on biomarkers, which are however of restricted availability in primary care. AD prediction tools for primary care are therefore needed. We present a prediction score based on information that can be obtained in the primary care setting. Methodology/Principal Findings We performed a longitudinal cohort study in 3.055 non-demented individuals above 75 years recruited via primary care chart registries (Study on Aging, Cognition and Dementia, AgeCoDe). After the baseline investigation we performed three follow-up investigations at 18 months intervals with incident dementia as the primary outcome. The best set of predictors was extracted from the baseline variables in one randomly selected half of the sample. This set included age, subjective memory impairment, performance on delayed verbal recall and verbal fluency, on the Mini-Mental-State-Examination, and on an instrumental activities of daily living scale. These variables were aggregated to a prediction score, which achieved a prediction accuracy of 0.84 for AD. The score was applied to the second half of the sample (test cohort). Here, the prediction accuracy was 0.79. With a cut-off of at least 80% sensitivity in the first cohort, 79.6% sensitivity, 66.4% specificity, 14.7% positive predictive value (PPV) and 97.8% negative predictive value of (NPV) for AD were achieved in the test cohort. At a cut-off for a high risk population (5% of individuals with the highest risk score in the first cohort) the PPV for AD was 39.1% (52% for any dementia) in the test cohort. Conclusions The prediction score has useful prediction accuracy. It can define individuals (1) sensitively for low cost-low risk interventions, or (2) more specific and with increased PPV for measures of prevention with greater costs or risks. As it is independent of technical aids, it may be used within large scale prevention programs. PMID:21364746

The incidence of severe hypoglycaemia in pregnant women with type 1 diabetes mellitus can be reduced with unchanged HbA1c levels and pregnancy outcomes in a routine care setting.

PubMed

Ringholm, Lene; Secher, A L; Pedersen-Bjergaard, U; Thorsteinsson, B; Andersen, H U; Damm, P; Mathiesen, E R

2013-08-01

To investigate whether the incidence of severe hypoglycaemia in pregnant women with type 1 diabetes can be reduced without deteriorating HbA1c levels or pregnancy outcomes in a routine care setting. Two cohorts (2004-2006; n=108 and 2009-2011; n=104) were compared. In between the cohorts a focused intervention including education of caregivers and patients in preventing hypoglycaemia was implemented. Women were included at median 8 (range 5-13) weeks. Severe hypoglycaemia (requiring assistance from others) was prospectively reported in structured interviews. In the first vs. second cohort, severe hypoglycaemia during pregnancy occurred in 45% vs. 23%, p=0.0006, corresponding to incidences of 2.5 vs. 1.6 events/patient-year, p=0.04. Unconsciousness and/or convulsions occurred at 24% vs. 8% of events. Glucagon and/or glucose injections were given at 15% vs. 5% of events. At inclusion HbA1c was comparable between the cohorts while in the second cohort fewer women reported impaired hypoglycaemia awareness (56% vs. 36%, p=0.0006), insulin dose in women on multiple daily injections was lower (0.77 IU/kg (0.4-1.7) vs. 0.65 (0.2-1.4), p=0.0006) and more women were on insulin analogues (rapid-acting 44% vs. 97%, p<0.0001; long-acting 6% vs. 76%, p<0.0001) and insulin pumps (5% vs. 23%, p<0.0001). Pregnancy outcomes were similar in the two cohorts. A 36% reduction in the incidence of severe hypoglycaemia in pregnancy with unchanged HbA1c levels and pregnancy outcomes was observed after implementation of focused intervention against severe hypoglycaemia in a routine care setting. Improved insulin treatment, increased health professional education and fewer women with impaired hypoglycaemia awareness may contribute. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Prediction of dementia in primary care patients.

PubMed

Jessen, Frank; Wiese, Birgitt; Bickel, Horst; Eiffländer-Gorfer, Sandra; Fuchs, Angela; Kaduszkiewicz, Hanna; Köhler, Mirjam; Luck, Tobias; Mösch, Edelgard; Pentzek, Michael; Riedel-Heller, Steffi G; Wagner, Michael; Weyerer, Siegfried; Maier, Wolfgang; van den Bussche, Hendrik

2011-02-18

Current approaches for AD prediction are based on biomarkers, which are however of restricted availability in primary care. AD prediction tools for primary care are therefore needed. We present a prediction score based on information that can be obtained in the primary care setting. We performed a longitudinal cohort study in 3.055 non-demented individuals above 75 years recruited via primary care chart registries (Study on Aging, Cognition and Dementia, AgeCoDe). After the baseline investigation we performed three follow-up investigations at 18 months intervals with incident dementia as the primary outcome. The best set of predictors was extracted from the baseline variables in one randomly selected half of the sample. This set included age, subjective memory impairment, performance on delayed verbal recall and verbal fluency, on the Mini-Mental-State-Examination, and on an instrumental activities of daily living scale. These variables were aggregated to a prediction score, which achieved a prediction accuracy of 0.84 for AD. The score was applied to the second half of the sample (test cohort). Here, the prediction accuracy was 0.79. With a cut-off of at least 80% sensitivity in the first cohort, 79.6% sensitivity, 66.4% specificity, 14.7% positive predictive value (PPV) and 97.8% negative predictive value of (NPV) for AD were achieved in the test cohort. At a cut-off for a high risk population (5% of individuals with the highest risk score in the first cohort) the PPV for AD was 39.1% (52% for any dementia) in the test cohort. The prediction score has useful prediction accuracy. It can define individuals (1) sensitively for low cost-low risk interventions, or (2) more specific and with increased PPV for measures of prevention with greater costs or risks. As it is independent of technical aids, it may be used within large scale prevention programs.

Aspirin for Primary Prevention of Cardiovascular Events

PubMed Central

Augustovski, Federico A.; Cantor, Scott B.; Thach, Chau T.; Spann, Stephen J.

1998-01-01

OBJECTIVE The use of aspirin for primary prevention of cardiovascular events in the general population is controversial. The purpose of this study was to create a versatile model to evaluate the effects of aspirin in the primary prevention of cardiovascular events in patients with different risk profiles. DESIGN A Markov decision-analytic model evaluated the expected length and quality of life for the cohort's next 10 years as measured by quality-adjusted survival for the options of taking or not taking aspirin. SETTING Hypothetical model of patients in a primary care setting. PATIENTS Several cohorts of patients with a range of risk profiles typically seen in a primary care setting were considered. Risk factors considered included gender, age, cholesterol levels, systolic blood pressure, smoking status, diabetes, and presence of left ventricular hypertrophy. The cohorts were followed for 10 years. Outcomes were myocardial infarction, stroke, gastrointestinal bleed, ulcer, and death. MAIN RESULTS For the cases considered, the effects of aspirin varied according to the cohort's risk profile. By taking aspirin, the lowest-risk cohort would be the most harmed with a loss of 1.8 quality-adjusted life days by taking aspirin; the highest risk cohort would achieve the most benefit with a gain of 11.3 quality-adjusted life days. Results without quality adjustment favored taking aspirin in all the cohorts, with a gain of 0.73 to 8.04 days. The decision was extremely sensitive to variations in the utility of taking aspirin and to aspirin's effects on cardiovascular mortality. The model was robust to other probability and utility changes within reasonable parameters. CONCLUSIONS The decision of whether to take aspirin as primary prevention for cardiovascular events depends on patient risk. It is a harmful intervention for patients with no risk factors, and it is beneficial in moderate and high-risk patients. The benefits of aspirin in this population are comparable to those of other widely accepted preventive strategies. It is especially dependent on the patient's risk profile, patient preferences for the adverse effects of aspirin, and on the level of beneficial effects of aspirin on cardiovascular-related mortality. PMID:9844080

Using probabilistic record linkage methods to identify Australian Indigenous women on the Queensland Pap Smear Register: the National Indigenous Cervical Screening Project

PubMed Central

Diaz, Abbey; Baade, Peter; Garvey, Gail; Cunningham, Joan; Brotherton, Julia M L; Canfell, Karen; Valery, Patricia C; O'Connell, Dianne L; Taylor, Catherine; Moore, Suzanne P; Condon, John R

2016-01-01

Objective To evaluate the feasibility and reliability of record linkage of existing population-based data sets to determine Indigenous status among women receiving Pap smears. This method may allow for the first ever population measure of Australian Indigenous women's cervical screening participation rates. Setting/participants A linked data set of women aged 20–69 in the Queensland Pap Smear Register (PSR; 1999–2011) and Queensland Cancer Registry (QCR; 1997–2010) formed the Initial Study Cohort. Two extracts (1995–2011) were taken from Queensland public hospitals data (Queensland Hospital Admitted Patient Data Collection, QHAPDC) for women, aged 20–69, who had ever been identified as Indigenous (extract 1) and had a diagnosis or procedure code relating to cervical cancer (extract 2). The Initial Study Cohort was linked to extract 1, and women with cervical cancer in the initial cohort were linked to extract 2. Outcome measures The proportion of women in the Initial Cohort who linked with the extracts (true -pairs) is reported, as well as the proportion of potential pairs that required clerical review. After assigning Indigenous status from QHAPDC to the PSR, the proportion of women identified as Indigenous was calculated using 4 algorithms, and compared. Results There were 28 872 women (2.1%) from the Initial Study Cohort who matched to an ever Indigenous record in extract 1 (n=76 831). Women with cervical cancer in the Initial Study Cohort linked to 1385 (71%) records in extract 2. The proportion of Indigenous women ranged from 2.00% to 2.08% when using different algorithms to define Indigenous status. The Final Study Cohort included 1 372 823 women (PSR n=1 374 401; QCR n=1955), and 5 062 118 records. Conclusions Indigenous status in Queensland cervical screening data was successfully ascertained through record linkage, allowing for the crucial assessment of the current cervical screening programme for Indigenous women. Our study highlights the need to include Indigenous status on Pap smear request and report forms in any renewed and redesigned cervical screening programme in Australia. PMID:26873047

Cost-utility analysis of great saphenous vein ablation with radiofrequency, foam and surgery in the emerging health-care setting of Thailand.

PubMed

Siribumrungwong, Boonying; Noorit, Pinit; Wilasrusmee, Chumpon; Leelahavarong, Pattara; Thakkinstian, Ammarin; Teerawattananon, Yot

2016-09-01

To conduct economic evaluations of radiofrequency ablation, ultrasound-guided foam sclerotherapy and surgery for great saphenous vein ablation. A cost-utility and cohort analysis from societal perspective was performed to estimate incremental cost-effectiveness ratio. Transitional probabilities were from meta-analysis. Direct medical, direct non-medical, indirect costs, and utility were from standard Thai costings and cohort. Probabilistic sensitivity analysis was performed to assess parameter uncertainties. Seventy-seven patients (31 radiofrequency ablation, 19 ultrasound-guided foam sclerotherapy, and 27 surgeries) were enrolled from October 2011 to February 2013. Compared with surgery, radiofrequency ablation costed 12,935 and 20,872 Baht higher, whereas ultrasound-guided foam sclerotherapy costed 6159 lower and 1558 Bath higher for outpatient and inpatient, respectively. At one year, radiofrequency ablation had slightly lower quality-adjusted life-year, whereas ultrasound-guided foam sclerotherapy yielded additional 0.025 quality-adjusted life-year gained. Because of costing lower and greater quality-adjusted life-year than other compared alternatives, outpatient ultrasound-guided foam sclerotherapy was an option being dominant. Probabilistic sensitivity analysis resulted that at the Thai ceiling threshold of 160,000 Baht/quality-adjusted life-year gained, ultrasound-guided foam sclerotherapy had chances of 0.71 to be cost-effective. Ultrasound-guided foam sclerotherapy seems to be cost-effective for treating great saphenous vein reflux compared to surgery in Thailand at one-year results. © The Author(s) 2015.

Automatic radiation dose monitoring for CT of trauma patients with different protocols: feasibility and accuracy.

PubMed

Higashigaito, K; Becker, A S; Sprengel, K; Simmen, H-P; Wanner, G; Alkadhi, H

2016-09-01

To demonstrate the feasibility and accuracy of automatic radiation dose monitoring software for computed tomography (CT) of trauma patients in a clinical setting over time, and to evaluate the potential of radiation dose reduction using iterative reconstruction (IR). In a time period of 18 months, data from 378 consecutive thoraco-abdominal CT examinations of trauma patients were extracted using automatic radiation dose monitoring software, and patients were split into three cohorts: cohort 1, 64-section CT with filtered back projection, 200 mAs tube current-time product; cohort 2, 128-section CT with IR and identical imaging protocol; cohort 3, 128-section CT with IR, 150 mAs tube current-time product. Radiation dose parameters from the software were compared with the individual patient protocols. Image noise was measured and image quality was semi-quantitatively determined. Automatic extraction of radiation dose metrics was feasible and accurate in all (100%) patients. All CT examinations were of diagnostic quality. There were no differences between cohorts 1 and 2 regarding volume CT dose index (CTDIvol; p=0.62), dose-length product (DLP), and effective dose (ED, both p=0.95), while noise was significantly lower (chest and abdomen, both -38%, p<0.017). Compared to cohort 1, CTDIvol, DLP, and ED in cohort 3 were significantly lower (all -25%, p<0.017), similar to the noise in the chest (-32%) and abdomen (-27%, both p<0.017). Compared to cohort 2, CTDIvol (-28%), DLP, and ED (both -26%) in cohort 3 was significantly lower (all, p<0.017), while noise in the chest (+9%) and abdomen (+18%) was significantly higher (all, p<0.017). Automatic radiation dose monitoring software is feasible and accurate, and can be implemented in a clinical setting for evaluating the effects of lowering radiation doses of CT protocols over time. Copyright © 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Hysteroscopic sterilization success in outpatient vs office setting is not affected by patient or procedural characteristics.

PubMed

Anderson, Ted L; Yunker, Amanda C; Scheib, Stacey A; Callahan, Tamara L

2013-01-01

To determine factors associated with hysteroscopic sterilization success and whether it differs between the operating room and office settings. Retrospective cohort analysis (Canadian Task Force classification II-2). Major university medical center. Six hundred thirty-eight women who underwent hysteroscopic sterilization between July 1, 2005, and June 30, 2011. Data collected included age, body mass index, previous office procedures, previous cesarean section, and presence of myomas or retroverted uterus. Place of surgery, experience of surgeon, insurance type, bilateral device placement, compliance with hysterosalpingography, and confirmation of occlusion were also recorded. Bivariate analysis of patient characteristics between groups was performed using χ(2) and independent t tests, and identified confounders and associated variables. Multivariate analysis was performed using logistic regression to assess for association and to adjust for confounders. Procedures were performed in the operating room (57%) or in the office (43%). There was no association between success in bilateral device placement or occlusion and any patient characteristic, regardless of surgery setting. Private insurance, patient age, and performance of procedures in the office setting were positively associated with likelihood of compliance with hysterosalpingography. Successful device placement and tubal occlusion are independent of patient age, body mass index, or setting of the procedure. Association between insurance type and completing hysterosalpingography illustrates an important public health problem. Patients who fail to undergo hysterosalpingography to confirm tubal occlusion may unknowingly be at risk of pregnancy and increased risk of ectopic pregnancy. Copyright © 2013 AAGL. Published by Elsevier Inc. All rights reserved.

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.

Changing trends in reproductive/lifestyle factors in UK women: descriptive study within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

PubMed Central

Gentry-Maharaj, Aleksandra; Glazer, Clara; Burnell, Matthew; Ryan, Andy; Berry, Hannah; Kalsi, Jatinderpal; Woolas, Robert; Skates, Steve J; Campbell, Stuart; Jacobs, Ian

2017-01-01

Objective There has been considerable interest in the impact of reproductive factors on health but there are little data on how these have varied over time. We explore trends in reproductive/lifestyle factors of postmenopausal British women by analysing self-reported data from participants of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Design Prospective birth cohort analysis. Setting Population cohort invited between 2001 and 2005 from age-sex registers of 27 Primary Care Trusts in England, Wales and Northern Ireland and recruited through 13 National Health Service Trusts. Participants 202 638 postmenopausal women aged 50–74 years at randomisation to UKCTOCS between April 2001 and October 2005. Interventions Women were stratified into the following six birth cohorts (1925–1929, 1930–1934, 1935–1939, 1940–1944, 1945–1949, 1950–1955) based on year of birth. Self-reported data on reproductive factors provided at recruitment were explored using tabular and graphical summaries to examine for differences between the birth cohorts. Outcome measures Trends in mean age at menarche and menopause, use of oral contraceptives, change in family size, infertility treatments, tubal ligation and hysterectomy rates. Results Women born between 1935 and 1955 made up 86% of the cohort. Median age at menarche decreased from 13.4 for women born between 1925 and 1929 to 12.8 for women born between 1950 and 1955. Increased use of the oral contraceptives, infertility treatments and smaller family size was observed in the younger birth cohorts. Tubal ligation rates increased for those born between 1925 and 1945, but this increase did not persist in subsequent cohorts. Hysterectomy rates (17–20%) did not change over time. Conclusions The trends seen in this large cohort are likely to reflect the reproductive history of the UK female postmenopausal population of similar age. Since these are risk factors for hormone-related cancers, these trends are important in understanding the changing incidence of these cancers. Trial registration number International Standard Randomised Controlled Trial Number: 22488978. PMID:28264823

Increases and decreases in drug use attributed to housing status among street-involved youth in a Canadian setting.

PubMed

Cheng, Tessa; Wood, Evan; Nguyen, Paul; Kerr, Thomas; DeBeck, Kora

2014-04-10

Among a cohort of drug-using street-involved youth, we sought to identify the prevalence of reporting increases and decreases in illicit drug use due to their current housing status and to identify factors associated with reporting these changes. This longitudinal study was based on data collected between June 2008 and May 2012 from a prospective cohort of street-involved youth aged 14-26 in Vancouver, Canada. At semi-annual study follow-up visits, youth were asked if their drug use was affected by their housing status. Using generalized estimating equations, we identified factors associated with perceived increases and decreases in drug use attributed to housing status. Among our sample of 536 participants at baseline, 164 (31%) youth reported increasing their drug use due to their housing situation and 71 (13%) reported decreasing their drug use. In multivariate analysis, factors that were positively associated with perceived increases in drug use attributed to housing status included the following: being homeless, engaging in sex work and drug dealing. Regular employment was negatively associated with increasing drug use due to housing status. Among those who reported decreasing their drug use, only homelessness was significant in bivariate analysis. Perceived changes in drug use due to housing status were relatively common in this setting and were associated with being homeless and, among those who increased their drug use, engaging in risky income generation activities. These findings suggest that structural factors, particularly housing and economic opportunities, may be crucial interventions for reducing or limiting drug use among street-involved youth.

Increases and decreases in drug use attributed to housing status among street-involved youth in a Canadian setting

PubMed Central

2014-01-01

Background Among a cohort of drug-using street-involved youth, we sought to identify the prevalence of reporting increases and decreases in illicit drug use due to their current housing status and to identify factors associated with reporting these changes. Findings This longitudinal study was based on data collected between June 2008 and May 2012 from a prospective cohort of street-involved youth aged 14–26 in Vancouver, Canada. At semi-annual study follow-up visits, youth were asked if their drug use was affected by their housing status. Using generalized estimating equations, we identified factors associated with perceived increases and decreases in drug use attributed to housing status. Among our sample of 536 participants at baseline, 164 (31%) youth reported increasing their drug use due to their housing situation and 71 (13%) reported decreasing their drug use. In multivariate analysis, factors that were positively associated with perceived increases in drug use attributed to housing status included the following: being homeless, engaging in sex work and drug dealing. Regular employment was negatively associated with increasing drug use due to housing status. Among those who reported decreasing their drug use, only homelessness was significant in bivariate analysis. Conclusion Perceived changes in drug use due to housing status were relatively common in this setting and were associated with being homeless and, among those who increased their drug use, engaging in risky income generation activities. These findings suggest that structural factors, particularly housing and economic opportunities, may be crucial interventions for reducing or limiting drug use among street-involved youth. PMID:24721725

Prenatal Ambient Air Pollution, Placental Mitochondrial DNA Content, and Birth Weight in the INMA (Spain) and ENVIRONAGE (Belgium) Birth Cohorts.

PubMed

Clemente, Diana B P; Casas, Maribel; Vilahur, Nadia; Begiristain, Haizea; Bustamante, Mariona; Carsin, Anne-Elie; Fernández, Mariana F; Fierens, Frans; Gyselaers, Wilfried; Iñiguez, Carmen; Janssen, Bram G; Lefebvre, Wouter; Llop, Sabrina; Olea, Nicolás; Pedersen, Marie; Pieters, Nicky; Santa Marina, Loreto; Souto, Ana; Tardón, Adonina; Vanpoucke, Charlotte; Vrijheid, Martine; Sunyer, Jordi; Nawrot, Tim S

2016-05-01

Mitochondria are sensitive to environmental toxicants due to their lack of repair capacity. Changes in mitochondrial DNA (mtDNA) content may represent a biologically relevant intermediate outcome in mechanisms linking air pollution and fetal growth restriction. We investigated whether placental mtDNA content is a possible mediator of the association between prenatal nitrogen dioxide (NO2) exposure and birth weight. We used data from two independent European cohorts: INMA (n = 376; Spain) and ENVIRONAGE (n = 550; Belgium). Relative placental mtDNA content was determined as the ratio of two mitochondrial genes (MT-ND1 and MTF3212/R3319) to two control genes (RPLP0 and ACTB). Effect estimates for individual cohorts and the pooled data set were calculated using multiple linear regression and mixed models. We also performed a mediation analysis. Pooled estimates indicated that a 10-μg/m3 increment in average NO2 exposure during pregnancy was associated with a 4.9% decrease in placental mtDNA content (95% CI: -9.3, -0.3%) and a 48-g decrease (95% CI: -87, -9 g) in birth weight. However, the association with birth weight was significant for INMA (-66 g; 95% CI: -111, -23 g) but not for ENVIRONAGE (-20 g; 95% CI: -101, 62 g). Placental mtDNA content was associated with significantly higher mean birth weight (pooled analysis, interquartile range increase: 140 g; 95% CI: 43, 237 g). Mediation analysis estimates, which were derived for the INMA cohort only, suggested that 10% (95% CI: 6.6, 13.0 g) of the association between prenatal NO2 and birth weight was mediated by changes in placental mtDNA content. Our results suggest that mtDNA content can be one of the potential mediators of the association between prenatal air pollution exposure and birth weight. Clemente DB, Casas M, Vilahur N, Begiristain H, Bustamante M, Carsin AE, Fernández MF, Fierens F, Gyselaers W, Iñiguez C, Janssen BG, Lefebvre W, Llop S, Olea N, Pedersen M, Pieters N, Santa Marina L, Souto A, Tardón A, Vanpoucke C, Vrijheid M, Sunyer J, Nawrot TS. 2016. Prenatal ambient air pollution, placental mitochondrial DNA content, and birth weight in the INMA (Spain) and ENVIRONAGE (Belgium) birth cohorts. Environ Health Perspect 124:659-665; http://dx.doi.org/10.1289/ehp.1408981.

Independent and parallel evolution of new genes by gene duplication in two origins of C4 photosynthesis provides new insight into the mechanism of phloem loading in C4 species

DOE PAGES

Emms, David M.; Covshoff, Sarah; Hibberd, Julian M.; ...

2016-03-24

C4 photosynthesis is considered one of the most remarkable examples of evolutionary convergence in eukaryotes. However, it is unknown whether the evolution of C4 photosynthesis required the evolution of new genes. Genome-wide gene-tree species-tree reconciliation of seven monocot species that span two origins of C4 photosynthesis revealed that there was significant parallelism in the duplication and retention of genes coincident with the evolution of C4 photosynthesis in these lineages. Specifically, 21 orthologous genes were duplicated and retained independently in parallel at both C4 origins. Analysis of this gene cohort revealed that the set of parallel duplicated and retained genes ismore » enriched for genes that are preferentially expressed in bundle sheath cells, the cell type in which photosynthesis was activated during C4 evolution. Moreover, functional analysis of the cohort of parallel duplicated genes identified SWEET-13 as a potential key transporter in the evolution of C4 photosynthesis in grasses, and provides new insight into the mechanism of phloem loading in these C4 species.« less

A New Genomewide Association Meta-Analysis of Alcohol Dependence.

PubMed

Zuo, Lingjun; Tan, Yunlong; Zhang, Xiangyang; Wang, Xiaoping; Krystal, John; Tabakoff, Boris; Zhong, Chunlong; Luo, Xingguang

2015-08-01

Conventional meta-analysis based on genetic markers may be less powerful for heterogeneous samples. In this study, we introduced a new meta-analysis for 4 genomewide association studies on alcohol dependence that integrated the information of putative causal variants. A total of 12,481 subjects in 4 independent cohorts were analyzed, including 1 European American cohort (1,409 cases with alcohol dependence and 1,518 controls), 1 European Australian cohort (a total of 6,438 family subjects with 1,645 probands), 1 African American cohort from SAGE + COGA (681 cases and 508 controls), and 1 African American cohort from Yale (1,429 cases and 498 controls). The genomewide association analysis was conducted for each cohort, and then, a new meta-analysis was performed to derive the combined p-values. cis-Acting expression of quantitative locus (cis-eQTL) analysis of each risk variant in human tissues and RNA expression analysis of each risk gene in rat brain served as functional validation. In meta-analysis of European American and European Australian cohorts, we found 10 top-ranked single nucleotide polymorphisms (SNPs) (p < 10(-6) ) that were associated with alcohol dependence. They included 6 at SERINC2 (3.1 × 10(-8) ≤ p ≤ 9.6 × 10(-8) ), 1 at STK40 (p = 1.3 × 10(-7) ), 2 at KIAA0040 (3.3 × 10(-7) ≤ p ≤ 5.2 × 10(-7) ), and 1 at IPO11 (p = 6.9 × 10(-7) ). In meta-analysis of 2 African American cohorts, we found 2 top-ranked SNPs including 1 at SLC6A11 (p = 2.7 × 10(-7) ) and 1 at CBLN2 (p = 7.4 × 10(-7) ). In meta-analysis of all 4 cohorts, we found 2 top-ranked SNPs in PTP4A1-PHF3 locus (6.0 × 10(-7) ≤ p ≤ 7.2 × 10(-7) ). In an African American cohort only, we found 1 top-ranked SNP at PLD1 (p = 8.3 × 10(-7) ; OR = 1.56). Many risk SNPs had positive cis-eQTL signals, and all these risk genes except KIAA0040 were found to express in both rat and mouse brains. We found multiple genes that were significantly or suggestively associated with alcohol dependence. They are among the most appropriate for follow-up as contributors to risk for alcohol dependence. Copyright © 2015 by the Research Society on Alcoholism.

Misuse of Trihexyphenidyl (Artane) on Réunion Island.

PubMed

Torrents, Romain; Ferré, Jean Francois; Konareff, Annie; Hemery, Patrice; Sherwin, Kenneth; Lassalle, Christian; Simon, Nicolas; Scerra, Sami

2018-06-01

Trihexyphenidyl (THP) is an anticholinergic drug misused to procure hallucination, sedation, and anxiolysis. The aim of this cohort was to show and describe, within a public health risk management policy, the risks of a long-standing but relatively unknown addiction: THP addiction. On Réunion island, a cohort with systematic data collection has been set up by addictologists working in the Centres for Addiction Prevention and Treatment, in the university hospital, and in general practices who have active lists of patients misusing THP. Data collection included socioeconomic data and clinical data concerning addiction. This cohort included 69 patients during November 2016. The average age of the patients was 36 years; 97% were men; 93% had living accommodation but only 32 % were employed. In this cohort drug administration was exclusively oral. The most common reasons for use were anxiolytic (46%), stimulation (26%), and sedation (10%), the main effects described were dyskinesia and behavioral disorders. Over half (61%) of the patients reported a coaddiction, mainly to benzodiazepines, cannabis, tobacco, alcohol, and buprenorphine. This cohort describing the clinical characteristics of 69 patients is the largest cohort studied for THP addiction. Patients from the Centres for Addiction Prevention and Treatment were the youngest and most recently addicted, whereas general practice patients had been addicted for longer and were more socially integrated. This clinical description of THP addiction therefore enables us to identify the patients who are the most at risk, to set up an adapted care protocol.

Investing in Prospective Cohorts for Etiologic Study of Occupational Exposures

PubMed Central

Blair, A.; Hines, C.J.; Thomas, K.W.; Alavanja, M.C.R.; Beane Freeman, L.E.; Hoppin, J.A.; Kamel, F.; Lynch, C.F.; Lubin, J.H.; Silverman, D.T.; Whelan, E.; Zahm, S. H.; Sandler, D. P.

2015-01-01

Prospective cohorts have played a major role in understanding the contribution of diet, physical activity, medical conditions, and genes to the development of many diseases, but have not been widely used for occupational exposures. Studies in agriculture are an exception. We draw upon our experience using this design to study agricultural workers to identify conditions that might foster use of prospective cohorts to study other occupational settings. Prospective cohort studies are perceived by many as the strongest epidemiologic design. It allows updating of information on exposure and other factors, collection of biologic samples before disease diagnosis for biomarker studies, assessment of effect modification by genes, lifestyle, and other occupational exposures, and evaluation of a wide range of health outcomes. Increased use of prospective cohorts would be beneficial in identifying hazardous exposures in the workplace. Occupational epidemiologists should seek opportunities to initiate prospective cohorts to investigate high priority, occupational exposures. PMID:25603935

CONSTANCES: a general prospective population-based cohort for occupational and environmental epidemiology: cohort profile.

PubMed

Goldberg, Marcel; Carton, Matthieu; Descatha, Alexis; Leclerc, Annette; Roquelaure, Yves; Santin, Gaëlle; Zins, Marie

2017-01-01

WHY THE COHORT WAS SET UP?: CONSTANCES is a general-purpose cohort with a focus on occupational and environmental factors. CONSTANCES was designed as a randomly selected sample of French adults aged 18-69 years at inception; 200 000 participants will be included. At enrolment, the participants are invited to complete questionnaires and to attend a health screening centre (HSC) for a health examination. A biobank will be set up. The follow-up includes an yearly self-administered questionnaire, a periodic visit to an HSC and linkage to social and national health administrative databases. Data collected for participants include social and demographic characteristics, socioeconomic status, life events and behaviours. Regarding occupational and environmental factors, a wealth of data on organisational, chemical, biological, biomechanical and psychosocial lifelong exposure, as well as residential characteristics, are collected at enrolment and during follow-up. The health data cover a wide spectrum: self-reported health scales, reported prevalent and incident diseases, long-term chronic diseases and hospitalisations, sick-leaves, handicaps, limitations, disabilities and injuries, healthcare usage and services provided, and causes of death. To take into account non-participation and attrition, a random cohort of non-participants was set up and will be followed through the same national databases as participants. Inclusions begun at the end of 2012 and more than 110 000 participants were already included by September 2016. Several projects on occupational and environmental risks already applied to a public call for nested research projects. 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/.

The Effect of Treating Institution on Outcomes in Head and Neck Cancer

PubMed Central

Lassig, Amy Anne D.; Joseph, Anne M.; Lindgren, Bruce R.; Fernandes, Patricia; Cooper, Sarah; Schotzko, Chelsea; Khariwala, Samir; Reynolds, Margaret; Yueh, Bevan

2017-01-01

Objective Factors leading patients with head and neck cancer (HNCA) to seek radiation or chemoradiation in an academic center versus the community are incompletely understood, as are the effects of site of treatment on treatment completion and survival. Study Design Historical cohort study. Setting Tertiary academic center, community practices. Methods A historical cohort study was completed of patients with mucosal HNCA identified by International Classification of Disease, Ninth Revision (ICD-9) codes receiving consultation at the authors’ institution from 2003 to 2008. Patients who received primary and adjuvant radiation at an academic center or in the community were included. The authors compared treatment completion rates and performed univariate and multivariate analyses of treatment outcomes. Results Of 388 patients, 210 completed treatment at an academic center and 145 at a community center (33 excluded, location unknown). Patients with HNCA undergoing radiation at an academic site had more advanced disease (P = .024) and were more likely to receive concurrent chemotherapy. Academic hospitals had a higher percentage of noncurrent smokers, higher median income, and higher percentage of oropharyngeal tumors. There was no significant difference in the rate of planned treatment completion between community and academic centers (93.7% vs 94.7%, P > .81) or rate of treatment breaks (22.4% vs 28.4%, P > .28). On Kaplan-Meier analysis, the 5-year survival rate was 53.2% (95% confidence interval [CI], 45.3%–61.1%) for academic centers and 32.8% (95% CI, 22.0%–43.6%) for community hospitals (P <.001). Conclusion In this cohort, although treatment completion and treatment breaks were similar between academic and community centers, survival rates were higher in patients treated in an academic setting. PMID:22875780

The role of depression and social support in non-fatal drug overdose among a cohort of injection drug users in a Canadian setting

PubMed Central

Pabayo, Roman; Alcantara, Carmela; Kawachi, Ichiro; Wood, Evan; Kerr, Thomas

2013-01-01

Objectives Non-fatal overdose remains a significant source of morbidity among people who inject drugs (IDU). Although depression and social support are important in shaping the health of IDU, little is known about the relationship between these factors and overdose. Therefore, we sought to determine whether depressive symptoms and social support predicted non-fatal overdose among IDU in a Canadian setting. Methods Data were derived from three prospective cohorts of people who use drugs: the Vancouver Injection Drug Users Study (VIDUS), the ACCESS Cohort, and the At-Risk Youth Study (ARYS). Multilevel modeling was used to determine if depression and social support were significant predictors of non-fatal overdose across time. Analyses were stratified by sex. Results There were 1,931 participants included in this analysis, including 653 (33.8%) females and 69 (3.6%) youth 20 years old or younger. Depressed men (Adjusted odds ratio [AOR] =1.53, 95% confidence intervals [CI] =1.25, 1.87) and women (Adjusted odds ratio [AOR] =2.23, 95% confidence intervals [CI] =1.65, 3.00) were more likely to experience a non-fatal overdose. Further, among women, those who reported having 3 or more persons they could rely upon for social support were less likely to experience a non-fatal overdose (AOR=0.54, 95% 0.31, 0.93). Conclusion Although depression was a significant predictor of non-fatal drug overdose, social support was a significant predictor among women only. Possible strategies to prevent non-fatal overdose may include identifying IDU experiencing severe depressive symptoms and providing targeted mental health treatments and mobilizing interpersonal social support among IDU, especially among women. PMID:23647731

Genetic Signatures of Exceptional Longevity in Humans

PubMed Central

Sebastiani, Paola; Solovieff, Nadia; DeWan, Andrew T.; Walsh, Kyle M.; Puca, Annibale; Hartley, Stephen W.; Melista, Efthymia; Andersen, Stacy; Dworkis, Daniel A.; Wilk, Jemma B.; Myers, Richard H.; Steinberg, Martin H.; Montano, Monty; Baldwin, Clinton T.; Hoh, Josephine; Perls, Thomas T.

2012-01-01

Like most complex phenotypes, exceptional longevity is thought to reflect a combined influence of environmental (e.g., lifestyle choices, where we live) and genetic factors. To explore the genetic contribution, we undertook a genome-wide association study of exceptional longevity in 801 centenarians (median age at death 104 years) and 914 genetically matched healthy controls. Using these data, we built a genetic model that includes 281 single nucleotide polymorphisms (SNPs) and discriminated between cases and controls of the discovery set with 89% sensitivity and specificity, and with 58% specificity and 60% sensitivity in an independent cohort of 341 controls and 253 genetically matched nonagenarians and centenarians (median age 100 years). Consistent with the hypothesis that the genetic contribution is largest with the oldest ages, the sensitivity of the model increased in the independent cohort with older and older ages (71% to classify subjects with an age at death>102 and 85% to classify subjects with an age at death>105). For further validation, we applied the model to an additional, unmatched 60 centenarians (median age 107 years) resulting in 78% sensitivity, and 2863 unmatched controls with 61% specificity. The 281 SNPs include the SNP rs2075650 in TOMM40/APOE that reached irrefutable genome wide significance (posterior probability of association = 1) and replicated in the independent cohort. Removal of this SNP from the model reduced the accuracy by only 1%. Further in-silico analysis suggests that 90% of centenarians can be grouped into clusters characterized by different “genetic signatures” of varying predictive values for exceptional longevity. The correlation between 3 signatures and 3 different life spans was replicated in the combined replication sets. The different signatures may help dissect this complex phenotype into sub-phenotypes of exceptional longevity. PMID:22279548

Chronic rhinosinusitis, race, and ethnicity.

PubMed

Soler, Zachary M; Mace, Jess C; Litvack, Jamie R; Smith, Timothy L

2012-01-01

Little is known regarding the epidemiology of chronic rhinosinusitis (CRS) in racial and ethnic minorities in the United States. This study was designed to comprehensively evaluate the current prevalence of CRS across various treatment settings to identify possible disparities in health care access and use between racial and ethnic populations. The National Health Interview Survey (NHIS), National Ambulatory Medical Care Survey (NAMCS), and National Hospital Ambulatory Medical Care Survey (NHAMCS) database registries were extracted to identify the national prevalence of CRS in race/ethnic populations and resource use in ambulatory care settings. Systematic literature review identified studies reporting treatment outcomes in minority patients electing endoscopic sinus surgery (ESS). Data were supplemented using a multi-institutional cohort of patients undergoing surgical treatment. National survey data suggest CRS is a significant health condition for all major race/ethnic groups in the United States, accounting for a sizable portion of office, emergency, and outpatient visits. Differences in insurance status, work absenteeism, and resource use were found between race/ethnic groups. Despite its prevalence, few published studies include information regarding minority patients with CRS. Most (90%) cohort studies did not provide details of race/ethnicity for ESS outcomes. Prospective cohort analysis indicated that minority surgical patients accounted for only 18%, when compared with national census estimates (35%). CRS is an important health condition for all major race/ethnic groups in the United States. Significant differences may exist across racial and ethnic categories with regard to CRS health status and health care use. Given current demographic shifts in the United States, specific attention should be given to understanding CRS within the context of racial and ethnic populations. Public clinical trial registration (www.clinicaltrials.gov) I.D. No. NCT00799097.

Age-period-cohort analysis of suicides among Japanese 1950-2003: a Bayesian cohort model analysis.

PubMed

Ooe, Yosuke; Ohno, Yuko; Nakamura, Takashi

2009-07-01

The suicide rate in Japan is one of the highest in the world and presents us with a considerable challenge. Demographic statistics show that the number of suicides is on the rise, and at roughly 30,000 people per year have committed suicide since 1998. Suicide trends are not only related to economic boom and bust but also to certain generations and age groups. During the 1950s, there was a remarkably high suicide rate among people in their 20s, and this cohort was identical to that of the middle-age generation in the 1980s. It is important to separately understand both the trend of suicide rates and the numbers analyzed to determine the different factors that influence suicide. These include age, time period, cohort, interaction between age and time period, and changes in population composition. We performed an age-period-cohort analysis of annual trends of suicide rates by age group in Japan using a Bayesian cohort model. With the help of the Nakamura method, we have been able to break down the effects of age, time period, cohort, and the age-by-period interaction. The cohort comprised of people born in the 1930s demonstrated a relatively high suicide rate. Men currently in their 50s also belong to a high suicide rate cohort. Regarding the period effect, business cycles and by-period interaction effect, it became apparent that the high suicide rate among young adults in their early 20s around 1960 was slowing, especially among men. Instead, there was an obvious recent trend for men in their late 50s to have the highest suicide rate. This study confirmed that age-period-cohort analysis can describe these trends of suicide mortality of the Japanese.

Influence of birth cohort on age of onset cluster analysis in bipolar I disorder.

PubMed

Bauer, M; Glenn, T; Alda, M; Andreassen, O A; Angelopoulos, E; Ardau, R; Baethge, C; Bauer, R; Bellivier, F; Belmaker, R H; Berk, M; Bjella, T D; Bossini, L; Bersudsky, Y; Cheung, E Y W; Conell, J; Del Zompo, M; Dodd, S; Etain, B; Fagiolini, A; Frye, M A; Fountoulakis, K N; Garneau-Fournier, J; Gonzalez-Pinto, A; Harima, H; Hassel, S; Henry, C; Iacovides, A; Isometsä, E T; Kapczinski, F; Kliwicki, S; König, B; Krogh, R; Kunz, M; Lafer, B; Larsen, E R; Lewitzka, U; Lopez-Jaramillo, C; MacQueen, G; Manchia, M; Marsh, W; Martinez-Cengotitabengoa, M; Melle, I; Monteith, S; Morken, G; Munoz, R; Nery, F G; O'Donovan, C; Osher, Y; Pfennig, A; Quiroz, D; Ramesar, R; Rasgon, N; Reif, A; Ritter, P; Rybakowski, J K; Sagduyu, K; Scippa, A M; Severus, E; Simhandl, C; Stein, D J; Strejilevich, S; Hatim Sulaiman, A; Suominen, K; Tagata, H; Tatebayashi, Y; Torrent, C; Vieta, E; Viswanath, B; Wanchoo, M J; Zetin, M; Whybrow, P C

2015-01-01

Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database. The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared. There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups. These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Longitudinal Surveys of Australian Youth (LSAY) 1998 Cohort: Wave 12 (2009)--Questionnaire. Technical Report 58A

ERIC Educational Resources Information Center

National Centre for Vocational Education Research (NCVER), 2010

2010-01-01

The Longitudinal Surveys of Australian Youth (LSAY) program studies the progress of several groups of young Australians as they move from school into post-secondary education and work. This technical paper contains the questionnaire for the LSAY 1998 cohort Wave 12 (2009) data set. [For the accompanying frequency tables, "Longitudinal Surveys…

Healthcare costs associated with nephrology care in pre-dialysis chronic kidney disease patients.

PubMed

Vekeman, Francis; Yameogo, Nadege-Desiree; Lefebvre, Patrick; Bailey, Robert A; McKenzie, R Scott; Piech, Catherine Tak

2010-01-01

To compare the healthcare costs of pre-dialysis chronic kidney disease (CKD) patients cared for in a nephrology clinic setting versus other care settings. An analysis of health claims between 01/2002 and 09/2007 from the Ingenix Impact Database was conducted. Inclusion criteria were ≥ 18 years of age, ≥ 1 ICD-9 claim for CKD, and ≥ 1 estimated glomerular filtration rate (eGFR) value of < 60 mL/min/1.73 m(2). Patients were classified in the nephrology care cohort if they were treated in a nephrology clinic setting at least once during the study period. Univariate and multivariate analyses were conducted to compare average annualized healthcare costs of patients in nephrology care versus other care settings. Among the 20,135 patients identified for analysis, 1,547 patients were cared for in a nephrology clinic setting. Nephrology care was associated with lower healthcare costs with an unadjusted cost savings of $3,049 ($11,303 vs. $14,352, p = 0.0014) and a cost ratio of 0.8:1 relative to other care settings. After adjusting for covariates, nephrology care remained associated with lower costs (adjusted cost savings: $2,742, p = 0.006). Key limitations included potential inaccuracies of claims data, the lack of control for patients' ethnicity in the calculation of eGFR values, and the presence of potential biases due to the observational design of the study. The current study demonstrated that pre-dialysis CKD patients treated in nephrology clinics were associated with significantly lower healthcare costs compared with patients treated in other healthcare settings.

Measles vaccination improves the equity of health outcomes: evidence from Bangladesh.

PubMed

Bishai, David; Koenig, Michael; Ali Khan, Mehrab

2003-05-01

This paper asks whether measles vaccination can reduce socioeconomic differentials in under five mortality rates (U5MR) in a setting characterized by extreme poverty and high levels of childhood mortality. Longitudinal cohort study based on quasi experimental design. Data come from the phased introduction of a measles vaccine intervention in Matlab, Bangladesh in 1982. There were 16 270 Bangladeshi children aged 9-60 months. The intervention cohort received measles vaccine. Socioeconomic differentials in U5MR between the lowest and highest socioeconomic status (SES) quintiles in a cohort of 8135 vaccinated children and a cohort of unvaccinated age matched controls. Mantel-Haenszel rate ratios for the lowest to highest SES quintile were computed. SES was measured by factor analysis of maternal schooling, land holdings, dwelling size, and number of rooms. The U5MR ratio of lowest SES to highest was 2.27 (95% CI=1.62-3.19) in the unvaccinated population and 1.42 (95%CI=0.94-2.15) in the vaccinated population. The difference between unvaccinated and vaccinated U5MR ratios was statistically significant (p<0.10) and robust across alternative measures of SES. Children from the poorest quintile were more than twice as likely to die as those from the least quintile in the absence of measles vaccination. Universal distribution of measles vaccination largely nullified SES related mortality differentials within a high mortality population of children. Copyright 2002 John Wiley & Sons, Ltd.

Night work and breast cancer in women: a Swedish cohort study

PubMed Central

Åkerstedt, Torbjörn; Knutsson, Anders; Narusyte, Jurgita; Svedberg, Pia; Kecklund, Göran; Alexanderson, Kristina

2015-01-01

Objectives Recent research has suggested a moderate link between night work and breast cancer in women, mainly through case–control studies, but non-significant studies are also common and cohort studies are few. The purpose of the present study was to provide new information from cohort data through investigating the association between the number of years with night work and breast cancer among women. Design Cohort study of individuals exposed to night shift work in relation to incidence of breast cancer in women. Setting Individuals in the Swedish Twin registry, with follow-up in the Swedish Cancer Registry. Participants 13 656 women from the Swedish Twin Registry, with 3404 exposed to night work. Outcome measures Breast cancer from the Swedish Cancer Registry (463 cases) during a follow-up time of 12 years. Results A Cox proportional hazards regression analysis with control for a large number of confounders showed that the HR was HR=1.68 (95% CI 0.98 to 2.88) for the group with >20 years of night work. When the follow-up time was limited to ages below 60 years, those exposed >20 years showed a HR=1.77 (95% CI 1.03 to 3.04). Shorter exposure to night work showed no significant effects. Conclusions The present results, together with previous work, suggest that night work is associated with an increased risk of breast cancer in women, but only after relatively long-term exposure. PMID:25877283

Sensory sensitivity and symptom severity represent unique dimensions of chronic pain: a MAPP Research Network study.

PubMed

Schrepf, Andrew; Williams, David A; Gallop, Robert; Naliboff, Bruce; Basu, Neil; Kaplan, Chelsea; Harper, Daniel E; Landis, Richard; Clemens, J Quentin; Strachan, Eric; Griffith, James W; Afari, Niloofar; Hassett, Afton; Pontari, Michel A; Clauw, Daniel J; Harte, Steven E

2018-05-28

Chronic Overlapping Pain Conditions (COPCs) are characterized by aberrant central nervous system processing of pain. This 'centralized pain' phenotype has been described using a large and diverse set of symptom domains, including the spatial distribution of pain, pain intensity, fatigue, mood imbalances, cognitive dysfunction, altered somatic sensations, and hypersensitivity to external stimuli. Here we used three cohorts, including patients with Urologic Chronic Pelvic Pain Syndrome (UCPPS), a mixed pain cohort with other COPCs, and healthy individuals (total n = 1039) from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network to explore the factor structure of symptoms of centralized pain. Using exploratory and confirmatory factor analysis, we identified two general factors in all three cohorts, one characterized by a broad increased sensitivity to internal somatic sensations and environmental stimuli, and diffuse pain, termed Generalized Sensory Sensitivity (GSS), and one characterized by constitutional symptoms - Sleep, Pain, Affect, Cognition, Energy (SPACE). Longitudinal analyses in the UCPPS cohort found the same two factor structure at month six and one year, suggesting that the two factor structure is reproducible over time. In secondary analyses we found that GSS particularly is associated with the presence of comorbid COPCs, while SPACE shows modest associations with measures of disability and urinary symptoms. These factors may represent important and distinct continuum of symptoms that are indicative of the centralized pain phenotype at high levels. Future research of COPCs should accommodate the measurement of each factor.

HIV Type 1 Disease Progression to AIDS and Death in a Rural Ugandan Cohort Is Primarily Dependent on Viral Load Despite Variable Subtype and T-Cell Immune Activation Levels

PubMed Central

Eller, Michael A.; Opollo, Marc S.; Liu, Michelle; Redd, Andrew D.; Eller, Leigh Anne; Kityo, Cissy; Kayiwa, Joshua; Laeyendecker, Oliver; Wawer, Maria J.; Milazzo, Mark; Kiwanuka, Noah; Gray, Ronald H.; Serwadda, David; Sewankambo, Nelson K.; Quinn, Thomas C.; Michael, Nelson L.; Wabwire-Mangen, Fred; Sandberg, Johan K.; Robb, Merlin L.

2015-01-01

Background. Untreated human immunodeficiency virus type 1 (HIV) infection is associated with persistent immune activation, which is an independent driver of disease progression in European and United States cohorts. In Uganda, HIV-1 subtypes A and D and recombinant AD viruses predominate and exhibit differential rates of disease progression. Methods. HIV-1 seroconverters (n = 156) from rural Uganda were evaluated to assess the effects of T-cell activation, viral load, and viral subtype on disease progression during clinical follow-up. Results. The frequency of activated T cells was increased in HIV-1–infected Ugandans, compared with community matched uninfected individuals, but did not differ significantly between viral subtypes. Higher HIV-1 load, subtype D, older age, and high T-cell activation levels were associated with faster disease progression to AIDS or death. In a multivariate Cox regression analysis, HIV-1 load was the strongest predictor of progression, with subtype also contributing. T-cell activation did not emerge an independent predictor of disease progression from this particular cohort. Conclusions. These findings suggest that the independent contribution of T-cell activation on morbidity and mortality observed in European and North American cohorts may not be directly translated to the HIV epidemic in East Africa. In this setting, HIV-1 load appears to be the primary determinant of disease progression. PMID:25404522

Polygenic risk for coronary artery disease is associated with cognitive ability in older adults

PubMed Central

Hagenaars, Saskia P; Harris, Sarah E; Clarke, Toni-Kim; Hall, Lynsey; Luciano, Michelle; Fernandez-Pujals, Ana Maria; Davies, Gail; Hayward, Caroline; Starr, John M; Porteous, David J; McIntosh, Andrew M; Deary, Ian J

2016-01-01

Abstract Background: Coronary artery disease (CAD) is associated with cognitive decrements and risk of later dementia, but it is not known if shared genetic factors underlie this association. We tested whether polygenic risk for CAD was associated with cognitive ability in community-dwelling cohorts of middle-aged and older adults. Methods: Individuals from Generation Scotland: Scottish Family Health Study (GS:SFHS, N = 9865) and from the Lothian Birth Cohorts of 1921 (LBC1921, N  = 517) and 1936 (LBC1936, N  = 1005) provided cognitive data and genome-wide genotype data. Polygenic risk profile scores for CAD were calculated for all of the cohorts using the largest available genome-wide association studies (GWAS) data set, the CARDIoGRAM consortium (22 233 cases and 64 762 controls). Polygenic risk profile scores for CAD were then tested for their association with cognitive abilities in the presence and absence of manifest cardiovascular disease. Results: A meta-analysis of all three cohorts showed a negative association between CAD polygenic risk and fluid cognitive ability (β = −0.022, P  = 0.016), verbal intelligence (β = −0.024, P  = 0.011) and memory (β = −0.021, P  = 0.028). Conclusions: Increased polygenic risk for CAD is associated with lower cognitive ability in older adults. Common genetic variants may underlie some of the association between age-related cognitive decrements and the risk for CAD. PMID:26822939

Cohort profile: the chronic kidney disease prognosis consortium.

PubMed

Matsushita, Kunihiro; Ballew, Shoshana H; Astor, Brad C; Jong, Paul E de; Gansevoort, Ron T; Hemmelgarn, Brenda R; Levey, Andrew S; Levin, Adeera; Wen, Chi-Pang; Woodward, Mark; Coresh, Josef

2013-12-01

The Chronic Kidney Disease Prognosis Consortium (CKD-PC) was established in 2009 to provide comprehensive evidence about the prognostic impact of two key kidney measures that are used to define and stage CKD, estimated glomerular filtration rate (eGFR) and albuminuria, on mortality and kidney outcomes. CKD-PC currently consists of 46 cohorts with data on these kidney measures and outcomes from >2 million participants spanning across 40 countries/regions all over the world. CKD-PC published four meta-analysis articles in 2010-11, providing key evidence for an international consensus on the definition and staging of CKD and an update for CKD clinical practice guidelines. The consortium continues to work on more detailed analysis (subgroups, different eGFR equations, other exposures and outcomes, and risk prediction). CKD-PC preferably collects individual participant data but also applies a novel distributed analysis model, in which each cohort runs statistical analysis locally and shares only analysed outputs for meta-analyses. This distributed model allows inclusion of cohorts which cannot share individual participant level data. According to agreement with cohorts, CKD-PC will not share data with third parties, but is open to including further eligible cohorts. Each cohort can opt in/out for each topic. CKD-PC has established a productive and effective collaboration, allowing flexible participation and complex meta-analyses for studying CKD.

Major prognostic role of Ki67 in localized adrenocortical carcinoma after complete resection.

PubMed

Beuschlein, Felix; Weigel, Jens; Saeger, Wolfgang; Kroiss, Matthias; Wild, Vanessa; Daffara, Fulvia; Libé, Rosella; Ardito, Arianna; Al Ghuzlan, Abir; Quinkler, Marcus; Oßwald, Andrea; Ronchi, Cristina L; de Krijger, Ronald; Feelders, Richard A; Waldmann, Jens; Willenberg, Holger S; Deutschbein, Timo; Stell, Anthony; Reincke, Martin; Papotti, Mauro; Baudin, Eric; Tissier, Frédérique; Haak, Harm R; Loli, Paola; Terzolo, Massimo; Allolio, Bruno; Müller, Hans-Helge; Fassnacht, Martin

2015-03-01

Recurrence of adrenocortical carcinoma (ACC) even after complete (R0) resection occurs frequently. The aim of this study was to identify markers with prognostic value for patients in this clinical setting. From the German ACC registry, 319 patients with the European Network for the Study of Adrenal Tumors stage I-III were identified. As an independent validation cohort, 250 patients from three European countries were included. Clinical, histological, and immunohistochemical markers were correlated with recurrence-free (RFS) and overall survival (OS). Although univariable analysis within the German cohort suggested several factors with potential prognostic power, upon multivariable adjustment only a few including age, tumor size, venous tumor thrombus (VTT), and the proliferation marker Ki67 retained significance. Among these, Ki67 provided the single best prognostic value for RFS (hazard ratio [HR] for recurrence, 1.042 per 1% increase; P < .0001) and OS (HR for death, 1.051; P < .0001) which was confirmed in the validation cohort. Accordingly, clinical outcome differed significantly between patients with Ki67 <10%, 10-19%, and ≥20% (for the German cohort: median RFS, 53.2 vs 31.6 vs 9.4 mo; median OS, 180.5 vs 113.5 vs 42.0 mo). Using the combined cohort prognostic scores including tumor size, VTT, and Ki67 were established. Although these scores discriminated slightly better between subgroups, there was no clinically meaningful advantage in comparison with Ki67 alone. This largest study on prognostic markers in localized ACC identified Ki67 as the single most important factor predicting recurrence in patients following R0 resection. Thus, evaluation of Ki67 indices should be introduced as standard grading in all pathology reports of patients with ACC.

THYROID CANCER STUDY AMONG UKRAINIAN CHILDREN EXPOSED TO RADIATION AFTER THE CHORNOBYL ACCIDENT: IMPROVED ESTIMATES OF THE THYROID DOSES TO THE COHORT MEMBERS

PubMed Central

Likhtarov, Ilya; Kovgan, Lina; Masiuk, Sergii; Talerko, Mykola; Chepurny, Mykola; Ivanova, Olga; Gerasymenko, Valentina; Boyko, Zulfira; Voillequé, Paul; Drozdovitch, Vladimir; Bouville, André

2013-01-01

In collaboration with the Ukrainian Research Center for Radiation Medicine, the U.S. National Cancer Institute initiated a cohort study of children and adolescents exposed to Chornobyl fallout in Ukraine to better understand the long-term health effects of exposure to radioactive iodines. All 13,204 cohort members were subjected to at least one direct thyroid measurement between 30 April and 30 June 1986 and resided at the time of the accident in the northern part of Kyiv, Zhytomyr, or Chernihiv Oblasts, which were the most contaminated territories of Ukraine as a result of radioactive fallout from the Chornobyl accident. Thyroid doses for the cohort members, which had been estimated following the first round of interviews, were re-evaluated following the second round of interviews. The revised thyroid doses range from 0.35 mGy to 42 Gy, with 95 percent of the doses between 1 mGy and 4.2 Gy, an arithmetic mean of 0.65 Gy, and a geometric mean of 0.19 Gy. These means are 70% of the previous estimates, mainly because of the use of country-specific thyroid masses. Many of the individual thyroid dose estimates show substantial differences because of the use of an improved questionnaire for the second round of interviews. Limitations of the current set of thyroid dose estimates are discussed. For the epidemiologic study, the most notable improvement is a revised assessment of the uncertainties, as shared and unshared uncertainties in the parameter values were considered in the calculation of the 1,000 stochastic estimates of thyroid dose for each cohort member. This procedure makes it possible to perform a more realistic risk analysis. PMID:25208014

Associations of estimated glomerular filtration rate and albuminuria with mortality and renal failure by sex: a meta-analysis

PubMed Central

Nitsch, Dorothea; Grams, Morgan; Sang, Yingying; Black, Corri; Cirillo, Massimo; Djurdjev, Ognjenka; Iseki, Kunitoshi; Jassal, Simerjot K; Kimm, Heejin; Kronenberg, Florian; Øien, Cecilia M; Levin, Adeera; Woodward, Mark; Hemmelgarn, Brenda R

2013-01-01

Objective To assess for the presence of a sex interaction in the associations of estimated glomerular filtration rate and albuminuria with all-cause mortality, cardiovascular mortality, and end stage renal disease. Design Random effects meta-analysis using pooled individual participant data. Setting 46 cohorts from Europe, North and South America, Asia, and Australasia. Participants 2 051 158 participants (54% women) from general population cohorts (n=1 861 052), high risk cohorts (n=151 494), and chronic kidney disease cohorts (n=38 612). Eligible cohorts (except chronic kidney disease cohorts) had at least 1000 participants, outcomes of either mortality or end stage renal disease of ≥50 events, and baseline measurements of estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology Collaboration equation (mL/min/1.73 m2) and urinary albumin-creatinine ratio (mg/g). Results Risks of all-cause mortality and cardiovascular mortality were higher in men at all levels of estimated glomerular filtration rate and albumin-creatinine ratio. While higher risk was associated with lower estimated glomerular filtration rate and higher albumin-creatinine ratio in both sexes, the slope of the risk relationship for all-cause mortality and for cardiovascular mortality were steeper in women than in men. Compared with an estimated glomerular filtration rate of 95, the adjusted hazard ratio for all-cause mortality at estimated glomerular filtration rate 45 was 1.32 (95% CI 1.08 to 1.61) in women and 1.22 (1.00 to 1.48) in men (Pinteraction<0.01). Compared with a urinary albumin-creatinine ratio of 5, the adjusted hazard ratio for all-cause mortality at urinary albumin-creatinine ratio 30 was 1.69 (1.54 to 1.84) in women and 1.43 (1.31 to 1.57) in men (Pinteraction<0.01). Conversely, there was no evidence of a sex difference in associations of estimated glomerular filtration rate and urinary albumin-creatinine ratio with end stage renal disease risk. Conclusions Both sexes face increased risk of all-cause mortality, cardiovascular mortality, and end stage renal disease with lower estimated glomerular filtration rates and higher albuminuria. These findings were robust across a large global consortium. PMID:23360717

Activities of daily living in nursing home and home care settings: a retrospective 1-year cohort study.

PubMed

Lee, Tae Wha; Cho, Eunhee; Yim, Eun Shil; Lee, Hye Sun; Ko, Yu Kyung; Kim, Bok Nam; Kim, Sinhye

2015-02-01

Korea introduced universal long-term care insurance (LTCI) for physically dependent older adults in 2008. Older adults, their family members, and policy makers in Korea want to know patient outcomes in different care modalities because older adults who have a similar functional status and LTC needs can choose either nursing home care or home care. The aim of this study was to compare activities of daily living (ADLs) in nursing home care and home care settings for physically dependent older adults in Korea. A retrospective 1-year cohort study using national LTCI data. This study used the LTCI dataset from the National Health Insurance Service in Korea. Participants were identified from among those in the LTCI dataset who enrolled from July 2008 to June 2010. We extracted a sample consisting of 22,557 older adults who consistently received either nursing home care (n = 11,678) or home care (n = 10,879) for 1 year. The outcome variable was change in ADLs after 1 year. Covariates were an older adult's home geographical region, LTC level, age, sex, primary caregiver, Medicaid beneficiary status, bedridden status, medical diagnosis, baseline ADLs, cognitive function, behavioral problems, nursing and special treatment, and rehabilitation needs. Multiple regression analysis of all participants unmatched and a paired t-test with a propensity-score-matched cohort were performed to explain the association of changes in ADLs with the types of LTC. Multiple regression analysis with all participants (n = 22,557) unmatched showed that compared with older adults who received home care, those who received nursing home care had deteriorated further in terms of ADLs after 1 year (β = 0.44108, P < .0001). After propensity-score matching, paired t-test analysis also found that the ADLs of older adults had deteriorated less in the home care group compared with the nursing home group after 1 year (P < .0001). The ADLs of older adults who received home care showed significantly less deterioration than those of the older adults in nursing home care after 1 year. The ADLs of older adults could differ according to the type of LTC they receive, and home care could result in better maintenance of ADLs than nursing home care. Copyright © 2015 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.

N-of-1-pathways MixEnrich: advancing precision medicine via single-subject analysis in discovering dynamic changes of transcriptomes.

PubMed

Li, Qike; Schissler, A Grant; Gardeux, Vincent; Achour, Ikbel; Kenost, Colleen; Berghout, Joanne; Li, Haiquan; Zhang, Hao Helen; Lussier, Yves A

2017-05-24

Transcriptome analytic tools are commonly used across patient cohorts to develop drugs and predict clinical outcomes. However, as precision medicine pursues more accurate and individualized treatment decisions, these methods are not designed to address single-patient transcriptome analyses. We previously developed and validated the N-of-1-pathways framework using two methods, Wilcoxon and Mahalanobis Distance (MD), for personal transcriptome analysis derived from a pair of samples of a single patient. Although, both methods uncover concordantly dysregulated pathways, they are not designed to detect dysregulated pathways with up- and down-regulated genes (bidirectional dysregulation) that are ubiquitous in biological systems. We developed N-of-1-pathways MixEnrich, a mixture model followed by a gene set enrichment test, to uncover bidirectional and concordantly dysregulated pathways one patient at a time. We assess its accuracy in a comprehensive simulation study and in a RNA-Seq data analysis of head and neck squamous cell carcinomas (HNSCCs). In presence of bidirectionally dysregulated genes in the pathway or in presence of high background noise, MixEnrich substantially outperforms previous single-subject transcriptome analysis methods, both in the simulation study and the HNSCCs data analysis (ROC Curves; higher true positive rates; lower false positive rates). Bidirectional and concordant dysregulated pathways uncovered by MixEnrich in each patient largely overlapped with the quasi-gold standard compared to other single-subject and cohort-based transcriptome analyses. The greater performance of MixEnrich presents an advantage over previous methods to meet the promise of providing accurate personal transcriptome analysis to support precision medicine at point of care.

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.

Is adjuvant chemotherapy indicated in ovarian immature teratomas? A combined data analysis from the Malignant Germ Cell Tumor International Collaborative.

PubMed

Pashankar, Farzana; Hale, Juliet P; Dang, Ha; Krailo, Mark; Brady, William E; Rodriguez-Galindo, Carlos; Nicholson, James C; Murray, Matthew J; Bilmire, Deborah F; Stoneham, Sara; Arul, G Suren; Olson, Thomas A; Stark, Daniel; Shaikh, Furqan; Amatruda, James F; Covens, Allan; Gershenson, David M; Frazier, A Lindsay

2016-01-15

There is a debate regarding the management of ovarian immature teratomas (ITs). In adult women, postoperative chemotherapy is standard except for stage I, grade 1 disease, whereas surgery alone is standard in pediatric patients. To determine the role of chemotherapy, a pooled analysis of pediatric and adult clinical trials was conducted. Data from 7 pediatric trials and 2 adult trials were merged in the Malignant Germ Cell International Collaborative data set. Four trials included patients with newly diagnosed pure ovarian ITs and were selected (Pediatric Oncology Group/Children's Cancer Group Intergroup Study (INT 0106), Second UKCCSG Germ Cell Tumor Study (GC2), Gynecologic Oncology Group (GOG 0078 and GOG 0090). Adult and pediatric trials were analyzed separately. The primary outcome measures were event-free survival (EFS) and overall survival (OS). One hundred seventy-nine patients were included (98 pediatric patients and 81 adult patients). Ninety pediatric patients were treated with surgery alone, whereas all adult patients received chemotherapy. The 5-year EFS and OS were 91% and 99%, respectively, for the pediatric cohort and 87% and 93%, respectively, for the adults. There were no relapses in grade 1 patients, regardless of the stage or age. Only 1 adult patient with a grade 2 IT relapsed. Among grade 3 patients, the 5-year EFS was 0.92 (0.72-0.98) for stage I/II and 0.52 (0.22-0.75) for stage III in the pediatric cohort (P = .005) and 0.91 (0.69-0.98) for stage I/II and 0.65 (0.39-0.83) for stage III/IV in the adult cohort (P = .01). Postoperative chemotherapy did not decrease relapses in the pediatric cohort. The grade was the most important risk factor for relapse in ovarian ITs. Among grade 3 patients, the stage was significantly associated with relapse. Adjuvant chemotherapy did not decrease relapses in the pediatric cohort; its role in adults remains unresolved. Cancer 2016;122:230-237. © 2015 American Cancer Society. © 2015 American Cancer Society.

Radio frequency radiation-related cancer: assessing causation in the occupational/military setting.

PubMed

Peleg, Michael; Nativ, Or; Richter, Elihu D

2018-05-01

We reexamine whether radio frequency radiation (RFR) in the occupational and military settings is a human carcinogen. We extended an analysis of an already-reported case series of patients with cancer previously exposed to whole-body prolonged RFR, mainly from communication equipment and radar. We focused on hematolymphatic (HL) cancers. We used analysis by percentage frequency (PF) of a cancer type, which is the proportion of a specific cancer type relative to the total number of cancer cases. We also examined and analyzed the published data on three other cohort studies from similar military settings from different countries. The PF of HL cancers in the case series was very high, at 40% with only 23% expected for the series age and gender profile, confidence interval CI95%: 26-56%, p<0.01, 19 out of 47 patients had HL cancers. We also found high PF for multiple primaries. As for the three other cohort studies: In the Polish military sector, the PF of HL cancers was 36% in the exposed population as compared to 12% in the unexposed population, p<0.001. In a small group of employees exposed to RFR in Israeli defense industry, the PF of HL cancers was 60% versus 17% expected for the group age and gender profile, p<0.05. In Belgian radar battalions the HL PF was 8.3% versus 1.4% in the control battalions as shown in a causes of deaths study and HL cancer mortality rate ratio was 7.2 and statistically significant. Similar findings were reported on radio amateurs and Korean war technicians. Elevated risk ratios were previously reported in most of the above studies. The consistent association of RFR and highly elevated HL cancer risk in the four groups spread over three countries, operating different RFR equipment types and analyzed by different research protocols, suggests a cause-effect relationship between RFR and HL cancers in military/occupational settings. While complete measurements of RFR exposures were not available and rough exposure assessments from patients interviews and from partial exposure data were used instead, we have demonstrated increased HL cancers in occupational groups with relatively high RFR exposures. Our findings, combined with other studies, indicate that exposures incurred in the military settings evaluated here significantly increased the risk of HL cancers. Accordingly, the RFR military exposures in these occupations should be substantially reduced and further efforts should be undertaken to monitor and measure those exposures and to follow cohorts exposed to RFR for cancers and other health effects. Overall, the epidemiological studies on excess risk for HL and other cancers together with brain tumors in cellphone users and experimental studies on RFR and carcinogenicity make a coherent case for a cause-effect relationship and classifying RFR exposure as a human carcinogen (IARC group 1). Copyright © 2018 Elsevier Inc. All rights reserved.

The rate of sputum smear-positive tuberculosis after treatment default in a high-burden setting: a retrospective cohort study.

PubMed

Marx, Florian M; Dunbar, Rory; Enarson, Donald A; Beyers, Nulda

2012-01-01

High rates of recurrent tuberculosis after successful treatment have been reported from different high burden settings in Sub-Saharan Africa. However, little is known about the rate of smear-positive tuberculosis after treatment default. In particular, it is not known whether or not treatment defaulters continue to be or become again smear-positive and thus pose a potential for transmission of infection to others. To investigate, in a high tuberculosis burden setting, the rate of re-treatment for smear-positive tuberculosis among cases defaulting from standardized treatment compared to successfully treated cases. Retrospective cohort study among smear-positive tuberculosis cases treated between 1996 and 2008 in two urban communities in Cape Town, South Africa. Episodes of re-treatment for smear-positive tuberculosis were ascertained via probabilistic record linkage. Survival analysis and Poisson regression were used to compare the rate of smear-positive tuberculosis after treatment default to that after successful treatment. A total of 2,136 smear-positive tuberculosis cases were included in the study. After treatment default, the rate of re-treatment for smear-positive tuberculosis was 6.86 (95% confidence interval [CI]: 5.59-8.41) per 100 person-years compared to 2.09 (95% CI: 1.81-2.41) after cure (adjusted Hazard Ratio [aHR]: 3.97; 95% CI: 3.00-5.26). Among defaulters, the rate was inversely associated with treatment duration and sputum conversion prior to defaulting. Smear grade at start of the index treatment episode (Smear3+: aHR 1.61; 95%CI 1.11-2.33) was independently associated with smear-positive tuberculosis re-treatment, regardless of treatment outcome. In this high-burden setting, there is a high rate of subsequent smear-positive tuberculosis after treatment default. Treatment defaulters are therefore likely to contribute to the pool of infectious source cases in the community. Our findings underscore the importance of preventing treatment default, as a means of successful tuberculosis control in high-burden settings.

Energy Setting and Visual Outcomes in SMILE: A Retrospective Cohort Study.

PubMed

Li, Liuyang; Schallhorn, Julie M; Ma, Jiaonan; Cui, Tong; Wang, Yan

2018-01-01

To assess the independent effect of energy setting on postoperative uncorrected distance visual acuity (UDVA) in small incision lenticule extraction (SMILE) and further investigate an optimal energy setting for the 4.5-μm spot-track-distance, which is in wide clinical use. A total of 1,130 eyes were included in a retrospective cohort study from Tianjin Eye Hospital, Tianjin Medical University from April 2015 to July 2016. Energy settings and baseline characteristics were recorded and 3-month UDVA was tested by a nurse blinded to the energy settings used. Multiple regression analysis and generalized estimating equations were used to take into account the correlation between the measurements from two eyes. The 3-month UDVA (mean ± standard deviation) of 125 to 160 nJ (by 5-nJ increments) was 1.39 ± 0.19, 1.40 ± 0.32, 1.33 ± 0.27, 1.36 ± 0.27, 1.34 ± 0.25, 1.29 ± 0.19, 1.36 ± 0.27, and 1.19 ± 0.22, respectively. Energy was significantly associated with postoperative logMAR UDVA in different models and the regression coefficient (β) was robust (β = 0.01, 95% confidence interval = 0.00 to 0.01). The regression coefficient β (0.01, 95% confidence interval = 0.00 to 0.02, P = .0029) of energy (125 to 150 nJ, by 5-nJ increments) on 4.5-μm spot-track-distance was still associated with the logMAR UDVA when adjusted for sex, age, myopia, astigmatism, mean keratometry, central corneal thickness, preoperative logMAR CDVA, and side spot-track-distance. The lower end of the energy studied was associated with a better postoperative UDVA in this population. The spot-track-distance of 4.5 μm with 125 nJ energy was the optimal combination within this range. [J Refract Surg. 2018;34(1):11-16.]. Copyright 2018, SLACK Incorporated.

Assessment of gene-by-sex interaction effect on bone mineral density.

PubMed

Liu, Ching-Ti; Estrada, Karol; Yerges-Armstrong, Laura M; Amin, Najaf; Evangelou, Evangelos; Li, Guo; Minster, Ryan L; Carless, Melanie A; Kammerer, Candace M; Oei, Ling; Zhou, Yanhua; Alonso, Nerea; Dailiana, Zoe; Eriksson, Joel; García-Giralt, Natalia; Giroux, Sylvie; Husted, Lise Bjerre; Khusainova, Rita I; Koromila, Theodora; Kung, Annie Waichee; Lewis, Joshua R; Masi, Laura; Mencej-Bedrac, Simona; Nogues, Xavier; Patel, Millan S; Prezelj, Janez; Richards, J Brent; Sham, Pak Chung; Spector, Timothy; Vandenput, Liesbeth; Xiao, Su-Mei; Zheng, Hou-Feng; Zhu, Kun; Balcells, Susana; Brandi, Maria Luisa; Frost, Morten; Goltzman, David; González-Macías, Jesús; Karlsson, Magnus; Khusnutdinova, Elza K; Kollia, Panagoula; Langdahl, Bente Lomholt; Ljunggren, Osten; Lorentzon, Mattias; Marc, Janja; Mellström, Dan; Ohlsson, Claes; Olmos, José M; Ralston, Stuart H; Riancho, José A; Rousseau, François; Urreizti, Roser; Van Hul, Wim; Zarrabeitia, María T; Castano-Betancourt, Martha; Demissie, Serkalem; Grundberg, Elin; Herrera, Lizbeth; Kwan, Tony; Medina-Gómez, Carolina; Pastinen, Tomi; Sigurdsson, Gunnar; Thorleifsson, Gudmar; Vanmeurs, Joyce Bj; Blangero, John; Hofman, Albert; Liu, Yongmei; Mitchell, Braxton D; O'Connell, Jeffrey R; Oostra, Ben A; Rotter, Jerome I; Stefansson, Kari; Streeten, Elizabeth A; Styrkarsdottir, Unnur; Thorsteinsdottir, Unnur; Tylavsky, Frances A; Uitterlinden, Andre; Cauley, Jane A; Harris, Tamara B; Ioannidis, John Pa; Psaty, Bruce M; Robbins, John A; Zillikens, M Carola; Vanduijn, Cornelia M; Prince, Richard L; Karasik, David; Rivadeneira, Fernando; Kiel, Douglas P; Cupples, L Adrienne; Hsu, Yi-Hsiang

2012-10-01

Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 × 10(-5) ) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 × 10(-5) ; female effect = -0.007 and p = 3.3 × 10(-2) ), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 × 10(-8) ) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP. © 2012 American Society for Bone and Mineral Research. Copyright © 2012 American Society for Bone and Mineral Research.

Anion gap as a prognostic tool for risk stratification in critically ill patients - a systematic review and meta-analysis.

PubMed

Glasmacher, Stella Andrea; Stones, William

2016-08-30

Lactate concentration is a robust predictor of mortality but in many low resource settings facilities for its analysis are not available. Anion gap (AG), calculated from clinical chemistry results, is a marker of metabolic acidosis and may be more easily obtained in such settings. In this systematic review and meta-analysis we investigated whether the AG predicts mortality in adult patients admitted to critical care settings. We searched Medline, Embase, Web of Science, Scopus, The Cochrane Library and regional electronic databases from inception until May 2016. Studies conducted in any clinical setting that related AG to in-hospital mortality, in-intensive care unit mortality, 31-day mortality or comparable outcome measures were eligible for inclusion. Methodological quality of included studies was assessed using the Quality in Prognostic Studies tool. Descriptive meta-analysis was performed and the I(2) test was used to quantify heterogeneity. Subgroup analysis was undertaken to identify potential sources of heterogeneity between studies. Nineteen studies reporting findings in 12,497 patients were included. Overall, quality of studies was poor and most studies were rated as being at moderate or high risk of attrition bias and confounding. There was substantial diversity between studies with regards to clinical setting, age and mortality rates of patient cohorts. High statistical heterogeneity was found in the meta-analyses of area under the ROC curve (I(2) = 99 %) and mean difference (I(2) = 97 %) for the observed AG. Three studies reported good discriminatory power of the AG to predict mortality and were responsible for a large proportion of statistical heterogeneity. The remaining 16 studies reported poor to moderate ability of the AG to predict mortality. Subgroup analysis suggested that intravenous fluids affect the ability of the AG to predict mortality. Based on the limited quality of available evidence, a single AG measurement cannot be recommended for risk stratification in critically ill patients. The probable influence of intravenous fluids on AG levels renders the AG an impractical tool in clinical practice. Future research should focus on increasing the availability of lactate monitoring in low resource settings. CRD42015015249 . Registered on 4th February 2015.

Systematic computation with functional gene-sets among leukemic and hematopoietic stem cells reveals a favorable prognostic signature for acute myeloid leukemia.

PubMed

Yang, Xinan Holly; Li, Meiyi; Wang, Bin; Zhu, Wanqi; Desgardin, Aurelie; Onel, Kenan; de Jong, Jill; Chen, Jianjun; Chen, Luonan; Cunningham, John M

2015-03-24

Genes that regulate stem cell function are suspected to exert adverse effects on prognosis in malignancy. However, diverse cancer stem cell signatures are difficult for physicians to interpret and apply clinically. To connect the transcriptome and stem cell biology, with potential clinical applications, we propose a novel computational "gene-to-function, snapshot-to-dynamics, and biology-to-clinic" framework to uncover core functional gene-sets signatures. This framework incorporates three function-centric gene-set analysis strategies: a meta-analysis of both microarray and RNA-seq data, novel dynamic network mechanism (DNM) identification, and a personalized prognostic indicator analysis. This work uses complex disease acute myeloid leukemia (AML) as a research platform. We introduced an adjustable "soft threshold" to a functional gene-set algorithm and found that two different analysis methods identified distinct gene-set signatures from the same samples. We identified a 30-gene cluster that characterizes leukemic stem cell (LSC)-depleted cells and a 25-gene cluster that characterizes LSC-enriched cells in parallel; both mark favorable-prognosis in AML. Genes within each signature significantly share common biological processes and/or molecular functions (empirical p = 6e-5 and 0.03 respectively). The 25-gene signature reflects the abnormal development of stem cells in AML, such as AURKA over-expression. We subsequently determined that the clinical relevance of both signatures is independent of known clinical risk classifications in 214 patients with cytogenetically normal AML. We successfully validated the prognosis of both signatures in two independent cohorts of 91 and 242 patients respectively (log-rank p < 0.0015 and 0.05; empirical p < 0.015 and 0.08). The proposed algorithms and computational framework will harness systems biology research because they efficiently translate gene-sets (rather than single genes) into biological discoveries about AML and other complex diseases.

Survivorship and functional outcomes of patellofemoral arthroplasty: a systematic review.

PubMed

van der List, J P; Chawla, H; Zuiderbaan, H A; Pearle, A D

2017-08-01

Historically poor results of survivorship and functional outcomes of patellofemoral arthroplasty (PFA) have been reported in the setting of isolated patellofemoral osteoarthritis. More recently, however, fairly good results of PFA were reported, but the current status of PFA outcomes is unknown. Therefore, a systematic review was performed to assess overall PFA survivorship and functional outcomes. A search was performed using PubMed, Embase and Cochrane systems, and the registries were searched. Twenty-three cohort studies and one registry reported survivorship using Kaplan-Meier curve, while 51 cohort studies reported functional outcomes of PFA. Twelve studies were level II studies, while 45 studies were level III or IV studies. Heterogeneity was mainly seen in type of prosthesis and year the cohort started. Nine hundred revisions in 9619 PFAs were reported yielding 5-, 10-, 15- and 20-year PFA survivorships of 91.7, 83.3, 74.9 and 66.6 %, respectively, and an annual revision rate of 2.18. Functional outcomes were reported in 2587 PFAs with an overall score of 82.2 % of the maximum score. KSS and Knee Function Score were 87.5 and 81.6 %, respectively. This systematic review showed that fairly good results of PFA survivorship and functional outcomes were reported at short- and midterm follow-up in the setting of isolated patellofemoral osteoarthritis. Heterogeneity existed mainly in prosthesis design and year the cohort started. These results provide a clear overview of the current status of PFA in the setting of isolated patellofemoral osteoarthritis. IV.

The role of environmental heterogeneity in meta-analysis of gene-environment interactions with quantitative traits.

PubMed

Li, Shi; Mukherjee, Bhramar; Taylor, Jeremy M G; Rice, Kenneth M; Wen, Xiaoquan; Rice, John D; Stringham, Heather M; Boehnke, Michael

2014-07-01

With challenges in data harmonization and environmental heterogeneity across various data sources, meta-analysis of gene-environment interaction studies can often involve subtle statistical issues. In this paper, we study the effect of environmental covariate heterogeneity (within and between cohorts) on two approaches for fixed-effect meta-analysis: the standard inverse-variance weighted meta-analysis and a meta-regression approach. Akin to the results in Simmonds and Higgins (), we obtain analytic efficiency results for both methods under certain assumptions. The relative efficiency of the two methods depends on the ratio of within versus between cohort variability of the environmental covariate. We propose to use an adaptively weighted estimator (AWE), between meta-analysis and meta-regression, for the interaction parameter. The AWE retains full efficiency of the joint analysis using individual level data under certain natural assumptions. Lin and Zeng (2010a, b) showed that a multivariate inverse-variance weighted estimator retains full efficiency as joint analysis using individual level data, if the estimates with full covariance matrices for all the common parameters are pooled across all studies. We show consistency of our work with Lin and Zeng (2010a, b). Without sacrificing much efficiency, the AWE uses only univariate summary statistics from each study, and bypasses issues with sharing individual level data or full covariance matrices across studies. We compare the performance of the methods both analytically and numerically. The methods are illustrated through meta-analysis of interaction between Single Nucleotide Polymorphisms in FTO gene and body mass index on high-density lipoprotein cholesterol data from a set of eight studies of type 2 diabetes. © 2014 WILEY PERIODICALS, INC.

A Meta-analysis of the Association of Estimated GFR, Albuminuria, Age, Race, and Sex With Acute Kidney Injury

PubMed Central

Grams, Morgan E.; Sang, Yingying; Ballew, Shoshana H.; Gansevoort, Ron T.; Kimm, Heejin; Kovesdy, Csaba P.; Naimark, David; Oien, Cecilia; Smith, David H.; Coresh, Josef; Sarnak, Mark J.; Stengel, Benedicte; Tonelli, Marcello

2015-01-01

Background Acute kidney injury (AKI) is a serious global public health problem. We aimed to quantify the risk of AKI associated with estimated glomerular filtration rate (eGFR), albuminuria (albumin-creatinine ratio [ACR]), age, sex, and race (African American and Caucasian). Study Design Collaborative meta-analysis. Setting & Population 8 general population cohorts (1,285,049 participants) and 5 chronic kidney disease (CKD) cohorts (79,519 participants). Selection Criteria for Studies Available eGFR, ACR, and ≥50 AKI events. Predictors Age, sex, race, eGFR, urine ACR, and interactions. Outcome Hospitalized with or for AKI, using Cox proportional hazards models to estimate HRs of AKI and random effects meta-analysis to pool results. Results 16,480 (1.3%) general population cohort participants had AKI over a mean follow-up of 4 years; 2,087 (2.6%) CKD participants had AKI over mean follow-up of 1 year. Lower eGFR and higher ACR were strongly associated with AKI. Compared with eGFR 80 ml/min/1.73 m2, the adjusted HR of AKI at eGFR 45 ml/min/1.73 m2 was 3.35 (95% CI, 2.75–4.07). Compared with ACR 5 mg/g, the risk of AKI at ACR 300 mg/g was 2.73 (95% CI, 2.18–3.43). Older age was associated with higher risk of AKI, but this effect was attenuated in lower eGFR or higher ACR. Male sex was associated with higher risk of AKI, with a slight attenuation in lower eGFR but not in higher ACR. African Americans had higher AKI risk at higher levels of eGFR and most levels of ACR. Limitations Only 2 general population cohorts could contribute to analyses by race; AKI identified by diagnostic code. Conclusions Reduced eGFR and increased ACR are consistent, strong risk factors for AKI whereas the associations of AKI with age, sex, and race may be weaker in more advanced stages of CKD. PMID:25943717

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.

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.

Four-gene Pan-African Blood Signature Predicts Progression to Tuberculosis.

PubMed

Suliman, Sara; Thompson, Ethan; Sutherland, Jayne; Weiner Rd, January; Ota, Martin O C; Shankar, Smitha; Penn-Nicholson, Adam; Thiel, Bonnie; Erasmus, Mzwandile; Maertzdorf, Jeroen; Duffy, Fergal J; Hill, Philip C; Hughes, E Jane; Stanley, Kim; Downing, Katrina; Fisher, Michelle L; Valvo, Joe; Parida, Shreemanta K; van der Spuy, Gian; Tromp, Gerard; Adetifa, Ifedayo M O; Donkor, Simon; Howe, Rawleigh; Mayanja-Kizza, Harriet; Boom, W Henry; Dockrell, Hazel; Ottenhoff, Tom H M; Hatherill, Mark; Aderem, Alan; Hanekom, Willem A; Scriba, Thomas J; Kaufmann, Stefan He; Zak, Daniel E; Walzl, Gerhard

2018-04-06

Contacts of tuberculosis (TB) patients constitute an important target population for preventative measures as they are at high risk of infection with Mycobacterium tuberculosis and progression to disease. We investigated biosignatures with predictive ability for incident tuberculosis. In a case-control study nested within the Grand Challenges 6-74 longitudinal HIV-negative African cohort of exposed household contacts, we employed RNA sequencing, polymerase chain reaction (PCR) and the Pair Ratio algorithm in a training/test set approach. Overall, 79 progressors, who developed tuberculosis between 3 and 24 months following exposure, and 328 matched non-progressors, who remained healthy during 24 months of follow-up, were investigated. A four-transcript signature (RISK4), derived from samples in a South African and Gambian training set, predicted progression up to two years before onset of disease in blinded test set samples from South Africa, The Gambia and Ethiopia with little population-associated variability and also validated on an external cohort of South African adolescents with latent Mycobacterium tuberculosis infection. By contrast, published diagnostic or prognostic tuberculosis signatures predicted on samples from some but not all 3 countries, indicating site-specific variability. Post-hoc meta-analysis identified a single gene pair, C1QC/TRAV27, that would consistently predict TB progression in household contacts from multiple African sites but not in infected adolescents without known recent exposure events. Collectively, we developed a simple whole blood-based PCR test to predict tuberculosis in household contacts from diverse African populations, with potential for implementation in national TB contact investigation programs.

Rare Variant, Gene-Based Association Study of Hereditary Melanoma Using Whole-Exome Sequencing.

PubMed

Artomov, Mykyta; Stratigos, Alexander J; Kim, Ivana; Kumar, Raj; Lauss, Martin; Reddy, Bobby Y; Miao, Benchun; Daniela Robles-Espinoza, Carla; Sankar, Aravind; Njauw, Ching-Ni; Shannon, Kristen; Gragoudas, Evangelos S; Marie Lane, Anne; Iyer, Vivek; Newton-Bishop, Julia A; Timothy Bishop, D; Holland, Elizabeth A; Mann, Graham J; Singh, Tarjinder; Daly, Mark J; Tsao, Hensin

2017-12-01

Extraordinary progress has been made in our understanding of common variants in many diseases, including melanoma. Because the contribution of rare coding variants is not as well characterized, we performed an exome-wide, gene-based association study of familial cutaneous melanoma (CM) and ocular melanoma (OM). Using 11 990 jointly processed individual DNA samples, whole-exome sequencing was performed, followed by large-scale joint variant calling using GATK (Genome Analysis ToolKit). PLINK/SEQ was used for statistical analysis of genetic variation. Four models were used to estimate the association among different types of variants. In vitro functional validation was performed using three human melanoma cell lines in 2D and 3D proliferation assays. In vivo tumor growth was assessed using xenografts of human melanoma A375 melanoma cells in nude mice (eight mice per group). All statistical tests were two-sided. Strong signals were detected for CDKN2A (Pmin = 6.16 × 10-8) in the CM cohort (n = 273) and BAP1 (Pmin = 3.83 × 10-6) in the OM (n = 99) cohort. Eleven genes that exhibited borderline association (P < 10-4) were independently validated using The Cancer Genome Atlas melanoma cohort (379 CM, 47 OM) and a matched set of 3563 European controls with CDKN2A (P = .009), BAP1 (P = .03), and EBF3 (P = 4.75 × 10-4), a candidate risk locus, all showing evidence of replication. EBF3 was then evaluated using germline data from a set of 132 familial melanoma cases and 4769 controls of UK origin (joint P = 1.37 × 10-5). Somatically, loss of EBF3 expression correlated with progression, poorer outcome, and high MITF tumors. Functionally, induction of EBF3 in melanoma cells reduced cell growth in vitro, retarded tumor formation in vivo, and reduced MITF levels. The results of this large rare variant germline association study further define the mutational landscape of hereditary melanoma and implicate EBF3 as a possible CM predisposition gene.

Rare Variant, Gene-Based Association Study of Hereditary Melanoma Using Whole-Exome Sequencing

PubMed Central

Artomov, Mykyta; Stratigos, Alexander J; Kim, Ivana; Kumar, Raj; Lauss, Martin; Reddy, Bobby Y; Miao, Benchun; Daniela Robles-Espinoza, Carla; Sankar, Aravind; Njauw, Ching-Ni; Shannon, Kristen; Gragoudas, Evangelos S; Marie Lane, Anne; Iyer, Vivek; Newton-Bishop, Julia A; Timothy Bishop, D; Holland, Elizabeth A; Mann, Graham J; Singh, Tarjinder; Daly, Mark J; Tsao, Hensin

2017-01-01

Abstract Background Extraordinary progress has been made in our understanding of common variants in many diseases, including melanoma. Because the contribution of rare coding variants is not as well characterized, we performed an exome-wide, gene-based association study of familial cutaneous melanoma (CM) and ocular melanoma (OM). Methods Using 11 990 jointly processed individual DNA samples, whole-exome sequencing was performed, followed by large-scale joint variant calling using GATK (Genome Analysis ToolKit). PLINK/SEQ was used for statistical analysis of genetic variation. Four models were used to estimate the association among different types of variants. In vitro functional validation was performed using three human melanoma cell lines in 2D and 3D proliferation assays. In vivo tumor growth was assessed using xenografts of human melanoma A375 melanoma cells in nude mice (eight mice per group). All statistical tests were two-sided. Results Strong signals were detected for CDKN2A (Pmin = 6.16 × 10-8) in the CM cohort (n = 273) and BAP1 (Pmin = 3.83 × 10‐6) in the OM (n = 99) cohort. Eleven genes that exhibited borderline association (P < 10‐4) were independently validated using The Cancer Genome Atlas melanoma cohort (379 CM, 47 OM) and a matched set of 3563 European controls with CDKN2A (P = .009), BAP1 (P = .03), and EBF3 (P = 4.75 × 10‐4), a candidate risk locus, all showing evidence of replication. EBF3 was then evaluated using germline data from a set of 132 familial melanoma cases and 4769 controls of UK origin (joint P = 1.37 × 10‐5). Somatically, loss of EBF3 expression correlated with progression, poorer outcome, and high MITF tumors. Functionally, induction of EBF3 in melanoma cells reduced cell growth in vitro, retarded tumor formation in vivo, and reduced MITF levels. Conclusions The results of this large rare variant germline association study further define the mutational landscape of hereditary melanoma and implicate EBF3 as a possible CM predisposition gene. PMID:29522175

Efficacy and immunogenicity of two or three dose rotavirus-vaccine regimen in South African children over two consecutive rotavirus-seasons: a randomized, double-blind, placebo-controlled trial.

PubMed

Madhi, S A; Kirsten, M; Louw, C; Bos, P; Aspinall, S; Bouckenooghe, A; Neuzil, K M; Steele, A D

2012-04-27

Human rotavirus vaccine (HRV; i.e., Rotarix) reduced the incidence of severe rotavirus gastroenteritis (RVGE) by 77% (95% Confidence interval: 56-88%) during the first year of life in South Africa. Persistence of HRV-derived protection against RVGE during subsequent rotavirus seasons, although evident in industrialized settings, remains to be established in African settings. This study reports on the efficacy of HRV against severe RVGE over two consecutive rotavirus seasons in South African children. A prospective, double-blind, placebo controlled multi-centered trial in South Africa and Malawi randomly assigned infants in a 1:1:1 ratio to receive either two (10 and 14 weeks; HRV_2D) or three (6, 10 and 14 weeks; HRV_3D) doses of HRV or placebo. The primary analysis involved pooling of HRV_2D and HRV_3D arms. Episodes of gastroenteritis caused by wild-type rotavirus were identified through active follow-up surveillance and graded by the Vesikari scale. 1339 infants (447 in the HRV_2D group, 447 in the HRV_3D group and 445 in the placebo group) were enrolled in Year 2 of the study, including 1035 (77.3%) who were followed up over two consecutive rotavirus seasons (i.e., Cohort 2 subjects). Rotarix was associated with ongoing protection against severe RVGE, preventing 2.5 episodes per 100 vaccinated children over two consecutive rotavirus seasons; vaccine efficacy: 59% (95% Confidence interval: 1-83%). An exploratory analysis indicated better immunogenicity (among Cohort 1 subjects) and a higher point-efficacy estimate over two seasons in the HRV_3D compared to HRV_2D arms of the study in Cohort 2 subjects. Rotarix is associated with significant reductions in severe gastroenteritis episodes through 2 years of life among South African children. Further research is needed to determine the optimal dosing schedule of Rotarix in providing long-term protection against rotavirus illness in African children. Copyright © 2011 Elsevier Ltd. All rights reserved.

Development and validation of electronic surveillance tool for acute kidney injury: A retrospective analysis.

PubMed

Ahmed, Adil; Vairavan, Srinivasan; Akhoundi, Abbasali; Wilson, Gregory; Chiofolo, Caitlyn; Chbat, Nicolas; Cartin-Ceba, Rodrigo; Li, Guangxi; Kashani, Kianoush

2015-10-01

Timely detection of acute kidney injury (AKI) facilitates prevention of its progress and potentially therapeutic interventions. The study objective is to develop and validate an electronic surveillance tool (AKI sniffer) to detect AKI in 2 independent retrospective cohorts of intensive care unit (ICU) patients. The primary aim is to compare the sensitivity, specificity, and positive and negative predictive values of AKI sniffer performance against a reference standard. This study is conducted in the ICUs of a tertiary care center. The derivation cohort study subjects were Olmsted County, MN, residents admitted to all Mayo Clinic ICUs from July 1, 2010, through December 31, 2010, and the validation cohort study subjects were all patients admitted to a Mayo Clinic, Rochester, campus medical/surgical ICU on January 12, 2010, through March 23, 2010. All included records were reviewed by 2 independent investigators who adjudicated AKI using the Acute Kidney Injury Network criteria; disagreements were resolved by a third reviewer. This constituted the reference standard. An electronic algorithm was developed; its precision and reliability were assessed in comparison with the reference standard in 2 separate cohorts, derivation and validation. Of 1466 screened patients, a total of 944 patients were included in the study: 482 for derivation and 462 for validation. Compared with the reference standard in the validation cohort, the sensitivity and specificity of the AKI sniffer were 88% and 96%, respectively. The Cohen κ (95% confidence interval) agreement between the electronic and the reference standard was 0.84 (0.78-0.89) and 0.85 (0.80-0.90) in the derivation and validation cohorts. Acute kidney injury can reliably and accurately be detected electronically in ICU patients. The presented method is applicable for both clinical (decision support) and research (enrollment for clinical trials) settings. Prospective validation is required. Copyright © 2015 Elsevier Inc. All rights reserved.

Over-reported peripheral neuropathy symptoms in a cohort of HIV infected and uninfected Rwandan women: the need for validated locally appropriate questionnaires.

PubMed

Tumusiime, David K; Musabeyezu, Emmanuel; Mutimurah, Eugene; Hoover, Donald R; Shi, Qiuhu; Rudakemwa, Emmanuel; Ndacyayisenga, Victorien; Dusingize, Jean Claude; Sinayobye, Jean D'Amour; Stewart, Aimee; Venter, Francois W D; Anastos, Kathryn

2014-06-01

Peripheral neuropathy symptoms (PNS) are commonly manifested in HIV-infected (HIV+) individuals, although data are limited on the prevalence and predictors of PNS in HIV+ patients from sub-Saharan Africa. To determine the prevalence and predictors of PNS in HIV+ and HIV-uninfected (HIV-) Rwandan women. Data were analysed from 936 (710 HIV+ and 226 HIV-) women from the Rwanda Women Interassociation Study and Assessment (RWISA), an observational prospective cohort study investigating the effectiveness and toxicity of ART in HIV+ women. Of 936 enrolled, 920 (98.3%) were included in this analysis with 44% of HIV- and 52% of the HIV+ women reporting PNS (p=0.06). CD4+ count was not associated with PNS, although there was a non-significant trend towards higher prevalence in those with lower CD4+ counts. For the HIV- women, only alcohol and co-trimoxazole use were independently associated with PNS. WHO HIV stage IV illness and albumin ≤ 3.5 were associated with PNS in HIV+ women. The rate of peripheral neuropathy symptoms reported in this cohort of HIV-infected African women seems implausible, and rather suggests that the screening tool for peripheral neuropathy in culturally diverse African settings be locally validated.

Cultivating cohort studies for observational translational research.

PubMed

Ransohoff, David F

2013-04-01

"Discovery" research about molecular markers for diagnosis, prognosis, or prediction of response to therapy has frequently produced results that were not reproducible in subsequent studies. What are the reasons, and can observational cohorts be cultivated to provide strong and reliable answers to those questions? Experimental Selected examples are used to illustrate: (i) what features of research design provide strength and reliability in observational studies about markers of diagnosis, prognosis, and response to therapy? (ii) How can those design features be cultivated in existing observational cohorts, for example, within randomized controlled clinical trial (RCT), other existing observational research studies, or practice settings like health maintenance organization (HMOs)? Examples include a study of RNA expression profiles of tumor tissue to predict prognosis of breast cancer, a study of serum proteomics profiles to diagnose ovarian cancer, and a study of stool-based DNA assays to screen for colon cancer. Strengths and weaknesses of observational study design features are discussed, along with lessons about how features that help assure strength might be "cultivated" in the future. By considering these examples and others, it may be possible to develop a process of "cultivating cohorts" in ongoing RCTs, observational cohort studies, and practice settings like HMOs that have strong features of study design. Such an effort could produce sources of data and specimens to reliably answer questions about the use of molecular markers in diagnosis, prognosis, and response to therapy.

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.

Two industrial cohorts: baseline characteristics and factors associated with obesity.

PubMed

Ott, Ulrike; Stanford, Joseph B; Thiese, Matthew S; Murtaugh, Maureen A; Greenwood, Jessica L J; Gren, Lisa H; Garg, Arun; Hegmann, Kurt T

2015-05-01

To describe demographic and health characteristics, and factors associated with obesity among production workers. This cross-sectional study analyzed baseline data from two occupational cohorts. Regression modeling was used to assess associations between worker characteristics and obesity. A total of 1974 subjects were included in these analyses. The mean body mass index was 29.5 kg/m (SD = 6.5). Having smoked in the past and currently smoking decreased the odds of being obese in the WISTAH Distal Upper Extremity cohort, whereas those feeling depressed had increased odds of being obese. Being a Pacific Islander/Native Hawaiian and married increased the odds of obesity in the BackWorks Low Back Pain cohort. Factors associated with obesity differed substantially between the two cohorts. Recognizing factors associated with obesity in specific work settings may provide opportunities for optimizing preventive workplace interventions.

Extending the scope of pooled analyses of individual patient biomarker data from heterogeneous laboratory platforms and cohorts using merging algorithms.

PubMed

Burke, Órlaith; Benton, Samantha; Szafranski, Pawel; von Dadelszen, Peter; Buhimschi, S Catalin; Cetin, Irene; Chappell, Lucy; Figueras, Francesc; Galindo, Alberto; Herraiz, Ignacio; Holzman, Claudia; Hubel, Carl; Knudsen, Ulla; Kronborg, Camilla; Laivuori, Hannele; Lapaire, Olav; McElrath, Thomas; Moertl, Manfred; Myers, Jenny; Ness, Roberta B; Oliveira, Leandro; Olson, Gayle; Poston, Lucilla; Ris-Stalpers, Carrie; Roberts, James M; Schalekamp-Timmermans, Sarah; Schlembach, Dietmar; Steegers, Eric; Stepan, Holger; Tsatsaris, Vassilis; van der Post, Joris A; Verlohren, Stefan; Villa, Pia M; Williams, David; Zeisler, Harald; Redman, Christopher W G; Staff, Anne Cathrine

2016-01-01

A common challenge in medicine, exemplified in the analysis of biomarker data, is that large studies are needed for sufficient statistical power. Often, this may only be achievable by aggregating multiple cohorts. However, different studies may use disparate platforms for laboratory analysis, which can hinder merging. Using circulating placental growth factor (PlGF), a potential biomarker for hypertensive disorders of pregnancy (HDP) such as preeclampsia, as an example, we investigated how such issues can be overcome by inter-platform standardization and merging algorithms. We studied 16,462 pregnancies from 22 study cohorts. PlGF measurements (gestational age ⩾20 weeks) analyzed on one of four platforms: R&D Systems, AlereTriage, RocheElecsys or AbbottArchitect, were available for 13,429 women. Two merging algorithms, using Z-Score and Multiple of Median transformations, were applied. Best reference curves (BRC), based on merged, transformed PlGF measurements in uncomplicated pregnancy across six gestational age groups, were estimated. Identification of HDP by these PlGF-BRCs was compared to that of platform-specific curves. We demonstrate the feasibility of merging PlGF concentrations from different analytical platforms. Overall BRC identification of HDP performed at least as well as platform-specific curves. Our method can be extended to any set of biomarkers obtained from different laboratory platforms in any field. Merged biomarker data from multiple studies will improve statistical power and enlarge our understanding of the pathophysiology and management of medical syndromes. Copyright © 2015 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.

Genetic Variation in SENP1 and ANP32D as Predictors of Chronic Mountain Sickness

PubMed Central

Petousi, Nayia; Cavalleri, Gianpiero L.; Robbins, Peter A.

2014-01-01

Abstract Cole, Amy M., Nayia Petousi, Gianpiero L. Cavalleri, and Peter A. Robbins Genetic variation in SENP1 and ANP32D as predictors of chronic mountain sickness. High Alt Med Biol 15:497–499, 2014.—Chronic mountain sickness (CMS) is a serious illness that affects life-long high-altitude residents. A recent study analyzed whole genome sequence data from residents of Cerro de Pasco (Peru) in an effort to identify the genetic basis of CMS and reported SENP1 (rs7963934) and ANP32D (rs72644851) to show signatures consistent with natural selection and protective against CMS (Zhou et al. 2013). We set out to replicate these observations in two Andean cohorts from Cerro de Pasco, consisting of 84 CMS cases and 91 healthy controls in total. We report evidence of association for rs7963934 (SENP1) in the combined cohorts (meta-analysis p=8.8 x 10−4 OR 2.91, CI 1.56–5.5, I=0). The direction of effect was the same as in the original publication. We did not observe any significant correlation between rs72644851 (ANP32D) and the CMS phenotype, within or across cohorts (meta-analysis p=0.204, OR 1.37, CI 0.84–2.241, I=0). Our results provide independent evidence in support of a role for SENP1 in CMS in individuals of Quechua ancestry and suggest the SENP1 and ANP32D signatures of selection are in tight linkage disequilibrium (LD). PMID:25225945

Safety of Temporary Discontinuation of Antihypertensive Medication in Patients With Difficult-to-Control Hypertension.

PubMed

Beeftink, Martine M A; van der Sande, Nicolette G C; Bots, Michiel L; Doevendans, Pieter A; Blankestijn, Peter J; Visseren, Frank L J; Voskuil, Michiel; Spiering, Wilko

2017-05-01

Successful control of blood pressure relies on identification of secondary causes and contributing factors of hypertension. As antihypertensive medication can interfere with diagnostic investigations, temporary discontinuation of medication is advised. However, there are concerns about the safety of temporary discontinuation of antihypertensive medication in patients with difficult-to-control hypertension. We assessed the occurrence of adverse cardiovascular and cerebrovascular events potentially attributable to temporary discontinuation of antihypertensive medication between February 2010 and March 2016 (n=604) in our Analysis of Complicated Hypertension screening program. A reference group (n=604) was extracted from the SMART study (Second Manifestations of Arterial Disease) cohort (comprising a similar cohort at our hospital in whom medication was not stopped) and individually matched for blood pressure, age, sex, and history of cardiovascular disease. Discontinuation of medication was well tolerated; 62% reported no complaints, 24% had mild discomfort that could be left untreated, and 14% experienced complaints that required prescription of antihypertensive escape medication. Three major adverse events were observed in the Analysis of Complicated Hypertension group between discontinuation of medication and 30 days after restart of medication (event rate=31.2 events per 1000 patient-year). In the reference cohort, 5 cardiovascular events were observed during a similar follow-up period (event rate=51.2 events per 1000 patient-year). In conclusion, discontinuation of antihypertensive medication for the diagnostic evaluation of hypertension does not increase the acute risk of cardiovascular events when performed in a well-controlled setting in specialized hospitals with appropriate protocols for monitoring safety. © 2017 American Heart Association, Inc.

Estimating the Effects of Parental Divorce and Death With Fixed Effects Models.

PubMed

Amato, Paul R; Anthony, Christopher J

2014-04-01

The authors used child fixed effects models to estimate the effects of parental divorce and death on a variety of outcomes using 2 large national data sets: (a) the Early Childhood Longitudinal Study, Kindergarten Cohort (kindergarten through the 5th grade) and (b) the National Educational Longitudinal Study (8th grade to the senior year of high school). In both data sets, divorce and death were associated with multiple negative outcomes among children. Although evidence for a causal effect of divorce on children was reasonably strong, effect sizes were small in magnitude. A second analysis revealed a substantial degree of variability in children's outcomes following parental divorce, with some children declining, others improving, and most not changing at all. The estimated effects of divorce appeared to be strongest among children with the highest propensity to experience parental divorce.

Longitudinal Surveys of Australian Youth (LSAY) 1998 Cohort: Wave 12 (2009)--Frequency Tables. Technical Report 58B

ERIC Educational Resources Information Center

National Centre for Vocational Education Research (NCVER), 2010

2010-01-01

The Longitudinal Surveys of Australian Youth (LSAY) program studies the progress of several groups of young Australians as they move from school into post-secondary education and work. This technical paper contains the frequency tables for the LSAY 1998 cohort Wave 12 (2009) data set. [For the accompanying questionnaire, "Longitudinal Surveys…

Longitudinal Surveys of Australian Youth (LSAY): 2003 Cohort Wave 7 (2009)--Frequency Tables. Technical Report 57B

ERIC Educational Resources Information Center

National Centre for Vocational Education Research (NCVER), 2010

2010-01-01

The Longitudinal Surveys of Australian Youth (LSAY) program studies the progress of several groups of young Australians as they move from school into post-secondary education and work. This technical paper contains the frequency tables for the LSAY 2003 cohort Wave 7 (2009) data set. [For the related questionnaire, see ED512164.

Longitudinal Surveys of Australian Youth (LSAY) 2009 Cohort: Wave 3 (2011)--Frequency Tables. Technical Report 72B

ERIC Educational Resources Information Center

National Centre for Vocational Education Research (NCVER), 2012

2012-01-01

The Longitudinal Surveys of Australian Youth (LSAY) program studies the progress of several groups of young Australians as they move from school into post-secondary education and work. This technical paper contains the frequency tables for the LSAY 2009 cohort Wave 3 (2011) data set. [For the related questionnaire, see ED536306.

Longitudinal Surveys of Australian Youth (LSAY) 2003 Cohort: Wave 7 (2009)--Questionnaire. Technical Report 57A

ERIC Educational Resources Information Center

National Centre for Vocational Education Research (NCVER), 2010

2010-01-01

The Longitudinal Surveys of Australian Youth (LSAY) program studies the progress of several groups of young Australians as they move from school into post-secondary education and work. This technical paper contains the questionnaire for the LSAY 2003 cohort Wave 7 (2009) data set. [For the related frequency tables, see ED512163.

Longitudinal Surveys of Australian Youth (LSAY): 1995 Cohort--User Guide. Data Elements B2: Education. Technical Report 49B2

ERIC Educational Resources Information Center

National Centre for Vocational Education Research (NCVER), 2009

2009-01-01

This technical paper contains information about the variables in the Longitudinal Surveys of Australian Youth (LSAY) Year 95 cohort data set. It groups each variable into data elements that identify common variables within and across waves. Information is provided about each data element, including its purpose, values, base populations and…

Longitudinal Surveys of Australian Youth (LSAY): 1995 Cohort--User Guide. Data Elements A: Demographics. Technical Report 49A

ERIC Educational Resources Information Center

National Centre for Vocational Education Research (NCVER), 2012

2012-01-01

This technical paper contains information about the variables in the LSAY (Longitudinal Surveys of Australian Youth) Y95 cohort data set. It groups each variable into data elements which identifies common variables within and across waves. Information is provided about each data element including its purpose, values, base populations and relevant…

Longitudinal Surveys of Australian Youth (LSAY): 1995 Cohort--User Guide. Data Elements C: Employment. Technical Report 49C

ERIC Educational Resources Information Center

National Centre for Vocational Education Research (NCVER), 2009

2009-01-01

This technical paper contains information about the variables in the Longitudinal Surveys of Australian Youth (LSAY) Year 95 cohort data set. It groups each variable into data elements that identify common variables within and across waves. Information is provided about each data element including its purpose, values, base populations and relevant…

Longitudinal Surveys of Australian Youth (LSAY): 1995 Cohort--User Guide. Data Elements D: Social. Technical Report 49D

ERIC Educational Resources Information Center

National Centre for Vocational Education Research (NCVER), 2009

2009-01-01

This technical paper contains information about the variables in the Longitudinal Surveys of Australian Youth (LSAY) Year 95 cohort data set. It groups each variable into data elements that identify common variables within and across waves. Information is provided about each data element including its purpose, values, base populations and relevant…

Longitudinal Surveys of Australian Youth (LSAY): 2006 Cohort Wave 4 (2009)--Frequency Tables. Technical Report 56B

ERIC Educational Resources Information Center

National Centre for Vocational Education Research (NCVER), 2010

2010-01-01

The Longitudinal Surveys of Australian Youth (LSAY) program studies the progress of several groups of young Australians as they move from school into post-secondary education and work. This technical paper contains the frequency tables for the LSAY 2006 cohort Wave 4 (2009) data set. [For the "Longitudinal Surveys of Australian Youth (LSAY):…

Longitudinal Surveys of Australian Youth (LSAY): 2006 Cohort Wave 4 (2009)--Questionnaire. Technical Report 56A

ERIC Educational Resources Information Center

National Centre for Vocational Education Research (NCVER), 2010

2010-01-01

The Longitudinal Surveys of Australian Youth (LSAY) program studies the progress of several groups of young Australians as they move from school into post-secondary education and work. This technical paper contains the questionnaire for the LSAY 2006 cohort Wave 4 (2009) data set. [For the "Longitudinal Surveys of Australian Youth (LSAY):…

Longitudinal Surveys of Australian Youth (LSAY) 2006 Cohort: Wave 6 (2011)--Questionnaire. Technical Report 75A

ERIC Educational Resources Information Center

National Centre for Vocational Education Research (NCVER), 2012

2012-01-01

The Longitudinal Surveys of Australian Youth (LSAY) program studies the progress of several groups of young Australians as they move from school into post-secondary education and work. This series of documents provides supporting information for the LSAY data set of the 2006 cohort at wave 6 (2011). The document presents the questionnaire for LSAY…

Legal Teaching Methods to Diverse Student Cohorts: A Comparison between the United Kingdom, the United States, Australia and New Zealand

ERIC Educational Resources Information Center

Kraal, Diane

2017-01-01

This article makes a comparison across the unique educational settings of law and business schools in the United Kingdom, the United States, Australia and New Zealand to highlight differences in teaching methods necessary for culturally and ethnically mixed student cohorts derived from high migration, student mobility, higher education rankings…

Longitudinal Surveys of Australian Youth (LSAY): 1998 Cohort--User Guide. Data Elements D: Social. Technical Report 53D

ERIC Educational Resources Information Center

National Centre for Vocational Education Research (NCVER), 2009

2009-01-01

This technical paper contains information about the variables in the Longitudinal Surveys of Australian Youth (LSAY) Year 1998 cohort data set. It groups each variable into data elements which identifies common variables within and across waves. Information is provided about each data element including its purpose, values, base populations and…

Global Quality of Life (QOL), Health and Ability Are Primarily Determined by Our Consciousness: Research Findings from Denmark 1991-2004

ERIC Educational Resources Information Center

Ventegodt, Soren; Flensborg-Madsen, Trine; Andersen, Niels Jorgen; Nielsen, Michael; Mohammed, Morad; Merrick, Joav

2005-01-01

Objective: To explain the global quality of life (QOL) from 2000 indicators representing all aspects of life. Design and setting: Two cross sectional population studies, one prospective cohort study and one retrospective cohort study. Participants: (1) Representative sample of 2500 Danes (18-88 years), (2) 7222 members of the Copenhagen Perinatal…

Performance of the disease risk score in a cohort study with policy-induced selection bias.

PubMed

Tadrous, Mina; Mamdani, Muhammad M; Juurlink, David N; Krahn, Murray D; Lévesque, Linda E; Cadarette, Suzanne M

2015-11-01

To examine the performance of the disease risk score (DRS) in a cohort study with evidence of policy-induced selection bias. We examined two cohorts of new users of bisphosphonates. Estimates for 1-year hip fracture rates between agents using DRS, exposure propensity scores and traditional multivariable analysis were compared. The results for the cohort with no evidence of policy-induced selection bias showed little variation across analyses (-4.1-2.0%). Analysis of the cohort with evidence of policy-induced selection bias showed greater variation (-13.5-8.1%), with the greatest difference seen with DRS analyses. Our findings suggest that caution may be warranted when using DRS methods in cohort studies with policy-induced selection bias, further research is needed.

The performance of seven QPrediction risk scores in an independent external sample of patients from general practice: a validation study

PubMed Central

Hippisley-Cox, Julia; Coupland, Carol; Brindle, Peter

2014-01-01

Objectives To validate the performance of a set of risk prediction algorithms developed using the QResearch database, in an independent sample from general practices contributing to the Clinical Research Data Link (CPRD). Setting Prospective open cohort study using practices contributing to the CPRD database and practices contributing to the QResearch database. Participants The CPRD validation cohort consisted of 3.3 million patients, aged 25–99 years registered at 357 general practices between 1 Jan 1998 and 31 July 2012. The validation statistics for QResearch were obtained from the original published papers which used a one-third sample of practices separate to those used to derive the score. A cohort from QResearch was used to compare incidence rates and baseline characteristics and consisted of 6.8 million patients from 753 practices registered between 1 Jan 1998 and until 31 July 2013. Outcome measures Incident events relating to seven different risk prediction scores: QRISK2 (cardiovascular disease); QStroke (ischaemic stroke); QDiabetes (type 2 diabetes); QFracture (osteoporotic fracture and hip fracture); QKidney (moderate and severe kidney failure); QThrombosis (venous thromboembolism); QBleed (intracranial bleed and upper gastrointestinal haemorrhage). Measures of discrimination and calibration were calculated. Results Overall, the baseline characteristics of the CPRD and QResearch cohorts were similar though QResearch had higher recording levels for ethnicity and family history. The validation statistics for each of the risk prediction scores were very similar in the CPRD cohort compared with the published results from QResearch validation cohorts. For example, in women, the QDiabetes algorithm explained 50% of the variation within CPRD compared with 51% on QResearch and the receiver operator curve value was 0.85 on both databases. The scores were well calibrated in CPRD. Conclusions Each of the algorithms performed practically as well in the external independent CPRD validation cohorts as they had in the original published QResearch validation cohorts. PMID:25168040

Robust tumor morphometry in multispectral fluorescence microscopy

NASA Astrophysics Data System (ADS)

Tabesh, Ali; Vengrenyuk, Yevgen; Teverovskiy, Mikhail; Khan, Faisal M.; Sapir, Marina; Powell, Douglas; Mesa-Tejada, Ricardo; Donovan, Michael J.; Fernandez, Gerardo

2009-02-01

Morphological and architectural characteristics of primary tissue compartments, such as epithelial nuclei (EN) and cytoplasm, provide important cues for cancer diagnosis, prognosis, and therapeutic response prediction. We propose two feature sets for the robust quantification of these characteristics in multiplex immunofluorescence (IF) microscopy images of prostate biopsy specimens. To enable feature extraction, EN and cytoplasm regions were first segmented from the IF images. Then, feature sets consisting of the characteristics of the minimum spanning tree (MST) connecting the EN and the fractal dimension (FD) of gland boundaries were obtained from the segmented compartments. We demonstrated the utility of the proposed features in prostate cancer recurrence prediction on a multi-institution cohort of 1027 patients. Univariate analysis revealed that both FD and one of the MST features were highly effective for predicting cancer recurrence (p <= 0.0001). In multivariate analysis, an MST feature was selected for a model incorporating clinical and image features. The model achieved a concordance index (CI) of 0.73 on the validation set, which was significantly higher than the CI of 0.69 for the standard multivariate model based solely on clinical features currently used in clinical practice (p < 0.0001). The contributions of this work are twofold. First, it is the first demonstration of the utility of the proposed features in morphometric analysis of IF images. Second, this is the largest scale study of the efficacy and robustness of the proposed features in prostate cancer prognosis.

Blinatumomab vs historical standard therapy of adult relapsed/refractory acute lymphoblastic leukemia

PubMed Central

Gökbuget, N; Kelsh, M; Chia, V; Advani, A; Bassan, R; Dombret, H; Doubek, M; Fielding, A K; Giebel, S; Haddad, V; Hoelzer, D; Holland, C; Ifrah, N; Katz, A; Maniar, T; Martinelli, G; Morgades, M; O'Brien, S; Ribera, J-M; Rowe, J M; Stein, A; Topp, M; Wadleigh, M; Kantarjian, H

2016-01-01

We compared outcomes from a single-arm study of blinatumomab in adult patients with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia (R/R ALL) with a historical data set from Europe and the United States. Estimates of complete remission (CR) and overall survival (OS) were weighted by the frequency distribution of prognostic factors in the blinatumomab trial. Outcomes were also compared between the trial and historical data using propensity score methods. The historical cohort included 694 patients with CR data and 1112 patients with OS data compared with 189 patients with CR and survival data in the blinatumomab trial. The weighted analysis revealed a CR rate of 24% (95% CI: 20–27%) and a median OS of 3.3 months (95% CI: 2.8–3.6) in the historical cohort compared with a CR/CRh rate of 43% (95% CI: 36–50%) and a median OS of 6.1 months (95% CI: 4.2–7.5) in the blinatumomab trial. Propensity score analysis estimated increased odds of CR/CRh (OR=2.68, 95% CI: 1.67–4.31) and improved OS (HR=0.536, 95% CI: 0.394–0.730) with blinatumomab. The analysis demonstrates the application of different study designs and statistical methods to compare novel therapies for R/R ALL with historical data. PMID:27662202

Factors Associated with Post-Seasonal Serological Titer and Risk Factors for Infection with the Pandemic A/H1N1 Virus in the French General Population

PubMed Central

Lapidus, Nathanael; de Lamballerie, Xavier; Salez, Nicolas; Setbon, Michel; Delabre, Rosemary M.; Ferrari, Pascal; Moyen, Nanikaly; Gougeon, Marie-Lise; Vely, Frédéric; Leruez-Ville, Marianne; Andreoletti, Laurent; Cauchemez, Simon; Boëlle, Pierre-Yves; Vivier, Éric; Abel, Laurent; Schwarzinger, Michaël; Legeas, Michèle; Le Cann, Pierre; Flahault, Antoine; Carrat, Fabrice

2013-01-01

The CoPanFlu-France cohort of households was set up in 2009 to study the risk factors for infection by the pandemic influenza virus (H1N1pdm) in the French general population. The authors developed an integrative data-driven approach to identify individual, collective and environmental factors associated with the post-seasonal serological H1N1pdm geometric mean titer, and derived a nested case-control analysis to identify risk factors for infection during the first season. This analysis included 1377 subjects (601 households). The GMT for the general population was 47.1 (95% confidence interval (CI): 45.1, 49.2). According to a multivariable analysis, pandemic vaccination, seasonal vaccination in 2009, recent history of influenza-like illness, asthma, chronic obstructive pulmonary disease, social contacts at school and use of public transports by the local population were associated with a higher GMT, whereas history of smoking was associated with a lower GMT. Additionally, young age at inclusion and risk perception of exposure to the virus at work were identified as possible risk factors, whereas presence of an air humidifier in the living room was a possible protective factor. These findings will be interpreted in light of the longitudinal analyses of this ongoing cohort. PMID:23613718

Massive sequencing of 70 genes reveals a myriad of missing genes or mechanisms to be uncovered in hereditary spastic paraplegias

PubMed Central

Morais, Sara; Raymond, Laure; Mairey, Mathilde; Coutinho, Paula; Brandão, Eva; Ribeiro, Paula; Loureiro, José Leal; Sequeiros, Jorge; Brice, Alexis; Alonso, Isabel; Stevanin, Giovanni

2017-01-01

Hereditary spastic paraplegias (HSP) are neurodegenerative disorders characterized by lower limb spasticity and weakness that can be complicated by other neurological or non-neurological signs. Despite a high genetic heterogeneity (>60 causative genes), 40–70% of the families remain without a molecular diagnosis. Analysis of one of the pioneer cohorts of 193 HSP families generated in the early 1990s in Portugal highlighted that SPAST and SPG11 are the most frequent diagnoses. We have now explored 98 unsolved families from this series using custom next generation sequencing panels analyzing up to 70 candidate HSP genes. We identified the likely disease-causing variant in 20 of the 98 families with KIF5A being the most frequently mutated gene. We also found 52 variants of unknown significance (VUS) in 38% of the cases. These new diagnoses resulted in 42% of solved cases in the full Portuguese cohort (81/193). Segregation of the variants was not always compatible with the presumed inheritance, indicating that the analysis of all HSP genes regardless of the inheritance mode can help to explain some cases. Our results show that there is still a large set of unknown genes responsible for HSP and most likely novel mechanisms or inheritance modes leading to the disease to be uncovered, but this will require international collaborative efforts, particularly for the analysis of VUS. PMID:28832565

Is rivaroxaban associated with lower inpatient costs compared to warfarin among patients with non-valvular atrial fibrillation?

PubMed

Laliberté, François; Pilon, Dominic; Raut, Monika K; Nelson, Winnie W; Olson, William H; Germain, Guillaume; Schein, Jeff R; Lefebvre, Patrick

2014-08-01

Warfarin has been the mainstay treatment used by patients with a moderate-to-high risk of stroke due to non-valvular atrial fibrillation (NVAF). Unlike rivaroxaban, laboratory monitoring to allow the attainment of the prothrombin time international normalized ratio goal is required with warfarin, thereby potentially increasing a patient's hospitalization costs. To compare hospitalization costs between hospitalized NVAF patients using rivaroxaban versus warfarin in a real-world setting. A retrospective claims analysis was conducted using the Premier Perspective Comparative Hospital Database from November 2010 to September 2012. The study included adult patients hospitalized for NVAF after November 2011. Patients using rivaroxaban during hospitalization were matched with up to four warfarin users by propensity score analyses. Hospitalization costs were compared between the matched cohorts using generalized estimating equations. A sub-analysis was performed for patients who were first administered their treatment on day three or later of their hospital stay. Sensitivity analyses were conducted on matched cohorts with a primary diagnosis of AF. The matched cohorts' (2809 rivaroxaban and 11,085 warfarin users) characteristics were well balanced. The mean age of cohorts was 71 years and 49% of patients were female. The average hospitalization cost of rivaroxaban users was $11,993 compared to $13,255 for warfarin users. The cost difference was significantly lower by $1284 (P < 0.001). Patients who were administered rivaroxaban treatment on day three or after incurred significantly lower hospitalization costs (cost difference: $4350; P < 0.001) compared to warfarin users. Rivaroxaban users with a primary diagnosis of AF also had significantly lower costs compared to warfarin users. These included possible inaccuracies or omissions in diagnoses, completeness of baseline characteristics, and a study population that included patients newly initiated on and patients who continued anticoagulant therapy. Hospitalization costs for rivaroxaban were significantly lower than those for warfarin in NVAF patients treated with rivaroxaban.

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.

Patient and cycle characteristics predicting high pregnancy rates with single-embryo transfer: an analysis of the Society for Assisted Reproductive Technology outcomes between 2004 and 2013.

PubMed

Mersereau, Jennifer; Stanhiser, Jamie; Coddington, Charles; Jones, Tiffany; Luke, Barbara; Brown, Morton B

2017-11-01

To analyze factors associated with high live birth rate and low multiple birth rate in fresh and frozen-thawed assisted reproductive technology (ART) cycles. Retrospective cohort analysis. Not applicable. The study population included 181,523 women undergoing in vitro fertilization with autologous fresh first cycles, 27,033 with fresh first oocyte donor cycles, 37,658 with fresh second cycles, and 35,446 with frozen-thawed second cycles. None. Live birth rate and multiple birth rate after single-embryo transfer (SET) and double embryo transfer (DET) were measured, in addition to cycle characteristics. In patients with favorable prognostic factors, including younger maternal age, transfer of a blastocyst, and additional embryos cryopreserved, the gain in the live birth rate from SET to DET was approximately 10%-15%; however, the multiple birth rate increased from approximately 2% to greater than 49% in both autologous and donor fresh and frozen-thawed transfer cycles. This study reports a 10%-15% reduction in live birth rate and a 47% decrement in multiple birth rate with SET compared with DET in the setting of favorable patient prognostic factors. Our findings present an opportunity to increase the rate of SET across the United States and thereby reduce the multiple birth rate and its associated poor perinatal outcomes with assisted reproductive technology pregnancies. Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Identification of V122I (Val122Ile) transthyretin cardiac amyloidosis (ATTR) using serum retinol-binding protein 4 (RBP4) and a clinical prediction model

PubMed Central

Arvanitis, Marios; Koch, Clarissa M; Chan, Gloria G.; Arancivia, Celia M.T.; LaValley, Michael; Jacobson, Daniel; Berk, John L.; Connors, Lawreen H.; Ruberg, Frederick L.

2017-01-01

Importance Transthyretin amyloid cardiomyopathy (ATTR) is an under-recognized cause of heart failure (HF) in the elderly, owing in part to difficulty in diagnosis. ATTR can result from mutant TTR protein with one of the most common mutations in the United States, V122I, present in 3.43% of African Americans. Objective To determine whether serum retinol-binding protein 4 (RBP4), an endogenous TTR ligand, could be used as a diagnostic test for ATTR V122I amyloidosis. Design Combined prospective and retrospective cohort study Setting Tertiary care referral center Participants Fifty prospectively genotyped African American patients over age 60 years with non-amyloid HF and cardiac wall thickening, and a comparator cohort of biopsy proven ATTR V122I amyloidosis patients (n=25) comprised the development cohort. Twenty-seven prospectively genotyped African American patients and 9 ATTR V122I amyloidosis patients comprised the validation cohort. Main Outcomes and Measures Circulating RBP4, TTR, B-type natriuretic peptide (BNP) and troponin I (TnI) concentrations, electrocardiography (ECG), echocardiography, and clinical characteristics were assessed in all patients. Receiver operating characteristic (ROC) analysis was performed to identify optimal thresholds for ATTR V122I amyloidosis identification. A clinical prediction rule was developed using penalized logistic regression, evaluated using ROC analysis and validated in an independent cohort of cases and controls. Results Age, gender, BNP and TnI were similar between ATTR V122I amyloidosis patients and controls. Serum RBP4 concentration was lower in patients with ATTR V122I amyloidosis compared to non-amyloid controls (31.5 vs. 49.4 ug/ml, p < 0.001) and the difference persisted after controlling for potential confounding parameters. Left ventricular ejection fraction (LVEF) was lower in ATTR V122I amyloidosis (40% vs. 57%, p<0.001), while interventricular septal diameter (IVSd) was higher (16 vs. 14 mm, p<0.001). ROC analysis identified RBP4 as a sensitive identifier of ATTR V122I amyloidosis (AUC 0.78). A clinical prediction algorithm comprised of RBP4, TTR, LVEF, IVSd, mean limb lead ECG voltage and grade 3 diastolic dysfunction yielded excellent discriminatory capacity for ATTR V122I amyloidosis (AUC 0.97), while a 4 parameter model including RBP4 concentration retained excellent discrimination (AUC 0.92). The models maintained excellent discrimination in the validation cohort. Conclusions and Relevance A prediction model employing circulating RBP4 concentration and readily available clinical parameters accurately discriminated ATTR V122I amyloid cardiomyopathy from non-amyloid HF in a case matched cohort. We propose that this clinical algorithm may be useful for identification of ATTR V122I amyloidosis in elderly, African American patients with heart failure. PMID:28196196

Pathway Analysis of Metabolic Syndrome Using a Genome-Wide Association Study of Korea Associated Resource (KARE) Cohorts.

PubMed

Shim, Unjin; Kim, Han-Na; Sung, Yeon-Ah; Kim, Hyung-Lae

2014-12-01

Metabolic syndrome (MetS) is a complex disorder related to insulin resistance, obesity, and inflammation. Genetic and environmental factors also contribute to the development of MetS, and through genome-wide association studies (GWASs), important susceptibility loci have been identified. However, GWASs focus more on individual single-nucleotide polymorphisms (SNPs), explaining only a small portion of genetic heritability. To overcome this limitation, pathway analyses are being applied to GWAS datasets. The aim of this study is to elucidate the biological pathways involved in the pathogenesis of MetS through pathway analysis. Cohort data from the Korea Associated Resource (KARE) was used for analysis, which include 8,842 individuals (age, 52.2 ± 8.9 years; body mass index, 24.6 ± 3.2 kg/m(2)). A total of 312,121 autosomal SNPs were obtained after quality control. Pathway analysis was conducted using Meta-analysis Gene-Set Enrichment of Variant Associations (MAGENTA) to discover the biological pathways associated with MetS. In the discovery phase, SNPs from chromosome 12, including rs11066280, rs2074356, and rs12229654, were associated with MetS (p < 5 × 10(-6)), and rs11066280 satisfied the Bonferroni-corrected cutoff (unadjusted p < 1.38 × 10(-7), Bonferroni-adjusted p < 0.05). Through pathway analysis, biological pathways, including electron carrier activity, signaling by platelet-derived growth factor (PDGF), the mitogen-activated protein kinase kinase kinase cascade, PDGF binding, peroxisome proliferator-activated receptor (PPAR) signaling, and DNA repair, were associated with MetS. Through pathway analysis of MetS, pathways related with PDGF, mitogen-activated protein kinase, and PPAR signaling, as well as nucleic acid binding, protein secretion, and DNA repair, were identified. Further studies will be needed to clarify the genetic pathogenesis leading to MetS.

Heterogeneity of chronic graft-versus-host disease biomarkers: association with CXCL10 and CXCR3+ NK cells

PubMed Central

Kariminia, Amina; Holtan, Shernan G.; Ivison, Sabine; Rozmus, Jacob; Hebert, Marie-Josée; Martin, Paul J.; Lee, Stephanie J.; Wolff, Daniel; Subrt, Peter; Abdossamadi, Sayeh; Sung, Susanna; Storek, Jan; Levings, Megan; Aljurf, Mahmoud; Arora, Mukta; Cutler, Corey; Gallagher, Geneviève; Kuruvilla, John; Lipton, Jeff; Nevill, Thomas J.; Newell, Laura F.; Panzarella, Tony; Pidala, Joseph; Popradi, Gizelle; Szwajcer, David; Tay, Jason; Toze, Cynthia L.; Walker, Irwin; Couban, Stephen; Storer, Barry E.

2016-01-01

Chronic graft-versus-host disease (cGVHD) remains one of the most significant long-term complications after allogeneic blood and marrow transplantation. Diagnostic biomarkers for cGVHD are needed for early diagnosis and may guide identification of prognostic markers. No cGVHD biomarker has yet been validated for use in clinical practice. We evaluated both previously known markers and performed discovery-based analysis for cGVHD biomarkers in a 2 independent test sets (total of 36 cases ≤1 month from diagnosis and 31 time-matched controls with no cGVHD). On the basis of these results, 11 markers were selected and evaluated in 2 independent replication cohorts (total of 134 cGVHD cases and 154 controls). cGVHD cases and controls were evaluated for several clinical covariates, and their impact on biomarkers was identified by univariate analysis. The 2 replications sets were relatively disparate in the biomarkers they replicated. Only sBAFF and, most consistently, CXCL10 were identified as significant in both replication sets. Other markers identified as significant in only 1 replication set included intercellular adhesion molecule 1 (ICAM-1), anti-LG3, aminopeptidase N, CXCL9, endothelin-1, and gelsolin. Multivariate analysis found that all covariates evaluated affected interpretation of the biomarkers. CXCL10 had an increased significance in combination with anti-LG3 and CXCL9, or inversely with CXCR3+CD56bright natural killer (NK) cells. There was significant heterogeneity of cGVHD biomarkers in a large comprehensive evaluation of cGVHD biomarkers impacted by several covariates. Only CXCL10 strongly correlated in both replication sets. Future analyses for plasma cGVHD biomarkers will need to be performed on very large patient groups with consideration of multiple covariates. PMID:27020088

Cancer-related Imaging in the Veterans Affairs Health Care System versus Medicare: Does a System with Lower Use Exhibit Less Geographic Variation?

PubMed Central

McWilliams, J. Michael; Dalton, Jesse B.; Landrum, Mary Beth; Frakt, Austin B.; Pizer, Steven D.; Keating, Nancy L.

2014-01-01

Background Geographic variations in use of medical services have been interpreted as indirect evidence of wasteful care. Less overuse of services, however, may not be reliably associated with less geographic variation. Objective To compare average use and geographic variation in use of cancer-related imaging between fee-for-service Medicare and the Department of Veterans Affairs (VA) health care system. Design Observational analysis of cancer-related imaging from 2003–2005, using Medicare and VA utilization data linked to cancer registry data. We used multilevel models to estimate mean differences in annual imaging use between cohorts of Medicare and VA patients within geographic areas and variation in use across areas for each cohort, adjusting for sociodemographic and tumor characteristics. Setting 40 hospital referral regions. Patients Older men with lung, colorectal, or prostate cancer, including 34,475 traditional Medicare beneficiaries (Medicare cohort) and 6,835 VA patients (VA cohort). Measurements 1)Per-patient count of imaging studies for which lung, colorectal, or prostate cancer was the primary diagnosis (each study weighted by a standardized price); 2)a direct measure of overuse—advanced imaging for prostate cancer at low risk of metastasis. Results Adjusted annual use of cancer-related imaging was lower in the VA cohort than the Medicare cohort (price-weighted count, $197 vs. $379/patient; P<0.001), as was annual use of advanced imaging for prostate cancer at low risk of metastasis ($41 vs. $117/patient; P<0.001). Geographic variation in cancer-related imaging use was similar in magnitude in the VA and Medicare cohorts. Limitations Observational study design. Conclusions Use of cancer-related imaging was lower in the VA health care system than in fee-for-service Medicare, but lower use was not associated with less geographic variation. Geographic variation in service use may not be a reliable indicator of the extent of overuse. Primary Funding Source Doris Duke Charitable Foundation and Department of Veterans Affairs Office of Policy and Planning. PMID:25437407

Cross-national associations between gender and mental disorders in the WHO World Mental Health Surveys

PubMed Central

Seedat, Soraya; Scott, Kate Margaret; Angermeyer, Matthias C.; Berglund, Patricia; Bromet, Evelyn J.; Brugha, Traolach S.; Demyttenaere, Koen; de Girolamo, Giovanni; Haro, Josep Maria; Jin, Robert; Karam, Elie G.; Kovess-Masfety, Viviane; Levinson, Daphna; Mora, Maria Elena Medina; Ono, Yutaka; Ormel, Johan; Pennell, Beth-Ellen; Posada-Villa, Jose; Sampson, Nancy A.; Williams, David; Kessler, Ronald C.

2009-01-01

Context Gender differences in mental disorders, including more anxiety-mood disorders among women and more externalizing disorders among men, are found consistently in epidemiological surveys. The “gender roles” hypothesis suggests that these differences should narrow as the roles of women and men become more equal. Objective To study time-space (i.e., cohort-country) variation in gender differences in lifetime DSM-IV mental disorders across cohorts in 15 countries in the WHO World Mental Health (WMH) Survey Initiative and determine if this variation is significantly related to time-space variation in female gender role traditionality (GRT) as measured by aggregate patterns of female education, employment, marital timing, and use of birth control. Design/Setting and Participants Face-to face household surveys of 72,933 community-dwelling adults in Africa, the Americas, Asia, Europe, the Middle East, and the Pacific. Main Outcomes The WHO Composite International Diagnostic Interview (CIDI) assessed lifetime prevalence and age-of-onset of 18 DSM-IV anxiety, mood, externalizing, and substance disorders. Survival analyses estimated time-space variation in Female:Male (F:M) odds-ratios (ORs) of these disorders across cohorts defined by age ranges 18–34, 35–49, 50–64, and 65+. Structural equation analysis examined predictive effects of variation in GRT on these ORs. Results Women had more anxiety-mood disorders than men and men more externalizing-substance disorders than women in all cohorts and countries. Although gender differences were generally consistent across cohorts, significant narrowing was found in recent cohorts for major depressive disorder (MDD) and substance disorders. This narrowing was significantly related to temporal (MDD) and spatial (substance disorders) variation in GRT. Conclusion While gender differences in most lifetime mental disorders were fairly stable over the time-space units studied, substantial inter-cohort narrowing of differences in major depression was found related to changes in the traditionality of female gender roles. Further research is needed to understand why this temporal narrowing was confined to major depression. PMID:19581570

Weight-Gain Reduction Among 2-Year College Students: The CHOICES RCT.

PubMed

Lytle, Leslie A; Laska, Melissa N; Linde, Jennifer A; Moe, Stacey G; Nanney, Marilyn S; Hannan, Peter J; Erickson, Darin J

2017-02-01

The young adult years have been recognized as an influential period for excess weight gain. Non-traditional students and those attending 2-year community colleges are at particularly high risk for a range of adverse weight-related outcomes. Choosing Healthy Options in College Environments and Settings was an RCT with students randomly assigned into a control or intervention condition after baseline assessment. The study was designed to evaluate if a 24-month weight-gain prevention intervention reduces the expected increase in BMI and overweight prevalence in young adults attending 2-year colleges. Two cohorts were recruited, corresponding to the fall and spring semesters. Data collection occurred at four time points for each cohort, with baseline occurring in fall 2011 for Cohort 1 and spring 2012 for Cohort 2. The 24-month follow-up occurred in fall 2013 for Cohort 1 and spring 2014 for Cohort 2. Data analysis occurred in 2015-2016. This research was conducted with 441 students from three community colleges in Minnesota. The 24-month intervention began with a 1-credit college course on healthy weight behaviors. A social networking and social support website was introduced as part of the course and participation encouraged for the duration of the trial. Changes in BMI, weight, body fat percentage, waist circumference, and weight status were assessed. Retention of the cohorts at 24 months was 83.4%. There was not a statistically significant difference in BMI between conditions at the end of the trial. However, there was a statically significant difference in the prevalence of overweight/obesity between treatment conditions at 24 months. Also, participants randomized to the intervention who were overweight or obese at baseline were more than three times as likely to transition to a healthy weight by the end of the trial as compared with control students. The intervention was not successful in achieving BMI differences between treatment groups. However, an 8% reduction in the prevalence of overweight and obesity over time may have population-level significance. This study is registered at www.clinicaltrials.gov NCT01134783. Copyright © 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

Antiepileptic drugs and the risk of ischaemic stroke and myocardial infarction: a population-based cohort study

PubMed Central

Renoux, Christel; Dell'Aniello, Sophie; Saarela, Olli; Filion, Kristian B; Boivin, Jean-François

2015-01-01

Objectives Hepatic enzyme-inducing antiepileptic drugs (AEDs) increase serum lipid levels and other atherogenic markers via the induction of cytochrome P450 and may therefore increase the risk of vascular events. We sought to assess the risk of ischaemic stroke and myocardial infarction (MI) according to AED enzymatic properties. Design Population-based cohort study with nested case–control analysis. Setting 650 general practices in the UK contributing to the Clinical Practice Research Datalink. Participants A cohort of 252 407 incident AED users aged 18 or older between January 1990 and April 2013. For each case of ischaemic stroke or MI, up to 10 controls were randomly selected among the cohort members in the risk sets defined by the case and matched on age, sex, indication for AED, calendar time and duration of follow-up. Interventions Current use of enzyme-inducing and enzyme-inhibiting AEDs compared with non-inducing AEDs. Primary outcome measures Incidence rate ratios (RRs) of ischaemic stroke and MI. Results 5069 strokes and 3636 MIs were identified during follow-up. Inducing AEDs use was associated with a small increased risk of ischaemic stroke (RR=1.16, 95% CI 1.02 to 1.33) relative to non-inducing AEDs, most likely due to residual confounding. However, current use of inducing AEDs for ≥24 months was associated with a 46% increased risk of MI (RR=1.46, 95% CI 1.15 to 1.85) compared with the same duration of non-inducing AED, corresponding to a risk difference of 1.39/1000 (95% CI 0.33 to 2.45) persons per year. Current use of inhibiting AED was associated with a decreased risk of MI (RR=0.81, 95% CI 0.66 to 1.00). Conclusions The use of enzyme-inducing AEDs was not associated with an increased risk of ischaemic stroke; a small increase of MI with prolonged use was observed. In contrast, use of inhibiting AEDs was associated with a decreased risk of MI. PMID:26270948

[Comorbidity and related costs as a burden in the treatment of outpatients with depressive disorders in a primary care setting].

PubMed

Sicras Mainar, A; Navarro Artieda, R; Rejas Gutiérrez, J; Blanca Tamayo, M; Serrat Tarrés, J; Llopart López, J R

2007-01-01

To study the impact of depressive disorders (DD) on health care expenditure and to measure associated comorbidity in patients in primary care settings (PCS) under normal clinical practice conditions. A retrospective cohort study was carried out. The study cohort consisted of outpatients aged over 14 years of age with an established diagnosis of DD (ICPC; P76) treated in a PC health centre during 2004. A comparative cohort was formed with the remaining outpatients without DD, treated in that health centre. Main factors for calculation were: age, gender, history/comorbidity and health resource use and the corresponding outpatient costs; drugs, diagnostic tests, visits to specialists and PC physicians. Multiple logistic regression analysis and ANCOVA models were used in order to adjust costs and comorbidities between the cohorts of patients. A total of 64,072 subjects were assessed; 6,592 patients with DD [10.3% (CI: 8.2-12.4%), 74.5% (CI: 73.4%-75.6%) females]. DD outpatients displayed a higher number of episodes of comorbidities/year (mean +/- SD; 7.4 +/- 4.3 vs. 4.7 +/- 3.3, p < 0.0001) and global medical visits/patient/year (12.0 +/- 9.3 vs. 7.4 +/- 7.6, p < 0.0001). The main comorbidities associated to DD were neurological disorders [Odds ratio (95% CI); 2.1 (CI: 1.5-2.6), p < 0.0001], alcoholism [1.6 (CI: 1.3-1.9), p < 0.0001] and malignancies [1.3 (CI: 1.1-1.5), p < 0.0001]. DD were associated with significantly higher adjusted total costs; 1,083.8 euro (SEM; 8.4 euro) vs. 684.1 euro (3.4 euro), p < 0.0001. Higher costs were displayed for elderly patients. Sixty-two percent of the total cost was related to drugs. Prevalence of DD was higher, particularly in women. Following adjustment in accordance with comorbidity, age and sex, DD outpatients used more health care resources and implied higher costs. Higher costs were associated with age.

Acquisition of Maternal Education and Its Relation to Single-Word Reading in Middle Childhood: An Analysis of the Millennium Cohort Study

ERIC Educational Resources Information Center

King, Thomas; McKean, Cristina; Rush, Robert; Westrupp, Elizabeth M.; Mensah, Fiona K.; Reilly, Sheena; Law, James

2017-01-01

Maternal education captured at a single time point is commonly employed as a predictor of a child's cognitive development. In this article, we ask what bearing the acquisition of additional qualifications has upon reading performance in middle childhood. This was a secondary analysis of the United Kingdom's Millennium Cohort Study, a cohort of…

T2* Mapping of the Hip in Asymptomatic Volunteers with Normal Cartilage Morphology: An Analysis of Regional and Age-Dependent Distribution.

PubMed

Hesper, Tobias; Schleich, Christoph; Buchwald, Alexander; Hosalkar, Harish S; Antoch, Gerald; Krauspe, Rüdiger; Zilkens, Christoph; Bittersohl, Bernd

2018-01-01

Objective To assess age-dependent and regional differences in T2* relaxation measurements in hip joint cartilage of asymptomatic volunteers at 3 T. Design Three age cohorts (cohort 1: age 20-30 years, 15 individuals; cohort 2: age 30-40 years, 17 individuals; cohort 3: age 40-50 years, 15 individuals) were enrolled. T2* values were obtained in the central and peripheral cartilage of the acetabulum and the femoral head in 7 regions (anterior to superior and posterior). Results T2* did not differ among age cohorts in acetabular cartilage (cohort 1: 24.65 ± 6.56 ms, cohort 2: 24.70 ± 4.83 ms, cohort 3: 25.81 ± 5.10 ms, P = 0.10) and femoral head cartilage (cohort 1: 27.08 ± 8.24 ms, cohort 2: 25.90 ± 7.82 ms, cohort 3: 26.50 ± 5.61 ms, P = 0.34). Analysis of the regional T2* distribution pattern indicates increased T2* values in the anterior, anterior-superior, superior-anterior, and the posterior-superior aspects of acetabular and femoral head cartilage. For acetabular cartilage, higher values were observed in the central region (25.90 ± 4.80 ms vs. 24.21 ± 4.05 ms, P < 0.0001) whereas femoral head cartilage did not reveal such differences (26.62 ± 5.74 ms vs. 26.37 ± 5.89 ms, P = 0.44). Conclusions The T2* analysis of presumably healthy hip joint cartilage does not seem to be stratified according to age in this population. Regional T2* variation throughout hip joint cartilage is apparent in this modality.

Stromal mast cells in invasive breast cancer are a marker of favourable prognosis: a study of 4,444 cases.

PubMed

Rajput, Ashish B; Turbin, Dmitry A; Cheang, Maggie Cu; Voduc, David K; Leung, Sam; Gelmon, Karen A; Gilks, C Blake; Huntsman, David G

2008-01-01

We have previously demonstrated in a pilot study of 348 invasive breast cancers that mast cell (MC) infiltrates within primary breast cancers are associated with a good prognosis. Our aim was to verify this finding in a larger cohort of invasive breast cancer patients and examine the relationship between the presence of MCs and other clinical and pathological features. Clinically annotated tissue microarrays (TMAs) containing 4,444 cases were constructed and stained with c-Kit (CD-117) using standard immunoperoxidase techniques to identify and quantify MCs. For statistical analysis, we applied a split-sample validation technique. Breast cancer specific survival was analyzed by Kaplan-Meier [KM] method and log rank test was used to compare survival curves. Survival analysis by KM method showed that the presence of stromal MCs was a favourable prognostic factor in the training set (P = 0.001), and the validation set group (P = 0.006). X-tile plot generated to define the optimal number of MCs showed that the presence of any number of stromal MCs predicted good prognosis. Multivariate analysis showed that the MC effect in the training set (Hazard ratio [HR] = 0.804, 95% Confidence interval [CI], 0.653-0.991, P = 0.041) and validation set analysis (HR = 0.846, 95% CI, 0.683-1.049, P = 0.128) was independent of age, tumor grade, tumor size, lymph node, ER and Her2 status. This study concludes that stromal MC infiltration in invasive breast cancer is an independent good prognostic marker and reiterates the critical role of local inflammatory responses in breast cancer progression.

Stromal mast cells in invasive breast cancer are a marker of favourable prognosis: a study of 4,444 cases

PubMed Central

Rajput, Ashish B.; Turbin, Dmitry A.; Cheang, Maggie CU; Voduc, David K.; Leung, Sam; Gelmon, Karen A.; Gilks, C. Blake

2007-01-01

Purpose We have previously demonstrated in a pilot study of 348 invasive breast cancers that mast cell (MC) infiltrates within primary breast cancers are associated with a good prognosis. Our aim was to verify this finding in a larger cohort of invasive breast cancer patients and examine the relationship between the presence of MCs and other clinical and pathological features. Experimental design Clinically annotated tissue microarrays (TMAs) containing 4,444 cases were constructed and stained with c-Kit (CD-117) using standard immunoperoxidase techniques to identify and quantify MCs. For statistical analysis, we applied a split-sample validation technique. Breast cancer specific survival was analyzed by Kaplan–Meier [KM] method and log rank test was used to compare survival curves. Results Survival analysis by KM method showed that the presence of stromal MCs was a favourable prognostic factor in the training set (P = 0.001), and the validation set group (P = 0.006). X-tile plot generated to define the optimal number of MCs showed that the presence of any number of stromal MCs predicted good prognosis. Multivariate analysis showed that the MC effect in the training set (Hazard ratio [HR] = 0.804, 95% Confidence interval [CI], 0.653–0.991, P = 0.041) and validation set analysis (HR = 0.846, 95% CI, 0.683–1.049, P = 0.128) was independent of age, tumor grade, tumor size, lymph node, ER and Her2 status. Conclusions This study concludes that stromal MC infiltration in invasive breast cancer is an independent good prognostic marker and reiterates the critical role of local inflammatory responses in breast cancer progression. PMID:17431762

Returning findings within longitudinal cohort studies: the 1958 birth cohort as an exemplar.

PubMed

Wallace, Susan E; Walker, Neil M; Elliott, Jane

2014-01-01

Population-based, prospective longitudinal cohort studies are considering the issues surrounding returning findings to individuals as a result of genomic and other medical research studies. While guidance is being developed for clinical settings, the process is less clear for those conducting longitudinal research. This paper discusses work conducted on behalf of The UK Cohort and Longitudinal Study Enhancement Resource programme (CLOSER) to examine consent requirements, process considerations and specific examples of potential findings in the context of the 1958 British Birth cohort. Beyond deciding which findings to return, there are questions of whether re-consent is needed and the possible impact on the study, how the feedback process will be managed, and what resources are needed to support that process. Recommendations are made for actions a cohort study should consider taking when making vital decisions regarding returning findings. Any decisions need to be context-specific, arrived at transparently, communicated clearly, and in the best interests of both the participants and the study.

Are quantitative trait-dependent sampling designs cost-effective for analysis of rare and common variants?

PubMed

Yilmaz, Yildiz E; Bull, Shelley B

2011-11-29

Use of trait-dependent sampling designs in whole-genome association studies of sequence data can reduce total sequencing costs with modest losses of statistical efficiency. In a quantitative trait (QT) analysis of data from the Genetic Analysis Workshop 17 mini-exome for unrelated individuals in the Asian subpopulation, we investigate alternative designs that sequence only 50% of the entire cohort. In addition to a simple random sampling design, we consider extreme-phenotype designs that are of increasing interest in genetic association analysis of QTs, especially in studies concerned with the detection of rare genetic variants. We also evaluate a novel sampling design in which all individuals have a nonzero probability of being selected into the sample but in which individuals with extreme phenotypes have a proportionately larger probability. We take differential sampling of individuals with informative trait values into account by inverse probability weighting using standard survey methods which thus generalizes to the source population. In replicate 1 data, we applied the designs in association analysis of Q1 with both rare and common variants in the FLT1 gene, based on knowledge of the generating model. Using all 200 replicate data sets, we similarly analyzed Q1 and Q4 (which is known to be free of association with FLT1) to evaluate relative efficiency, type I error, and power. Simulation study results suggest that the QT-dependent selection designs generally yield greater than 50% relative efficiency compared to using the entire cohort, implying cost-effectiveness of 50% sample selection and worthwhile reduction of sequencing costs.

The structure of the Hospital Anxiety and Depression Scale in four cohorts of community-based, healthy older people: the HALCyon program.

PubMed

Gale, Catharine R; Allerhand, Michael; Sayer, Avan Aihie; Cooper, Cyrus; Dennison, Elaine M; Starr, John M; Ben-Shlomo, Yoav; Gallacher, John E; Kuh, Diana; Deary, Ian J

2010-06-01

The Hospital Anxiety and Depression Scale (HADS) is widely used but evaluation of its psychometric properties has produced equivocal results. Little is known about its structure in non-clinical samples of older people. We used data from four cohorts in the HALCyon collaborative research program into healthy aging: the Caerphilly Prospective Study, the Hertfordshire Ageing Study, the Hertfordshire Cohort Study, and the Lothian Birth Cohort 1921. We used exploratory factor analysis and confirmatory factor analysis with multi-group comparisons to establish the structure of the HADS and test for factorial invariance between samples. Exploratory factor analysis showed a bi-dimensional structure (anxiety and depression) of the scale in men and women in each cohort. We tested a hypothesized three-factor model but high correlations between two of the factors made a two-factor model more psychologically plausible. Multi-group confirmatory factor analysis revealed that the sizes of the respective item loadings on the two factors were effectively identical in men and women from the same cohort. There was more variation between cohorts, particularly those from different parts of the U.K. and in whom the HADS was administered differently. Differences in social-class distribution accounted for part of this variation. Scoring the HADS as two subscales of anxiety and depression is appropriate in non-clinical populations of older men and women. However, there were differences between cohorts in the way that individual items were linked with the constructs of anxiety and depression, perhaps due to differences in sociocultural factors and/or in the administration of the scale.

Educational expansion and the education gradient in health: A hierarchical age-period-cohort analysis.

PubMed

Delaruelle, Katrijn; Buffel, Veerle; Bracke, Piet

2015-11-01

Researchers have recently been investigating the temporal variation in the educational gradient in health. While there is abundant literature concerning age trajectories, theoretical knowledge about cohort differences is relatively limited. Therefore, in analogy with the life course perspective, we introduce two contrasting cohort-specific hypotheses. The diminishing health returns hypothesis predicts a decrease in educational disparities in health across cohorts. By contrast, the cohort accretion hypothesis suggests that the education-health gap will be more pronounced among younger cohorts. To shed light on this, we perform a hierarchical age-period-cohort analysis (HAPC), using data from a subsample of individuals between 25 and 85 years of age (N = 232,573) from 32 countries in the European Social Survey (six waves: 2002-2012). The analysis leads to three important conclusions. First, we observe a widening health gap between different educational levels over the life course. Second, we find that these educational differences in the age trajectories of health seem to strengthen with each successive birth cohort. However, the two age-related effects disappear when we control for employment status, household income, and family characteristics. Last, when adjusting for these mediators, we reveal evidence to support the diminishing health returns hypothesis, implying that it is primarily the direct association between education and health that decreases across cohorts. This finding raises concerns about potential barriers to education being a vehicle for empowerment and the promotion of health. Copyright © 2015 Elsevier Ltd. All rights reserved.

Signaling protein signature predicts clinical outcome of non-small-cell lung cancer.

PubMed

Jin, Bao-Feng; Yang, Fan; Ying, Xiao-Min; Gong, Lin; Hu, Shuo-Feng; Zhao, Qing; Liao, Yi-Da; Chen, Ke-Zhong; Li, Teng; Tai, Yan-Hong; Cao, Yuan; Li, Xiao; Huang, Yan; Zhan, Xiao-Yan; Qin, Xuan-He; Wu, Jin; Chen, Shuai; Guo, Sai-Sai; Zhang, Yu-Cheng; Chen, Jing; Shen, Dan-Hua; Sun, Kun-Kun; Chen, Lu; Li, Wei-Hua; Li, Ai-Ling; Wang, Na; Xia, Qing; Wang, Jun; Zhou, Tao

2018-03-06

Non-small-cell lung cancer (NSCLC) is characterized by abnormalities of numerous signaling proteins that play pivotal roles in cancer development and progression. Many of these proteins have been reported to be correlated with clinical outcomes of NSCLC. However, none of them could provide adequate accuracy of prognosis prediction in clinical application. A total of 384 resected NSCLC specimens from two hospitals in Beijing (BJ) and Chongqing (CQ) were collected. Using immunohistochemistry (IHC) staining on stored formalin-fixed paraffin-embedded (FFPE) surgical samples, we examined the expression levels of 75 critical proteins on BJ samples. Random forest algorithm (RFA) and support vector machines (SVM) computation were applied to identify protein signatures on 2/3 randomly assigned BJ samples. The identified signatures were tested on the remaining BJ samples, and were further validated with CQ independent cohort. A 6-protein signature for adenocarcinoma (ADC) and a 5-protein signature for squamous cell carcinoma (SCC) were identified from training sets and tested in testing sets. In independent validation with CQ cohort, patients can also be divided into high- and low-risk groups with significantly different median overall survivals by Kaplan-Meier analysis, both in ADC (31 months vs. 87 months, HR 2.81; P <  0.001) and SCC patients (27 months vs. not reached, HR 9.97; P <  0.001). Cox regression analysis showed that both signatures are independent prognostic indicators and outperformed TNM staging (ADC: adjusted HR 3.07 vs. 2.43, SCC: adjusted HR 7.84 vs. 2.24). Particularly, we found that only the ADC patients in high-risk group significantly benefited from adjuvant chemotherapy (P = 0.018). Both ADC and SCC protein signatures could effectively stratify the prognosis of NSCLC patients, and may support patient selection for adjuvant chemotherapy.

Use of systemic antifungals in daily clinical practice in the haematology and oncology setting: results of a prospective observational analysis.

PubMed

Metzke, Barbara; Neubauer, Werner Christian; Hieke, Stefanie; Jung, Manfred; Wäsch, Ralph; Engelhardt, Monika

2012-09-01

To assess the role of systemic antifungal drugs as well as the frequency of potential drug interactions and adverse drug events of commonly used antifungals in an unselected haematology/oncology patient cohort. A prospective analysis was performed in our haematology/oncology department between October 2006 and September 2009. Data were obtained from 250 consecutive patients who received treatment and/or prophylaxis with fluconazole (n = 191), liposomal amphotericin B (n = 105), voriconazole (n = 62), caspofungin (n = 27) and/or posaconazole (n = 22). We performed detailed reviews of patient charts and laboratory values in close cooperation with treating physicians and nursing staff and participated regularly in ward and chart rounds. Potential drug interactions were assessed using the electronic database Micromedex® 1.0 (Healthcare Series). In terms of adverse drug events, caspofungin (56%) and voriconazole (58%) revealed a slightly more favourable safety profile than liposomal amphotericin B (66%) and posaconazole (64%). We confirmed frequent nephrotoxic effects with the use of liposomal amphotericin B (20%). Regarding potential drug interactions, 97 (66%) of 147 evaluated patients were exposed to at least 1 of 22 different potentially interacting drug combinations involving systemic antifungal agents. Cyclosporine was the most prevalent potentially interacting drug in our cohort. Systemic antifungal drugs are widely used in the haematology/oncology setting and exhibit numerous potential drug interactions and adverse events in cancer patients. Our results highlight the challenges related to antifungal drugs and should valuably contribute to a safe and efficient application of this increasingly important class of drugs. Copyright © 2012 John Wiley & Sons, Ltd.

Longitudinal Surveys of Australian Youth (LSAY) 2003 Cohort: Wave 9 (2011)--Frequency Tables. Technical Report 76B

ERIC Educational Resources Information Center

National Centre for Vocational Education Research (NCVER), 2012

2012-01-01

The Longitudinal Surveys of Australian Youth (LSAY) program studies the progress of several groups of young Australians as they move from school into post-secondary education and work. This series of documents provides supporting information for the LSAY data set of the 2003 cohort at wave 9 (2011). This document presents the frequency tables for…

Longitudinal Surveys of Australian Youth (LSAY) 2006 Cohort: Wave 6 (2011)--Frequency Tables. Technical Report 75B

ERIC Educational Resources Information Center

National Centre for Vocational Education Research (NCVER), 2012

2012-01-01

The Longitudinal Surveys of Australian Youth (LSAY) program studies the progress of several groups of young Australians as they move from school into post-secondary education and work. This series of documents provides supporting information for the LSAY data set of the 2006 cohort at wave 6 (2011). This document presents the frequency tables for…

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…

Longitudinal Surveys of Australian Youth (LSAY): 1995 Cohort--User Guide. Data Elements B1: Education. Technical Report 49B1

ERIC Educational Resources Information Center

National Centre for Vocational Education Research (NCVER), 2009

2009-01-01

This technical paper contains information about the variables in the LSAY (Longitudinal Surveys of Australian Youth) Y95 cohort data set. It groups each variable into data elements which identifies common variables within and across waves. Information is provided about each data element including its purpose, values, base populations and relevant.…

Ageing and the economic life cycle: The National Transfer Accounts approach.

PubMed

Temple, Jeromey B; Rice, James M; McDonald, Peter F

2017-12-01

To illustrate the use of National Transfer Accounts (NTA) for understanding ageing and the economic life cycle in Australia. The NTA methodology is applied utilising a range of unit record, demographic and administrative data sets from 1981 to 2010. During early and later life, total consumption (public and private) is greater than labour income. On a time series and cohort basis, we show that each successive generation has improved their level of well-being (as measured by consumption) relative to the previous years or previous cohorts from 1981 to 1982 onwards. We also show a substantial increase in labour income earned by mature age workers over this period. International comparisons show Australia to have consumption and labour income age profiles very similar to those of Canada but dissimilar to many other countries, driven by differences in demographic and policy settings. The NTA approach provides a powerful framework to track differences in the economic life cycle across age groups, across time, across cohorts and across countries. © 2017 AJA Inc.

Travel distance as factor in follow-up visit compliance in postlaparoscopic adjustable gastric banding population.

PubMed

DeNino, Walter F; Osler, Turner; Evans, Ellen G; Forgione, Patrick M

2010-01-01

Despite the 2008 "American Association of Clinical Endocrinologists, The Obesity Society, and American Society for Metabolic and Bariatric Surgery Medical Guidelines for Clinical Practice for the Perioperative Nutritional, Metabolic, and Nonsurgical Support of the Bariatric Surgery Patient," consensus does not exist for postoperative care in laparoscopic adjustable gastric banding (LAGB) patients (grade D evidence). It has been suggested that regular follow-up is related to better outcomes, specifically greater weight loss. The aim of the present study was to investigate the effects of travel distance to the clinic on the adherence to follow-up visits and weight loss in a cohort of LAGB patients in the setting of a rural, university-affiliated teaching hospital in the United States. A retrospective chart review was performed of all consecutive LAGB patients for a 1-year period. Linear regression analysis was used to identify the relationships between appointment compliance and the distance traveled and between the amount of weight loss and the distance traveled. Linear regression analysis was performed to investigate the effect of the travel distance to the clinic on the percentage of follow-up visits postoperatively. This effect was not significant (P = .4). Linear regression analysis was also performed to elucidate the effect of the travel distance to the clinic on the amount of weight loss. This effect was significant (P = .04). The travel distance to the clinic did not seem to be a significant predictor of compliance in a cohort of LAGB patients with ≤ 1 year of follow-up in a rural setting. However, a weak relationship was found between the travel distance to the clinic and weight loss, with patients who traveled further seeming to lose slightly more weight. Copyright © 2010 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

Luminal-like HER2-negative stage IA breast cancer: a multicenter retrospective study on long-term outcome with propensity score analysis

PubMed Central

De Angelis, Carmine; Di Maio, Massimo; Crispo, Anna; Giuliano, Mario; Schettini, Francesco; Bonotto, Marta; Gerratana, Lorenzo; Iacono, Donatella; Cinausero, Marika; Riccardi, Ferdinando; Ciancia, Giuseppe; De Laurentiis, Michelino; Puglisi, Fabio; De Placido, Sabino; Arpino, Grazia

2017-01-01

The benefit of adding chemotherapy (CT) to adjuvant hormone therapy (HT) in stage IA luminal-like HER2-negative breast cancer (BC) is unclear. We retrospectively evaluated predictive factors and clinical outcome of 1,222 patients from 4 oncologic centers. Three hundred and eighty patients received CT and HT (CT-cohort) and 842 received HT alone (HT-cohort). Disease-free survival (DFS) and overall survival (OS) were evaluated with univariate and multivariate analyses. We also applied the propensity score methodology. Compared with the HT-cohort, patients in the CT-cohort were more likely to be younger, have larger tumors of a higher histological grade that were Ki67-positive, and lower estrogen and progesterone receptor expression. At univariate analysis, a higher histological grade and Ki67 were significantly associated to a lower DFS. At multivariable analysis, only histological grade was predictive of DFS. The CT-cohort had a worse outcome than the HT-cohort in terms of DFS and OS, but differences disappeared when matched according to propensity score. In summary, patients with stage IA luminal-like BC had an excellent prognosis, however relapse and mortality were higher in the CT-cohort than in the HT-cohort. Longer use of adjuvant HT or other therapeutic strategies may be needed to improve outcome. PMID:29348868

Exposure reconstruction for the TCDD-exposed NIOSH cohort using a concentration- and age-dependent model of elimination.

PubMed

Aylward, Lesa L; Brunet, Robert C; Starr, Thomas B; Carrier, Gaétan; Delzell, Elizabeth; Cheng, Hong; Beall, Colleen

2005-08-01

Recent studies demonstrating a concentration dependence of elimination of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suggest that previous estimates of exposure for occupationally exposed cohorts may have underestimated actual exposure, resulting in a potential overestimate of the carcinogenic potency of TCDD in humans based on the mortality data for these cohorts. Using a database on U.S. chemical manufacturing workers potentially exposed to TCDD compiled by the National Institute for Occupational Safety and Health (NIOSH), we evaluated the impact of using a concentration- and age-dependent elimination model (CADM) (Aylward et al., 2005) on estimates of serum lipid area under the curve (AUC) for the NIOSH cohort. These data were used previously by Steenland et al. (2001) in combination with a first-order elimination model with an 8.7-year half-life to estimate cumulative serum lipid concentration (equivalent to AUC) for these workers for use in cancer dose-response assessment. Serum lipid TCDD measurements taken in 1988 for a subset of the cohort were combined with the NIOSH job exposure matrix and work histories to estimate dose rates per unit of exposure score. We evaluated the effect of choices in regression model (regression on untransformed vs. ln-transformed data and inclusion of a nonzero regression intercept) as well as the impact of choices of elimination models and parameters on estimated AUCs for the cohort. Central estimates for dose rate parameters derived from the serum-sampled subcohort were applied with the elimination models to time-specific exposure scores for the entire cohort to generate AUC estimates for all cohort members. Use of the CADM resulted in improved model fits to the serum sampling data compared to the first-order models. Dose rates varied by a factor of 50 among different combinations of elimination model, parameter sets, and regression models. Use of a CADM results in increases of up to five-fold in AUC estimates for the more highly exposed members of the cohort compared to estimates obtained using the first-order model with 8.7-year half-life. This degree of variation in the AUC estimates for this cohort would affect substantially the cancer potency estimates derived from the mortality data from this cohort. Such variability and uncertainty in the reconstructed serum lipid AUC estimates for this cohort, depending on elimination model, parameter set, and regression model, have not been described previously and are critical components in evaluating the dose-response data from the occupationally exposed populations.

Study protocol title: a prospective cohort study of low back pain

PubMed Central

2013-01-01

Background Few prospective cohort studies of workplace low back pain (LBP) with quantified job physical exposure have been performed. There are few prospective epidemiological studies for LBP occupational risk factors and reported data generally have few adjustments for many personal and psychosocial factors. Methods/design A multi-center prospective cohort study has been incepted to quantify risk factors for LBP and potentially develop improved methods for designing and analyzing jobs. Due to the subjectivity of LBP, six measures of LBP are captured: 1) any LBP, 2) LBP ≥ 5/10 pain rating, 3) LBP with medication use, 4) LBP with healthcare provider visits, 5) LBP necessitating modified work duties and 6) LBP with lost work time. Workers have thus far been enrolled from 30 different employment settings in 4 diverse US states and performed widely varying work. At baseline, workers undergo laptop-administered questionnaires, structured interviews, and two standardized physical examinations to ascertain demographics, medical history, psychosocial factors, hobbies and physical activities, and current musculoskeletal disorders. All workers’ jobs are individually measured for physical factors and are videotaped. Workers are followed monthly for the development of low back pain. Changes in jobs necessitate re-measure and re-videotaping of job physical factors. The lifetime cumulative incidence of low back pain will also include those with a past history of low back pain. Incident cases will exclude prevalent cases at baseline. Statistical methods planned include survival analyses and logistic regression. Discussion Data analysis of a prospective cohort study of low back pain is underway and has successfully enrolled over 800 workers to date. PMID:23497211

Study on Dialysis Session Length and Mortality in Maintenance Hemodialysis Patients: The Q-Cohort Study.

PubMed

Fujisaki, Kiichiro; Tanaka, Shigeru; Taniguchi, Masatomo; Matsukuma, Yuta; Masutani, Kosuke; Hirakata, Hideki; Kitazono, Takanari; Tsuruya, Kazuhiko

2018-06-07

Hemodialysis (HD) time has been recognized as an important factor in dialysis adequacy. However, few studies have reported on associations between HD time and prognosis among maintenance HD patients. We present some findings from a prospective cohort study, the -Q-Cohort Study, which was set up to explore risk factors for mortality in Japanese HD patients. We hypothesized that HD ≥5 h was associated with a significant survival advantage compared with HD < 5 h. The present study examined association between HD time and mortality in Japanese HD patients. The prospective multicenter Q-Cohort Study was conducted between December 2006 and December 2010, following 3,456 Japanese HD patients for 4 years. We examined the association between HD time and prognosis using Cox proportional hazards modeling. Propensity scores were calculated using logistic regression. During follow-up, 566 patients died from any cause. Patients with HD ≥5 h (n = 2,141) showed -significantly lower risk of all-cause death (hazards ratio = 0.82; 95% CI 0.68-0.99) than those with HD < 5 h (n = 1,315), after adjusting for confounding risk factors. This -association remained significant using a propensity score-based approach. After stratifying the analysis by patient age in 10-year increments, this finding remained -significant only in patients who were ≥80 years of age. Our results suggest that HD ≥5 h has a more favorable effect on mortality than HD < 5 h. © 2018 S. Karger AG, Basel.

Study protocol title: a prospective cohort study of low back pain.

PubMed

Garg, Arun; Hegmann, Kurt T; Moore, J Steven; Kapellusch, Jay; Thiese, Matthew S; Boda, Sruthi; Bhoyr, Parag; Bloswick, Donald; Merryweather, Andrew; Sesek, Richard; Deckow-Schaefer, Gwen; Foster, James; Wood, Eric; Sheng, Xiaoming; Holubkov, Richard

2013-03-07

Few prospective cohort studies of workplace low back pain (LBP) with quantified job physical exposure have been performed. There are few prospective epidemiological studies for LBP occupational risk factors and reported data generally have few adjustments for many personal and psychosocial factors. A multi-center prospective cohort study has been incepted to quantify risk factors for LBP and potentially develop improved methods for designing and analyzing jobs. Due to the subjectivity of LBP, six measures of LBP are captured: 1) any LBP, 2) LBP ≥ 5/10 pain rating, 3) LBP with medication use, 4) LBP with healthcare provider visits, 5) LBP necessitating modified work duties and 6) LBP with lost work time. Workers have thus far been enrolled from 30 different employment settings in 4 diverse US states and performed widely varying work. At baseline, workers undergo laptop-administered questionnaires, structured interviews, and two standardized physical examinations to ascertain demographics, medical history, psychosocial factors, hobbies and physical activities, and current musculoskeletal disorders. All workers' jobs are individually measured for physical factors and are videotaped. Workers are followed monthly for the development of low back pain. Changes in jobs necessitate re-measure and re-videotaping of job physical factors. The lifetime cumulative incidence of low back pain will also include those with a past history of low back pain. Incident cases will exclude prevalent cases at baseline. Statistical methods planned include survival analyses and logistic regression. Data analysis of a prospective cohort study of low back pain is underway and has successfully enrolled over 800 workers to date.

Meta-analysis identifies a MECOM gene as a novel predisposing factor of osteoporotic fracture

PubMed Central

Hwang, Joo-Yeon; Lee, Seung Hun; Go, Min Jin; Kim, Beom-Jun; Kou, Ikuyo; Ikegawa, Shiro; Guo, Yan; Deng, Hong-Wen; Raychaudhuri, Soumya; Kim, Young Jin; Oh, Ji Hee; Kim, Youngdoe; Moon, Sanghoon; Kim, Dong-Joon; Koo, Heejo; Cha, My-Jung; Lee, Min Hye; Yun, Ji Young; Yoo, Hye-Sook; Kang, Young-Ah; Cho, Eun-Hee; Kim, Sang-Wook; Oh, Ki Won; Kang, Moo II; Son, Ho Young; Kim, Shin-Yoon; Kim, Ghi Su; Han, Bok-Ghee; Cho, Yoon Shin; Cho, Myeong-Chan; Lee, Jong-Young; Koh, Jung-Min

2014-01-01

Background Osteoporotic fracture (OF) as a clinical endpoint is a major complication of osteoporosis. To screen for OF susceptibility genes, we performed a genome-wide association study and carried out de novo replication analysis of an East Asian population. Methods Association was tested using a logistic regression analysis. A meta-analysis was performed on the combined results using effect size and standard errors estimated for each study. Results In a combined meta-analysis of a discovery cohort (288 cases and 1139 controls), three hospital based sets in replication stage I (462 cases and 1745 controls), and an independent ethnic group in replication stage II (369 cases and 560 for controls), we identified a new locus associated with OF (rs784288 in the MECOM gene) that showed genome-wide significance (p=3.59×10−8; OR 1.39). RNA interference revealed that a MECOM knockdown suppresses osteoclastogenesis. Conclusions Our findings provide new insights into the genetic architecture underlying OF in East Asians. PMID:23349225

Using full-cohort data in nested case-control and case-cohort studies by multiple imputation.

PubMed

Keogh, Ruth H; White, Ian R

2013-10-15

In many large prospective cohorts, expensive exposure measurements cannot be obtained for all individuals. Exposure-disease association studies are therefore often based on nested case-control or case-cohort studies in which complete information is obtained only for sampled individuals. However, in the full cohort, there may be a large amount of information on cheaply available covariates and possibly a surrogate of the main exposure(s), which typically goes unused. We view the nested case-control or case-cohort study plus the remainder of the cohort as a full-cohort study with missing data. Hence, we propose using multiple imputation (MI) to utilise information in the full cohort when data from the sub-studies are analysed. We use the fully observed data to fit the imputation models. We consider using approximate imputation models and also using rejection sampling to draw imputed values from the true distribution of the missing values given the observed data. Simulation studies show that using MI to utilise full-cohort information in the analysis of nested case-control and case-cohort studies can result in important gains in efficiency, particularly when a surrogate of the main exposure is available in the full cohort. In simulations, this method outperforms counter-matching in nested case-control studies and a weighted analysis for case-cohort studies, both of which use some full-cohort information. Approximate imputation models perform well except when there are interactions or non-linear terms in the outcome model, where imputation using rejection sampling works well. Copyright © 2013 John Wiley & Sons, Ltd.

Independent and Parallel Evolution of New Genes by Gene Duplication in Two Origins of C4 Photosynthesis Provides New Insight into the Mechanism of Phloem Loading in C4 Species.

PubMed

Emms, David M; Covshoff, Sarah; Hibberd, Julian M; Kelly, Steven

2016-07-01

C4 photosynthesis is considered one of the most remarkable examples of evolutionary convergence in eukaryotes. However, it is unknown whether the evolution of C4 photosynthesis required the evolution of new genes. Genome-wide gene-tree species-tree reconciliation of seven monocot species that span two origins of C4 photosynthesis revealed that there was significant parallelism in the duplication and retention of genes coincident with the evolution of C4 photosynthesis in these lineages. Specifically, 21 orthologous genes were duplicated and retained independently in parallel at both C4 origins. Analysis of this gene cohort revealed that the set of parallel duplicated and retained genes is enriched for genes that are preferentially expressed in bundle sheath cells, the cell type in which photosynthesis was activated during C4 evolution. Furthermore, functional analysis of the cohort of parallel duplicated genes identified SWEET-13 as a potential key transporter in the evolution of C4 photosynthesis in grasses, and provides new insight into the mechanism of phloem loading in these C4 species. C4 photosynthesis, gene duplication, gene families, parallel evolution. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Enhancing knowledge discovery from cancer genomics data with Galaxy

PubMed Central

Albuquerque, Marco A.; Grande, Bruno M.; Ritch, Elie J.; Pararajalingam, Prasath; Jessa, Selin; Krzywinski, Martin; Grewal, Jasleen K.; Shah, Sohrab P.; Boutros, Paul C.

2017-01-01

Abstract The field of cancer genomics has demonstrated the power of massively parallel sequencing techniques to inform on the genes and specific alterations that drive tumor onset and progression. Although large comprehensive sequence data sets continue to be made increasingly available, data analysis remains an ongoing challenge, particularly for laboratories lacking dedicated resources and bioinformatics expertise. To address this, we have produced a collection of Galaxy tools that represent many popular algorithms for detecting somatic genetic alterations from cancer genome and exome data. We developed new methods for parallelization of these tools within Galaxy to accelerate runtime and have demonstrated their usability and summarized their runtimes on multiple cloud service providers. Some tools represent extensions or refinement of existing toolkits to yield visualizations suited to cohort-wide cancer genomic analysis. For example, we present Oncocircos and Oncoprintplus, which generate data-rich summaries of exome-derived somatic mutation. Workflows that integrate these to achieve data integration and visualizations are demonstrated on a cohort of 96 diffuse large B-cell lymphomas and enabled the discovery of multiple candidate lymphoma-related genes. Our toolkit is available from our GitHub repository as Galaxy tool and dependency definitions and has been deployed using virtualization on multiple platforms including Docker. PMID:28327945

Night work and prostate cancer in men: a Swedish prospective cohort study

PubMed Central

Åkerstedt, Torbjrn; Narusyte, Jurgita; Svedberg, Pia; Kecklund, Göran; Alexanderson, Kristina

2017-01-01

Objectives Prostate cancer is the most common cancer and the second leading cause of cancer-related deaths among men, but the contributing factors are unclear. One such may be night work because of the day/night alternation of work and the resulting disturbance of the circadian system. The purpose of the present study was to investigate the prospective relation between number of years with night work and prostate cancer in men. Design Cohort study comparing night and day working twins with respect to incident prostate cancer in 12 322 men. Setting Individuals in the Swedish Twin Registry. Participants 12 322 male twins. Outcome measures Prostate cancer diagnoses obtained from the Swedish Cancer Registry with a follow-up time of 12 years, with a total number of cases=454. Results Multiple Cox proportional hazard regression analysis, adjusted for a number of covariates, showed no association between ever night work and prostate cancer, nor for duration of night work and prostate cancer. Analysis of twin pairs discordant for prostate cancer (n=332) showed no significant association between night work and prostate cancer. Conclusions The results, together with previous studies, suggest that night work does not seem to constitute a risk factor for prostate cancer. PMID:28600375

Association between ventilatory settings and development of acute respiratory distress syndrome in mechanically ventilated patients due to brain injury.

PubMed

Tejerina, Eva; Pelosi, Paolo; Muriel, Alfonso; Peñuelas, Oscar; Sutherasan, Yuda; Frutos-Vivar, Fernando; Nin, Nicolás; Davies, Andrew R; Rios, Fernando; Violi, Damian A; Raymondos, Konstantinos; Hurtado, Javier; González, Marco; Du, Bin; Amin, Pravin; Maggiore, Salvatore M; Thille, Arnaud W; Soares, Marco Antonio; Jibaja, Manuel; Villagomez, Asisclo J; Kuiper, Michael A; Koh, Younsuck; Moreno, Rui P; Zeggwagh, Amine Ali; Matamis, Dimitrios; Anzueto, Antonio; Ferguson, Niall D; Esteban, Andrés

2017-04-01

In neurologically critically ill patients with mechanical ventilation (MV), the development of acute respiratory distress syndrome (ARDS) is a major contributor to morbidity and mortality, but the role of ventilatory management has been scarcely evaluated. We evaluate the association of tidal volume, level of PEEP and driving pressure with the development of ARDS in a population of patients with brain injury. We performed a secondary analysis of a prospective, observational study on mechanical ventilation. We included 986 patients mechanically ventilated due to an acute brain injury (hemorrhagic stroke, ischemic stroke or brain trauma). Incidence of ARDS in this cohort was 3%. Multivariate analysis suggested that driving pressure could be associated with the development of ARDS (odds ratio for unit increment of driving pressure 1.12; confidence interval for 95%: 1.01 to 1.23) whereas we did not observe association for tidal volume (in ml per kg of predicted body weight) or level of PEEP. ARDS was associated with an increase in mortality, longer duration of mechanical ventilation, and longer ICU length of stay. In a cohort of brain-injured patients the development of ARDS was not common. Driving pressure was associated with the development of this disease. Copyright © 2016 Elsevier Inc. All rights reserved.

Enhancing knowledge discovery from cancer genomics data with Galaxy.

PubMed

Albuquerque, Marco A; Grande, Bruno M; Ritch, Elie J; Pararajalingam, Prasath; Jessa, Selin; Krzywinski, Martin; Grewal, Jasleen K; Shah, Sohrab P; Boutros, Paul C; Morin, Ryan D

2017-05-01

The field of cancer genomics has demonstrated the power of massively parallel sequencing techniques to inform on the genes and specific alterations that drive tumor onset and progression. Although large comprehensive sequence data sets continue to be made increasingly available, data analysis remains an ongoing challenge, particularly for laboratories lacking dedicated resources and bioinformatics expertise. To address this, we have produced a collection of Galaxy tools that represent many popular algorithms for detecting somatic genetic alterations from cancer genome and exome data. We developed new methods for parallelization of these tools within Galaxy to accelerate runtime and have demonstrated their usability and summarized their runtimes on multiple cloud service providers. Some tools represent extensions or refinement of existing toolkits to yield visualizations suited to cohort-wide cancer genomic analysis. For example, we present Oncocircos and Oncoprintplus, which generate data-rich summaries of exome-derived somatic mutation. Workflows that integrate these to achieve data integration and visualizations are demonstrated on a cohort of 96 diffuse large B-cell lymphomas and enabled the discovery of multiple candidate lymphoma-related genes. Our toolkit is available from our GitHub repository as Galaxy tool and dependency definitions and has been deployed using virtualization on multiple platforms including Docker. © The Author 2017. Published by Oxford University Press.

Independent and Parallel Evolution of New Genes by Gene Duplication in Two Origins of C4 Photosynthesis Provides New Insight into the Mechanism of Phloem Loading in C4 Species

PubMed Central

Emms, David M.; Covshoff, Sarah; Hibberd, Julian M.; Kelly, Steven

2016-01-01

C4 photosynthesis is considered one of the most remarkable examples of evolutionary convergence in eukaryotes. However, it is unknown whether the evolution of C4 photosynthesis required the evolution of new genes. Genome-wide gene-tree species-tree reconciliation of seven monocot species that span two origins of C4 photosynthesis revealed that there was significant parallelism in the duplication and retention of genes coincident with the evolution of C4 photosynthesis in these lineages. Specifically, 21 orthologous genes were duplicated and retained independently in parallel at both C4 origins. Analysis of this gene cohort revealed that the set of parallel duplicated and retained genes is enriched for genes that are preferentially expressed in bundle sheath cells, the cell type in which photosynthesis was activated during C4 evolution. Furthermore, functional analysis of the cohort of parallel duplicated genes identified SWEET-13 as a potential key transporter in the evolution of C4 photosynthesis in grasses, and provides new insight into the mechanism of phloem loading in these C4 species. Key words: C4 photosynthesis, gene duplication, gene families, parallel evolution. PMID:27016024

Dissecting DNA repair in adult high grade gliomas for patient stratification in the post-genomic era

PubMed Central

Perry, Christina; Agarwal, Devika; Abdel-Fatah, Tarek M.A.; Lourdusamy, Anbarasu; Grundy, Richard; Auer, Dorothee T.; Walker, David; Lakhani, Ravi; Scott, Ian S.; Chan, Stephen; Ball, Graham; Madhusudan, Srinivasan

2014-01-01

Deregulation of multiple DNA repair pathways may contribute to aggressive biology and therapy resistance in gliomas. We evaluated transcript levels of 157 genes involved in DNA repair in an adult glioblastoma Test set (n=191) and validated in ‘The Cancer Genome Atlas’ (TCGA) cohort (n=508). A DNA repair prognostic index model was generated. Artificial neural network analysis (ANN) was conducted to investigate global gene interactions. Protein expression by immunohistochemistry was conducted in 61 tumours. A fourteen DNA repair gene expression panel was associated with poor survival in Test and TCGA cohorts. A Cox multivariate model revealed APE1, NBN, PMS2, MGMT and PTEN as independently associated with poor prognosis. A DNA repair prognostic index incorporating APE1, NBN, PMS2, MGMT and PTEN stratified patients in to three prognostic sub-groups with worsening survival. APE1, NBN, PMS2, MGMT and PTEN also have predictive significance in patients who received chemotherapy and/or radiotherapy. ANN analysis of APE1, NBN, PMS2, MGMT and PTEN revealed interactions with genes involved in transcription, hypoxia and metabolic regulation. At the protein level, low APE1 and low PTEN remain associated with poor prognosis. In conclusion, multiple DNA repair pathways operate to influence biology and clinical outcomes in adult high grade gliomas. PMID:25026297

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

Occurrence of occult CSF leaks during standard FESS procedures.

PubMed

Bucher, S; Kugler, A; Probst, E; Epprecht, L; Stadler, R S; Holzmann, D; Soyka, M B

2018-03-18

To determine the incidence of occult cerebrospinal fluid leaks (CSF) after functional endoscopic sinus surgery (FESS) and to evaluate the diagnostic performance of beta2-transferrin in blood-contaminated conditions. Prospective cohort study. An analysis of 57 intraoperative samples using hydrogel 6 beta2-transferrin assay after FESS was undertaken. In case of CSF positive samples and continuing rhinorrhea, reanalysis after more than 1 year was conducted. In-vivo analysis of a primary spontaneous CSF leak sample took place to verify difficulties in detecting beta2-transferrin in blood-contaminated settings. Own titrations were performed to evaluate detection limits of CSF by beta2-transferrin and beta-trace protein assays in these settings. An incidence of 13% for occult CSF leaks after FESS was found. In blood-contaminated conditions, routine beta2-transferrin assays showed low sensitivity. In over 1 year follow-up, all samples were negative for CSF and none of them developed clinical relevant CSF leaks or meningitis. Occult and clinically irrelevant CSF leaks do occur in a significant proportion of patients during and shortly after FESS. Intra- and postoperatively, routine beta2-transferrin assays show low sensitivity. They should not be used in these settings. The clinical course of patients with occult CSF leaks indicated possibility of an uneventful follow-up.

Evidence from prospective cohort studies does not support current dietary fat guidelines: a systematic review and meta-analysis.

PubMed

Harcombe, Zoë; Baker, Julien S; Davies, Bruce

2017-12-01

National dietary guidelines were introduced in 1977 and 1983, by the US and UK governments to reduce coronary heart disease (CHD) mortality by reducing dietary fat intake. Our 2016 systematic review examined the epidemiological evidence available to the dietary committees at the time; we found no support for the recommendations to restrict dietary fat. The present investigation extends our work by re-examining the totality of epidemiological evidence currently available relating to dietary fat guidelines. A systematic review and meta-analysis of prospective cohort studies currently available, which examined the relationship between dietary fat, serum cholesterol and the development of CHD, were undertaken. Across 7 studies, involving 89 801 participants (94% male), there were 2024 deaths from CHD during the mean follow-up of 11.9±5.6 years. The death rate from CHD was 2.25%. Eight data sets were suitable for inclusion in meta-analysis; all excluded participants with previous heart disease. Risk ratios (RRs) from meta-analysis were not statistically significant for CHD deaths and total or saturated fat consumption. The RR from meta-analysis for total fat intake and CHD deaths was 1.04 (95% CI 0.98 to 1.10). The RR from meta-analysis for saturated fat intake and CHD deaths was 1.08 (95% CI 0.94 to 1.25). Epidemiological evidence to date found no significant difference in CHD mortality and total fat or saturated fat intake and thus does not support the present dietary fat guidelines. The evidence per se lacks generalisability for population-wide guidelines. 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/.

Decreased serum pyridoxal levels in schizophrenia: meta-analysis and Mendelian randomization analysis

PubMed Central

Tomioka, Yukiko; Kinoshita, Makoto; Umehara, Hidehiro; Watanabe, Shin-ya; Nakataki, Masahito; Iwayama, Yoshimi; Toyota, Tomoko; Ikeda, Masashi; Yamamori, Hidenaga; Shimodera, Shinji; Tajima, Atsushi; Hashimoto, Ryota; Iwata, Nakao; Yoshikawa, Takeo; Ohmori, Tetsuro

2018-01-01

Background Alterations in one-carbon metabolism have been associated with schizophrenia, and vitamin B6 is one of the key components in this pathway. Methods We first conducted a case–control study of serum pyridoxal levels and schizophrenia in a large Japanese cohort (n = 1276). Subsequently, we conducted a meta-analysis of association studies (n = 2125). Second, we investigated whether rs4654748, which was identified in a genome-wide association study as a vitamin B6-related single nucleotide polymorphism, was genetically implicated in patients with schizophrenia in the Japanese population (n = 10 689). Finally, we assessed the effect of serum pyridoxal levels on schizophrenia risk using a Mendelian randomization (MR) approach. Results Serum pyridoxal levels were significantly lower in patients with schizophrenia than in controls, not only in our cohort, but also in the pooled data set of the meta-analysis of association studies (standardized mean difference −0.48, 95% confidence interval [CI] −0.57 to −0.39, p = 9.8 × 10−24). We failed to find a significant association between rs4654748 and schizophrenia. Furthermore, an MR analysis failed to find a causal relationship between pyridoxal levels and schizophrenia risk (odds ratio 0.99, 95% CI 0.65–1.51, p = 0.96). Limitations Food consumption and medications may have affected serum pyridoxal levels in our cross-sectional study. Sample size, number of instrumental variables and substantial heterogeneity among patients with schizophrenia are limitations of an MR analysis. Conclusion We found decreased serum pyridoxal levels in patients with schizophrenia in this observational study. However, we failed to obtain data supporting a causal relationship between pyridoxal levels and schizophrenia risk using the MR approach. PMID:29688875

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

The two-dimensional Monte Carlo: a new methodologic paradigm for dose reconstruction for epidemiological studies.

PubMed

Simon, Steven L; Hoffman, F Owen; Hofer, Eduard

2015-01-01

Retrospective dose estimation, particularly dose reconstruction that supports epidemiological investigations of health risk, relies on various strategies that include models of physical processes and exposure conditions with detail ranging from simple to complex. Quantification of dose uncertainty is an essential component of assessments for health risk studies since, as is well understood, it is impossible to retrospectively determine the true dose for each person. To address uncertainty in dose estimation, numerical simulation tools have become commonplace and there is now an increased understanding about the needs and what is required for models used to estimate cohort doses (in the absence of direct measurement) to evaluate dose response. It now appears that for dose-response algorithms to derive the best, unbiased estimate of health risk, we need to understand the type, magnitude and interrelationships of the uncertainties of model assumptions, parameters and input data used in the associated dose estimation models. Heretofore, uncertainty analysis of dose estimates did not always properly distinguish between categories of errors, e.g., uncertainty that is specific to each subject (i.e., unshared error), and uncertainty of doses from a lack of understanding and knowledge about parameter values that are shared to varying degrees by numbers of subsets of the cohort. While mathematical propagation of errors by Monte Carlo simulation methods has been used for years to estimate the uncertainty of an individual subject's dose, it was almost always conducted without consideration of dependencies between subjects. In retrospect, these types of simple analyses are not suitable for studies with complex dose models, particularly when important input data are missing or otherwise not available. The dose estimation strategy presented here is a simulation method that corrects the previous deficiencies of analytical or simple Monte Carlo error propagation methods and is termed, due to its capability to maintain separation between shared and unshared errors, the two-dimensional Monte Carlo (2DMC) procedure. Simply put, the 2DMC method simulates alternative, possibly true, sets (or vectors) of doses for an entire cohort rather than a single set that emerges when each individual's dose is estimated independently from other subjects. Moreover, estimated doses within each simulated vector maintain proper inter-relationships such that the estimated doses for members of a cohort subgroup that share common lifestyle attributes and sources of uncertainty are properly correlated. The 2DMC procedure simulates inter-individual variability of possibly true doses within each dose vector and captures the influence of uncertainty in the values of dosimetric parameters across multiple realizations of possibly true vectors of cohort doses. The primary characteristic of the 2DMC approach, as well as its strength, are defined by the proper separation between uncertainties shared by members of the entire cohort or members of defined cohort subsets, and uncertainties that are individual-specific and therefore unshared.

Proton Pump Inhibitor Use and Risk of Chronic Kidney Disease

PubMed Central

Lazarus, Benjamin; Chen, Yuan; Wilson, Francis P.; Sang, Yingying; Chang, Alex R.; Coresh, Josef; Grams, Morgan E.

2016-01-01

Context Proton pump inhibitors (PPIs) are among the most commonly used drugs worldwide, and have been linked to acute interstitial nephritis. Less is known about the relationship between PPI use and chronic kidney disease (CKD). Objective To quantify the association between PPI use and incident CKD in a population-based cohort. Design, Setting and Participants 10,482 participants in the Atherosclerosis Risk in Communities (ARIC) study with an estimated glomerular filtration rate (eGFR) of ≥60mL/min/1.73m2 were followed from a baseline visit (1996–1999) to December 31, 2011. Findings were replicated in an administrative cohort of 248,751 patients with eGFR ≥60mL/min/1.73m2 from Geisinger Health System. Exposure Self-reported PPI use in ARIC, or an outpatient PPI prescription in the replication cohort. Histamine-2 receptor (H2) antagonist use was considered a negative control and active comparator. Main Outcome Measure Incident CKD, using diagnostic codes indicating CKD at hospital discharge or death. In the replication cohort, incident CKD was defined by outpatient eGFR <60 mL/min/1.73 m2. Results Compared to non-users, PPI-users were more often white, obese, and taking antihypertensive medication. In ARIC, PPI use was associated with incident CKD in unadjusted analysis (hazard ratio [HR], 1.45; 95% confidence interval [CI], 1.11–1.90), analysis adjusted for demographic, socioeconomic, and clinical parameters (HR, 1.50; 95% CI, 1.14–1.96), and in analysis with PPI ever-use modeled as a time-varying variable (adjusted HR, 1.35; 95% CI, 1.17–1.55). The association persisted when baseline PPI users were compared directly to H2-antagonist users (adjusted HR, 1.39; 95% CI, 1.01–1.91), and to propensity-score matched non-users (HR, 1.76; 95% CI, 1.13–2.74). In the replication cohort, PPI use was associated with CKD in all analyses, including a time-varying new user design (adjusted HR 1.24; 95% CI, 1.20–1.28). Twice-daily PPI dosing was associated with a higher risk (adjusted HR, 1.46; 95% CI, 1.28–1.67) than once-daily dosing (adjusted HR, 1.15; 95% CI, 1.09–1.21). Conclusions PPI use is associated with a 20%–50% higher risk of incident CKD. Future research should evaluate whether limiting PPI use reduces the incidence of CKD. PMID:26752337

Prenatal Ambient Air Pollution, Placental Mitochondrial DNA Content, and Birth Weight in the INMA (Spain) and ENVIRONAGE (Belgium) Birth Cohorts

PubMed Central

Clemente, Diana B.P.; Casas, Maribel; Vilahur, Nadia; Begiristain, Haizea; Bustamante, Mariona; Carsin, Anne-Elie; Fernández, Mariana F.; Fierens, Frans; Gyselaers, Wilfried; Iñiguez, Carmen; Janssen, Bram G.; Lefebvre, Wouter; Llop, Sabrina; Olea, Nicolás; Pedersen, Marie; Pieters, Nicky; Santa Marina, Loreto; Souto, Ana; Tardón, Adonina; Vanpoucke, Charlotte; Vrijheid, Martine; Sunyer, Jordi; Nawrot, Tim S.

2015-01-01

Background: Mitochondria are sensitive to environmental toxicants due to their lack of repair capacity. Changes in mitochondrial DNA (mtDNA) content may represent a biologically relevant intermediate outcome in mechanisms linking air pollution and fetal growth restriction. Objective: We investigated whether placental mtDNA content is a possible mediator of the association between prenatal nitrogen dioxide (NO2) exposure and birth weight. Methods: We used data from two independent European cohorts: INMA (n = 376; Spain) and ENVIRONAGE (n = 550; Belgium). Relative placental mtDNA content was determined as the ratio of two mitochondrial genes (MT-ND1 and MTF3212/R3319) to two control genes (RPLP0 and ACTB). Effect estimates for individual cohorts and the pooled data set were calculated using multiple linear regression and mixed models. We also performed a mediation analysis. Results: Pooled estimates indicated that a 10-μg/m3 increment in average NO2 exposure during pregnancy was associated with a 4.9% decrease in placental mtDNA content (95% CI: –9.3, –0.3%) and a 48-g decrease (95% CI: –87, –9 g) in birth weight. However, the association with birth weight was significant for INMA (–66 g; 95% CI: –111, –23 g) but not for ENVIRONAGE (–20 g; 95% CI: –101, 62 g). Placental mtDNA content was associated with significantly higher mean birth weight (pooled analysis, interquartile range increase: 140 g; 95% CI: 43, 237 g). Mediation analysis estimates, which were derived for the INMA cohort only, suggested that 10% (95% CI: 6.6, 13.0 g) of the association between prenatal NO2 and birth weight was mediated by changes in placental mtDNA content. Conclusion: Our results suggest that mtDNA content can be one of the potential mediators of the association between prenatal air pollution exposure and birth weight. Citation: Clemente DB, Casas M, Vilahur N, Begiristain H, Bustamante M, Carsin AE, Fernández MF, Fierens F, Gyselaers W, Iñiguez C, Janssen BG, Lefebvre W, Llop S, Olea N, Pedersen M, Pieters N, Santa Marina L, Souto A, Tardón A, Vanpoucke C, Vrijheid M, Sunyer J, Nawrot TS. 2016. Prenatal ambient air pollution, placental mitochondrial DNA content, and birth weight in the INMA (Spain) and ENVIRONAGE (Belgium) birth cohorts. Environ Health Perspect 124:659–665; http://dx.doi.org/10.1289/ehp.1408981 PMID:26317635

The marriage boom and marriage bust in the United States: An age-period-cohort analysis.

PubMed

Schellekens, Jona

2017-03-01

In the 1950s and 1960s there was an unprecedented marriage boom in the United States. This was followed in the 1970s by a marriage bust. Some argue that both phenomena are cohort effects, while others argue that they are period effects. The study reported here tested the major period and cohort theories of the marriage boom and bust, by estimating an age-period-cohort model of first marriage for the years 1925-79 using census microdata. The results of the analysis indicate that the marriage boom was mostly a period effect, although there were also cohort influences. More specifically, the hypothesis that the marriage boom was mostly a response to rising wages is shown to be consistent with the data. However, much of the marriage bust can be accounted for by unidentified cohort influences, at least until 1980.

Estimating the Effects of Parental Divorce and Death With Fixed Effects Models

PubMed Central

Amato, Paul R.; Anthony, Christopher J.

2014-01-01

The authors used child fixed effects models to estimate the effects of parental divorce and death on a variety of outcomes using 2 large national data sets: (a) the Early Childhood Longitudinal Study, Kindergarten Cohort (kindergarten through the 5th grade) and (b) the National Educational Longitudinal Study (8th grade to the senior year of high school). In both data sets, divorce and death were associated with multiple negative outcomes among children. Although evidence for a causal effect of divorce on children was reasonably strong, effect sizes were small in magnitude. A second analysis revealed a substantial degree of variability in children’s outcomes following parental divorce, with some children declining, others improving, and most not changing at all. The estimated effects of divorce appeared to be strongest among children with the highest propensity to experience parental divorce. PMID:24659827

The General Education Astronomy Source (GEAS) Project: Extending the Reach of Astronomy Education

NASA Astrophysics Data System (ADS)

Vogt, N. P.; Muise, A. S.

2014-07-01

We present a set of NASA and NSF sponsored resources to aid in teaching astronomy remotely and in the classroom at the college level, with usage results for pilot groups of students. Our goal is to increase the accessibility of general education science coursework to underserved populations nationwide. Our materials are available for use without charge, and we are actively looking for pilot instructors. Primary components of our program include an interactive online tutorial program with over 12,000 questions, an instructor review interface, a set of hands-on and imaging- and spectra-driven laboratory exercises, including video tutorials, and interviews with diverse individuals working in STEM fields to help combat stereotypes. We discuss learning strategies often employed by students without substantial scientific training and suggest ways to incorporate them into a framework based on the scientific method and techniques for data analysis, and we compare cohorts of in-class and distance-education students.

ImmunoRatio: a publicly available web application for quantitative image analysis of estrogen receptor (ER), progesterone receptor (PR), and Ki-67

PubMed Central

2010-01-01

Introduction Accurate assessment of estrogen receptor (ER), progesterone receptor (PR), and Ki-67 is essential in the histopathologic diagnostics of breast cancer. Commercially available image analysis systems are usually bundled with dedicated analysis hardware and, to our knowledge, no easily installable, free software for immunostained slide scoring has been described. In this study, we describe a free, Internet-based web application for quantitative image analysis of ER, PR, and Ki-67 immunohistochemistry in breast cancer tissue sections. Methods The application, named ImmunoRatio, calculates the percentage of positively stained nuclear area (labeling index) by using a color deconvolution algorithm for separating the staining components (diaminobenzidine and hematoxylin) and adaptive thresholding for nuclear area segmentation. ImmunoRatio was calibrated using cell counts defined visually as the gold standard (training set, n = 50). Validation was done using a separate set of 50 ER, PR, and Ki-67 stained slides (test set, n = 50). In addition, Ki-67 labeling indexes determined by ImmunoRatio were studied for their prognostic value in a retrospective cohort of 123 breast cancer patients. Results The labeling indexes by calibrated ImmunoRatio analyses correlated well with those defined visually in the test set (correlation coefficient r = 0.98). Using the median Ki-67 labeling index (20%) as a cutoff, a hazard ratio of 2.2 was obtained in the survival analysis (n = 123, P = 0.01). ImmunoRatio was shown to adapt to various staining protocols, microscope setups, digital camera models, and image acquisition settings. The application can be used directly with web browsers running on modern operating systems (e.g., Microsoft Windows, Linux distributions, and Mac OS). No software downloads or installations are required. ImmunoRatio is open source software, and the web application is publicly accessible on our website. Conclusions We anticipate that free web applications, such as ImmunoRatio, will make the quantitative image analysis of ER, PR, and Ki-67 easy and straightforward in the diagnostic assessment of breast cancer specimens. PMID:20663194

ImmunoRatio: a publicly available web application for quantitative image analysis of estrogen receptor (ER), progesterone receptor (PR), and Ki-67.

PubMed

Tuominen, Vilppu J; Ruotoistenmäki, Sanna; Viitanen, Arttu; Jumppanen, Mervi; Isola, Jorma

2010-01-01

Accurate assessment of estrogen receptor (ER), progesterone receptor (PR), and Ki-67 is essential in the histopathologic diagnostics of breast cancer. Commercially available image analysis systems are usually bundled with dedicated analysis hardware and, to our knowledge, no easily installable, free software for immunostained slide scoring has been described. In this study, we describe a free, Internet-based web application for quantitative image analysis of ER, PR, and Ki-67 immunohistochemistry in breast cancer tissue sections. The application, named ImmunoRatio, calculates the percentage of positively stained nuclear area (labeling index) by using a color deconvolution algorithm for separating the staining components (diaminobenzidine and hematoxylin) and adaptive thresholding for nuclear area segmentation. ImmunoRatio was calibrated using cell counts defined visually as the gold standard (training set, n = 50). Validation was done using a separate set of 50 ER, PR, and Ki-67 stained slides (test set, n = 50). In addition, Ki-67 labeling indexes determined by ImmunoRatio were studied for their prognostic value in a retrospective cohort of 123 breast cancer patients. The labeling indexes by calibrated ImmunoRatio analyses correlated well with those defined visually in the test set (correlation coefficient r = 0.98). Using the median Ki-67 labeling index (20%) as a cutoff, a hazard ratio of 2.2 was obtained in the survival analysis (n = 123, P = 0.01). ImmunoRatio was shown to adapt to various staining protocols, microscope setups, digital camera models, and image acquisition settings. The application can be used directly with web browsers running on modern operating systems (e.g., Microsoft Windows, Linux distributions, and Mac OS). No software downloads or installations are required. ImmunoRatio is open source software, and the web application is publicly accessible on our website. We anticipate that free web applications, such as ImmunoRatio, will make the quantitative image analysis of ER, PR, and Ki-67 easy and straightforward in the diagnostic assessment of breast cancer specimens.

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

Time trends in exposure of cattle to bovine spongiform encephalopathy and cohort effect in France and Italy: value of the classical Age-Period-Cohort approach.

PubMed

Sala, Carole; Ru, Giuseppe

2009-09-18

The Age-Period-Cohort (APC) analysis is routinely used for time trend analysis of cancer incidence or mortality rates, but in veterinary epidemiology, there are still only a few examples of this application. APC models were recently used to model the French epidemic assuming that the time trend for BSE was mainly due to a cohort effect in relation to the control measures that may have modified the BSE exposure of cohorts over time. We used a categorical APC analysis which did not require any functional form for the effect of the variables, and examined second differences to estimate the variation of the BSE trend. We also reanalysed the French epidemic and performed a simultaneous analysis of Italian data using more appropriate birth cohort categories for comparison. We used data from the exhaustive surveillance carried out in France and Italy between 2001 and 2007, and comparatively described the trend of the epidemic in both countries. At the end, the shape and irregularities of the trends were discussed in light of the main control measures adopted to control the disease. In Italy a decrease in the epidemic became apparent from 1996, following the application of rendering standards for the processing of specific risk material (SRM). For the French epidemic, the pattern of second differences in the birth cohorts confirmed the beginning of the decrease from 1995, just after the implementation of the meat and bone meal (MBM) ban for all ruminants (1994). The APC analysis proved to be highly suitable for the study of the trend in BSE epidemics and was helpful in understanding the effects of management and control of the disease. Additionally, such an approach may help in the implementation of changes in BSE regulations.

Contemporary management of frontal sinus mucoceles: a meta-analysis.

PubMed

Courson, Andy M; Stankiewicz, James A; Lal, Devyani

2014-02-01

To analyze trends in the surgical management of frontal and fronto-ethmoid mucoceles through meta-analysis. Meta-analysis and case series. A systematic literature review on surgical management of frontal and fronto-ethmoid mucoceles was conducted. Studies were divided into historical (1975-2001) and contemporary (2002-2012) groups. A meta-analysis of these studies was performed. The historical and contemporary cohorts were compared (surgical approach, recurrence, and complications). To study evolution in surgical management, a senior surgeon's experience over 28 years was analyzed separately. Thirty-one studies were included for meta-analysis. The historical cohort included 425 mucoceles from 11 studies. The contemporary cohort included 542 mucoceles from 20 studies. More endoscopic techniques were used in the contemporary versus historical cohort (53.9% vs. 24.7%; P = <0.001). In the authors' series, a higher percentage was treated endoscopically (82.8% of 122 mucoceles). Recurrence (P = 0.20) and major complication (P = 0.23) rates were similar between cohorts. Minor complication rates were superior for endoscopic techniques in both cohorts (P = 0.02 historical; P = <0.001 contemporary). In the historical cohort, higher recurrence was noted in the external group (P = 0.03). Results from endoscopic and open approaches are comparable. Although endoscopic techniques are being increasingly adopted, comparison with our series shows that more cases could potentially be treated endoscopically. Frequent use of open approaches may reflect efficacy, or perhaps lack of expertise and equipment required for endoscopic management. Most contemporary authors favor endoscopic management, limiting open approaches for specific indications (unfavorable anatomy, lateral disease, and scarring). N/A. Copyright © 2013 The American Laryngological, Rhinological and Otological Society, Inc.

Adherence to antiretroviral therapy for HIV in sub-Saharan Africa and Asia: a comparative analysis of two regional cohorts.

PubMed

Bijker, Rimke; Jiamsakul, Awachana; Kityo, Cissy; Kiertiburanakul, Sasisopin; Siwale, Margaret; Phanuphak, Praphan; Akanmu, Sulaimon; Chaiwarith, Romanee; Wit, Ferdinand W; Sim, Benedict Lh; Boender, Tamara Sonia; Ditangco, Rossana; Rinke De Wit, Tobias F; Sohn, Annette H; Hamers, Raph L

2017-03-03

Our understanding of how to achieve optimal long-term adherence to antiretroviral therapy (ART) in settings where the burden of HIV disease is highest remains limited. We compared levels and determinants of adherence over time between HIV-positive persons receiving ART who were enrolled in a bi-regional cohort in sub-Saharan Africa and Asia. This multicentre prospective study of adults starting first-line ART assessed patient-reported adherence at follow-up clinic visits using a 30-day visual analogue scale. Determinants of suboptimal adherence (<95%) were assessed for six-month intervals, using generalized estimating equations multivariable logistic regression with multiple imputations. Region of residence (Africa vs. Asia) was assessed as a potential effect modifier. Of 13,001 adherence assessments in 3934 participants during the first 24 months of ART, 6.4% (837) were suboptimal, with 7.3% (619/8484) in the African cohort versus 4.8% (218/4517) in the Asian cohort ( p  < 0.001). In the African cohort, determinants of suboptimal adherence were male sex (odds ratio (OR) 1.27, 95% confidence interval (CI) 1.06-1.53; p  = 0.009), younger age (OR 0.8 per 10 year increase; 0.8-0.9; p  = 0.003), use of concomitant medication (OR 1.8, 1.0-3.2; p  = 0.044) and attending a public facility (OR 1.3, 95% CI 1.1-1.7; p  = 0.004). In the Asian cohort, adherence was higher in men who have sex with men (OR for suboptimal adherence 0.6, 95% CI 0.4-0.9; p  = 0.029) and lower in injecting drug users (OR for suboptimal adherence 1.6, 95% CI 0.9-2.6; p  = 0.075), compared to heterosexuals. Risk of suboptimal adherence decreased with longer ART duration in both regions. Participants in low- and lower-middle-income countries had a higher risk of suboptimal adherence (OR 1.6, 1.3-2.0; p  < 0.001), compared to those in upper-middle or high-income countries. Suboptimal adherence was strongly associated with virological failure, in Africa (OR 5.8, 95% CI 4.3-7.7; p  < 0.001) and Asia (OR 9.0, 95% CI 5.0-16.2; p  < 0.001). Patient-reported adherence barriers among African participants included scheduling demands, drug stockouts, forgetfulness, sickness or adverse events, stigma or depression, regimen complexity and pill burden. Psychosocial factors and health system resources may explain regional differences. Adherence-enhancing interventions should address patient-reported barriers tailored to local settings, prioritizing the first years of ART.

Pay Differences among the Highly Trained: Cohort Differences in the Sex Gap in Lawyers' Earnings

ERIC Educational Resources Information Center

Noonan, Mary C.; Corcoran, Mary E.; Courant, Paul N.

2005-01-01

Using unique data from a survey of University of Michigan Law School graduates, we test various models of how sex differences in pay, labor supply and job settings should have evolved as women entered the elite male field of law. We compare the sex gap in earnings 15 years after graduation for two cohorts of lawyers and find that it has remained…

Inter-cohort growth for three tropical resources: tilapia, octopus and lobster.

PubMed

Velázquez-Abunader, Iván; Gómez-Muñoz, Victor Manuel; Salas, Silvia; Ruiz-Velazco, Javier M J

2015-09-01

Growth parameters are an important component for the stock assessment of exploited aquatic species. However, it is often difficult to apply direct methods to estimate growth and to analyse the differences between males and females, particularly in tropical areas. The objective of this study was to analyse the inter-cohort growth of three tropical resources and discuss the possible fisheries management implications. A simple method was used to compare individual growth curves obtained from length frequency distribution analysis, illustrated by case studies of three tropical species from different aquatic environments: tilapia (Oreochromis aureus), red octopus (Octopus maya) and the Caribbean spiny lobster (Panulirus argus). The analysis undertaken compared the size distribution of males and females of a given cohort through modal progression analysis. The technique used proved to be useful for highlighting the differences in growth between females and males of a specific cohort. The potential effect of extrinsic and intrinsic factors on the organism's development as reflected in the size distribution of the cohorts is discussed.

Use of a Simple Criteria Set for Guiding Echocardiography in Nosocomial Staphylococcus aureus Bacteremia

PubMed Central

Fowler, Vance G.; Rieg, Siegbert; Peyerl-Hoffmann, Gabriele; Birkholz, Hanna; Hellmich, Martin; Kern, Winfried V.; Seifert, Harald

2011-01-01

(see the editorial commentary and Soriano and Mensa, on pages 10–12.) Background. Infective endocarditis (IE) is a severe complication in patients with nosocomial Staphylococcus aureus bacteremia (SAB). We sought to develop and validate criteria to identify patients at low risk for the development of IE in whom transesophageal echocardiography (TEE) might be dispensable. Methods. Consecutive patients with nosocomial SAB from independent cohorts in Europe (Invasive S. aureus Infection Cohort [INSTINCT]) and North America (S. aureus Bacteremia Group [SABG]) were evaluated for the presence of clinical criteria predicting an increased risk for the development of IE (ie, prolonged bacteremia of >4 days' duration, presence of a permanent intracardiac device, hemodialysis dependency, spinal infection, and nonvertebral osteomyelitis). Patients were observed closely for clinical signs and symptoms of IE during hospitalization and a 3-month follow-up period. Results. IE was present in 13 (4.3%) of 304 patients in the INSTINCT cohort and in 40 (9.3%) of 432 patients in the SABG cohort. Within 14 days after the first positive blood culture result, echocardiography was performed in 39.8% and 57.4% of patients in the INSTINCT and SABG cohorts, respectively. In patients with IE, the most common clinical prediction criteria present were prolonged bacteremia (69.2% vs 90% for INSTINCT vs SABG, respectively) and presence of a permanent intracardiac device (53.8% vs 32.5%). In total, 13 of 13 patients in the INSTINCT cohort and 39 of 40 patients in the SABG cohort with documented IE fulfilled at least 1 criterion (sensitivity, 100% vs. 97.5%; negative predictive value, 100% vs 99.2%). Conclusions. A simple criteria set for patients with nosocomial SAB can identify patients at low risk of IE. Patients who meet these criteria may not routinely require TEE. PMID:21653295

Cohort profile: a data linkage cohort to examine health service profiles of people with intellectual disability in New South Wales, Australia

PubMed Central

Reppermund, Simone; Srasuebkul, Preeyaporn; Heintze, Theresa; Reeve, Rebecca; Dean, Kimberlie; Emerson, Eric; Coyne, David; Snoyman, Phillip; Baldry, Eileen; Dowse, Leanne; Szanto, Tracey; Sara, Grant; Florio, Tony

2017-01-01

Purpose People with intellectual disability are a minority group who experience poorer physical and mental health than the general population and have difficulty accessing healthcare services. There is lack of knowledge about healthcare service needs and gaps experienced by people with intellectual disability. This study aims to interrogate a large linked administrative data set containing hospital admissions, presentations to emergency departments (ED) and mortality data to provide evidence to inform the development of improved health and mental health services for this population. Participants A retrospective cohort of people with intellectual disability (n=51 452) from New South Wales (NSW), Australia, to explore health and mental health profiles, mortality, pattern of health service use and associated costs between 2005 and 2013. The cohort is drawn from: the Disability Services Minimum Data Set; Admitted Patients Data Collection; Emergency Department Data Collection, Australian Bureau of Statistics Death Registry and Registry of Births, Deaths and Marriages. Mental health service usage among those with intellectual disability will be compared to a cohort of people who used mental health services (n=1 073 139) and service usage other than for mental health will be compared with published data from the general population. Findings to date The median age of the cohort was 24 at the time of the last hospital admission and 21 at the last ED presentation. The cohort has a higher proportion of men than women and accounts for 0.6% of the NSW population in 2011. Over 70% had up to 5 ED presentations and hospitalisations between 2005 and 2012. A high proportion of people with intellectual disability live in the most disadvantaged neighbourhoods. Future plans Results will be used to inform the development of more responsive healthcare, including improved interactions between health, social and disability supports. More generally, the results will assist the development of more inclusive policy frameworks for people with intellectual disability. PMID:28404614

Early predictors of study success in a Dutch advanced nurse practitioner education program: A retrospective cohort study.

PubMed

Bossema, Ercolie R; Meijs, Tineke H J M; Peters, Jeroen W B

2017-10-01

Study delay and attrition are major concerns in higher education. They cost time and effort, and threaten the availability of higher qualified professionals. Knowing early what factors contribute to delay and attrition may help prevent this. The aim of this study was to examine whether student characteristics, including a literature study report grade as a proxy of cognitive abilities, predicted study success in a dual advanced nurse practitioner education program. Retrospective cohort study, including all 214 students who between September 2009 and September 2015 started the two-year program at the HAN University of Applied Sciences in Nijmegen, the Netherlands. Study success was defined as having completed the program within the envisaged period. Variables examined included: age, gender, previous education (bachelor's degree or in-service training in nursing), work setting (general health, mental health, public health, or nursing home care), and literature study report grade (from 1 to 10). A hierarchical logistic regression analysis was performed. Most students were female (80%), had a bachelor's degree in nursing (67%), and were employed in a general healthcare setting (58%). Mean age was 40.5years (SD 9.4). One hundred thirty-seven students (64%) had study success. Being employed in a general healthcare setting (p≤0.004) and a higher literature study report grade (p=0.001) were associated with a higher study success rate. In advanced nurse practitioner education, study success rate seems associated with the student's cognitive abilities and work field. It might be worthwhile to identify students 'at risk of failure' before the start of the program and offer them extra support. Copyright © 2017 Elsevier Ltd. All rights reserved.

Predictors of liver-related death among people who inject drugs in Vancouver, Canada: a 15-year prospective cohort study

PubMed Central

Hayashi, Kanna; Milloy, Michael-John; Wood, Evan; Dong, Huiru; Montaner, Julio SG; Kerr, Thomas

2014-01-01

Introduction While HIV/AIDS remains an important cause of death among people who inject drugs (PWID), the potential mortality burden attributable to hepatitis C virus (HCV) infection among this population is of increasing concern. Therefore, we sought to identify trends in and predictors of liver-related mortality among PWID. Methods Data were derived from prospective cohorts of PWID in Vancouver, Canada, between 1996 and 2011. Cohort data were linked to the provincial vital statistics database to ascertain mortality rates and causes of death. Multivariate Cox proportional hazards regression was used to examine the relationship between HCV infection and time to liver-related death. A sub-analysis examined the effect of HIV/HCV co-infection. Results and discussion In total, 2,279 PWID participated in this study, with 1,921 (84.3%) having seroconverted to anti-HCV prior to baseline assessments and 124 (5.4%) during follow-up. The liver-related mortality rate was 2.1 (95% confidence interval [CI]: 1.5–3.0) deaths per 1,000 person-years and was stable over time. In multivariate analyses, HCV seropositivity was not significantly associated with liver-related mortality (adjusted relative hazard [ARH]: 0.45; 95% CI: 0.15–1.37), but HIV seropositivity was (ARH: 2.67; 95% CI: 1.27–5.63). In sub-analysis, HIV/HCV co-infection had a 2.53 (95% CI: 1.18–5.46) times hazard of liver-related death compared with HCV mono-infection. Conclusions In this study, HCV seropositivity did not predict liver-related mortality while HIV seropositivity did. The findings highlight the critical role of HIV mono- and co-infection rather than HCV infection in contributing to liver-related mortality among PWID in this setting. PMID:25391765

Health Benefits and Cost-Effectiveness of Brief Clinician Tobacco Counseling for Youth and Adults.

PubMed

Maciosek, Michael V; LaFrance, Amy B; Dehmer, Steven P; McGree, Dana A; Xu, Zack; Flottemesch, Thomas J; Solberg, Leif I

2017-01-01

To help clinicians and care systems determine the priority for tobacco counseling in busy clinic schedules, we assessed the lifetime health and economic value of annually counseling youth to discourage smoking initiation and of annually counseling adults to encourage cessation. We conducted a microsimulation analysis to estimate the health impact and cost effectiveness of both types of tobacco counseling in a US birth cohort of 4,000,000. The model used for the analysis was constructed from nationally representative data sets and structured literature reviews. Compared with no tobacco counseling, the model predicts that annual counseling for youth would reduce the average prevalence of smoking cigarettes during adult years by 2.0 percentage points, whereas annual counseling for adults will reduce prevalence by 3.8 percentage points. Youth counseling would prevent 42,686 smoking-attributable fatalities and increase quality-adjusted life years (QALYs) by 756,601 over the lifetime of the cohort. Adult counseling would prevent 69,901 smoking-attributable fatalities and increase QALYs by 1,044,392. Youth and adult counseling would yield net savings of $225 and $580 per person, respectively. If annual tobacco counseling was provided to the cohort during both youth and adult years, then adult smoking prevalence would be 5.5 percentage points lower compared with no counseling, and there would be 105,917 fewer smoking-attributable fatalities over their lifetimes. Only one-third of the potential health and economic benefits of counseling are being realized at current counseling rates. Brief tobacco counseling provides substantial health benefits while producing cost savings. Both youth and adult intervention are high-priority uses of limited clinician time. © 2017 Annals of Family Medicine, Inc.

Health Benefits and Cost-Effectiveness of Brief Clinician Tobacco Counseling for Youth and Adults

PubMed Central

Maciosek, Michael V.; LaFrance, Amy B.; Dehmer, Steven P.; McGree, Dana A.; Xu, Zack; Flottemesch, Thomas J.; Solberg, Leif I.

2017-01-01

PURPOSE To help clinicians and care systems determine the priority for tobacco counseling in busy clinic schedules, we assessed the lifetime health and economic value of annually counseling youth to discourage smoking initiation and of annually counseling adults to encourage cessation. METHODS We conducted a microsimulation analysis to estimate the health impact and cost effectiveness of both types of tobacco counseling in a US birth cohort of 4,000,000. The model used for the analysis was constructed from nationally representative data sets and structured literature reviews. RESULTS Compared with no tobacco counseling, the model predicts that annual counseling for youth would reduce the average prevalence of smoking cigarettes during adult years by 2.0 percentage points, whereas annual counseling for adults will reduce prevalence by 3.8 percentage points. Youth counseling would prevent 42,686 smoking-attributable fatalities and increase quality-adjusted life years (QALYs) by 756,601 over the lifetime of the cohort. Adult counseling would prevent 69,901 smoking-attributable fatalities and increase QALYs by 1,044,392. Youth and adult counseling would yield net savings of $225 and $580 per person, respectively. If annual tobacco counseling was provided to the cohort during both youth and adult years, then adult smoking prevalence would be 5.5 percentage points lower compared with no counseling, and there would be 105,917 fewer smoking-attributable fatalities over their lifetimes. Only one-third of the potential health and economic benefits of counseling are being realized at current counseling rates. CONCLUSIONS Brief tobacco counseling provides substantial health benefits while producing cost savings. Both youth and adult intervention are high-priority uses of limited clinician time. PMID:28376459

No increased risk of relapse after meningococcal C conjugate vaccine in nephrotic syndrome

PubMed Central

Taylor, Brent; Andrews, Nick; Stowe, Julia; Hamidi‐Manesh, Laila; Miller, Elizabeth

2007-01-01

Objectives To investigate whether meningococcal C conjugate vaccine (MCCV) caused relapse in children with steroid‐responsive nephrotic syndrome. Design A population‐based study was conducted using an active surveillance system, developed to assess adverse events following vaccination, which linked hospital record information on relapses of nephrotic syndrome to community child health population MCCV data. An ecological study looking at hospital admissions for nephrotic syndrome in different age cohorts of children before and after the MCCV introductory campaign was also carried out. Settings South East England, and England and Wales. Patients 52 children having 162 relapses of nephrotic syndrome. Also, all hospital admissions of children aged 2–18 years with steroid‐responsive nephrotic syndrome in England and Wales between 1995 and 2003, relating admissions to when MCCV was introduced in specific age cohorts. Main outcome measures and analysis method Self‐controlled case series analysis looking for increased risk of relapse following MCCV and changes in admission rates for nephrotic syndrome (incidence ratio) following the introduction of MCCV to different age cohorts of children. Results There was no increased risk of relapse following MCCV in the self‐control case series, where a relative incidence of 0.95 (95% confidence interval (CI) 0.61–1.47) was found in the 6‐month post‐vaccination period, or in the ecological study, which gave an incidence rate ratio of 1.05 (95% CI 0.95 to 1.15) for the quarter when MCCV was introduced and the following two quarters. Conclusions We found no association between MCCV and nephrotic syndrome, which is therefore not a contraindication to meningococcal vaccination. PMID:17468130

Impact of Short Daily Hemodialysis on Restless Legs Symptoms and Sleep Disturbances

PubMed Central

Schiller, Brigitte; Burkart, John M.; Daoui, Rachid; Kraus, Michael A.; Lee, Yoojin; Miller, Brent W.; Teitelbaum, Isaac; Williams, Amy W.; Finkelstein, Fredric O.

2011-01-01

Summary Background and objectives Restless legs syndrome (RLS) and sleep disturbances are common among in-center hemodialysis patients and are associated with increased morbidity/mortality. Design, setting, participants, & measurements The FREEDOM study is an ongoing prospective cohort study investigating the benefits of home short daily hemodialysis (SDHD) (6 times/week). In this interim report, we examine the long-term effect of SDHD on the prevalence and severity of RLS, as measured by the International Restless Legs Syndrome (IRLS) Study Group rating scale, and sleep disturbances, as measured by the Medical Outcomes Study sleep survey. Results 235 participants were included in this report (intention-to-treat cohort), of which 127 completed the 12-month follow-up (per-protocol cohort). Mean age was 52 years, 55% had an arteriovenous fistula, and 40% suffered from RLS. In the per-protocol analysis, among patients with RLS, the mean IRLS score improved significantly at month 12, after adjustment for use of RLS-related medications (18 versus 11). Among patients with moderate-to-severe RLS (IRLS score ≥15), there was an even greater improvement in the IRLS score (23 versus 13). The intention-to-treat analysis yielded similar results. Over 12 months, there was decline in the percentage of patients reporting RLS (35% versus 26%) and those reporting moderate-to-severe RLS (59% versus 43%). There was a similar and sustained 12-month improvement in several scales of the sleep survey, after adjustment for presence of RLS and use of anxiolytics and hypnotics. Conclusions Home SDHD is associated with long-term improvement in the prevalence and severity of RLS and sleep disturbances. PMID:21415315

Perceptions and practices of commensality and solo-eating among Korean and Japanese university students: A cross-cultural analysis

PubMed Central

Cho, Wookyoun; Oh, Yujin; Aiba, Naomi; Lee, Youngmee

2015-01-01

BACKGROUND/OBJECTIVES Commensality, eating together with others, is a major representation of human sociality. In recent time, environments around commensality have changed significantly due to rapid social changes, and the decline of commensality is perceived as a serious concern in many modern societies. This study employs a cross-cultural analysis of university students in two East Asian countries, and examines cross-cultural variations of perceptions and actual practices of commensality and solo-eating. SUBJECTS/METHODS The analysis was drawn from a free-list survey and a self-administrative questionnaires of university students in urban Korea and Japan. The free-listing survey was conducted with a small cohort to explore common images and meanings of commensality and solo-eating. The self-administrative questionnaire was developed based on the result of the free-list survey, and conducted with a larger cohort to examine reasons and problems of practices and associated behaviors and food intake. RESULTS We found that Korean subjects tended to show stronger associations between solo-eating and negative emotions while the Japanese subjects expressed mixed emotions towards the practice of solo-eating. In the questionnaire, more Korean students reported they prefer commensality and tend to eat more quantities when they eat commensally. In contrast, more Japanese reported that they do not have preference on commensality and there is no notable difference in food quantities when they eat commensally and alone. Compared to the general Korean cohort finding, more proportion of overweight and obese groups of Korean subjects reported that they tend to eat more when they are alone than normal and underweight groups. This difference was not found in the overweight Japanese subjects. CONCLUSION Our study revealed cross-cultural variations of perceptions and practices of commensality and solo-eating in a non-western setting. PMID:26425283

Cost-effectiveness of partially-hydrolyzed formula for prevention of atopic dermatitis in Australia.

PubMed

Su, John; Prescott, Susan; Sinn, John; Tang, Mimi; Smith, Peter; Heine, Ralf G; Spieldenner, Jörg; Iskedjian, Michael

2012-01-01

To perform an economic evaluation of a specific brand of partially hydrolyzed infant formula (PHF-W) in the prevention of atopic dermatitis (AD) among Australian infants. A cost-effectiveness analysis was undertaken from the perspectives of the Department of Health and Aging (DHA), of the family of the affected subject and of society as a whole in Australia, based on a decision-analytic model following a hypothetical representative cohort of Australian newborns who are not exclusively breastfed and who have a familial history of allergic disease (i.e., are deemed 'at risk'). Costs, consequences, and incremental cost-effectiveness ratios (ICER) were calculated for PHF-W vs standard cow's milk based infant formula (SF), and, in a secondary analysis, vs extensively hydrolyzed infant formula (EHF-Whey), when the latter was used for the prevention of AD. From a representative starting cohort of 87,724 'at risk' newborns in Australia in 2009, the expected ICERs for PHF-W vs SF were AU$496 from the perspective of the DHA and savings of AUD1739 and AU$1243 from the family and societal perspectives, respectively. When compared to EHF-Whey, PHF-W was associated with savings for the cohort of AU$5,183,474 and AU$6,736,513 from the DHA and societal perspectives. The generalizability and transferability of results to other settings, populations, or brands of infant formula should be made with caution. Whenever possible, a conservative approach directing bias against PHF-W rather than its comparators was applied in the base case analysis. Assumptions were verified in one-way and probabilistic sensitivity analyses, which confirmed the robustness of the model. PHF-W appears to be cost-effective when compared to SF from the DHA perspective, dominant over SF from the other perspectives, and dominant over EHF-Whey from all perspectives, in the prevention of AD in 'at risk' infants not exclusively breastfed, in Australia.

Urinary Creatinine Excretion, Bioelectrical Impedance Analysis, and Clinical Outcomes in Patients with CKD: The CRIC Study

PubMed Central

Xie, Dawei; Anderson, Amanda H.; Leonard, Mary B.; Reese, Peter P.; Delafontaine, Patrice; Horwitz, Edward; Kallem, Radhakrishna; Navaneethan, Sankar; Ojo, Akinlolu; Porter, Anna C.; Sondheimer, James H.; Sweeney, H. Lee; Townsend, Raymond R.; Feldman, Harold I.

2014-01-01

Background and objectives Previous studies in chronic disease states have demonstrated an association between lower urinary creatinine excretion (UCr) and increased mortality, a finding presumed to reflect the effect of low muscle mass on clinical outcomes. Little is known about the relationship between UCr and other measures of body composition in terms of the ability to predict outcomes of interest. Design, setting, participants, & measurements Using data from the Chronic Renal Insufficiency Cohort (CRIC), the relationship between UCr, fat free mass (FFM) as estimated by bioelectrical impedance analysis, and (in a subpopulation) whole-body dual-energy x-ray absorptiometry assessment of appendicular lean mass were characterized. The associations of UCr and FFM with mortality and ESRD were compared using Cox proportional hazards models. Results A total of 3604 CRIC participants (91% of the full CRIC cohort) with both a baseline UCr and FFM measurement were included; of these, 232 had contemporaneous dual-energy x-ray absorptiometry measurements. Participants were recruited between July 2003 and March 2007. UCr and FFM were modestly correlated (rho=0.50; P<0.001), while FFM and appendicular lean mass were highly correlated (rho=0.91; P<0.001). Higher urinary urea nitrogen, black race, younger age, and lower serum cystatin C level were all significantly associated with higher UCr. Over a median (interquartile range) of 4.2 (3.1–5.0) years of follow-up, 336 (9.3%) participants died and 510 (14.2%) reached ESRD. Lower UCr was associated with death and ESRD even after adjustment for FFM (adjusted hazard ratio for death per 1 SD higher level of UCr, 0.63 [95% confidence interval, 0.56 to 0.72]; adjusted hazard ratio for ESRD per 1 SD higher level of UCr, 0.70 [95% confidence interval, 0.63 to 0.75]). Conclusions Among a cohort of individuals with CKD, lower UCr is associated with death and ESRD independent of FFM as assessed by bioelectrical impedance analysis. PMID:25381342

Do changing levels of maternal exercise during pregnancy affect neonatal adiposity? Secondary analysis of the babies after SCOPE: evaluating the longitudinal impact using neurological and nutritional endpoints (BASELINE) birth cohort (Cork, Ireland)

PubMed Central

Norris, Tom; McCarthy, Fergus P; Khashan, Ali S; Murray, Deidre M; Kiely, Mairead; Hourihane, Jonathan O’B; Baker, Philip N; Kenny, Louise C

2017-01-01

Objective To investigate whether changing levels of exercise during pregnancy are related to altered neonatal adiposity. Design Secondary analysis of data from a prospective cohort study. Setting Cork, Ireland. Participants 1200 mother–infant pairs recruited as part of a prospective birth cohort, Babies After SCOPE: Evaluating the Longitudinal Impact Using Neurological and Nutritional Endpoints (BASELINE). Main outcome measures Neonatal adiposity was assessed within several days of birth using air displacement plethysmography (PEAPOD). Per cent body fat (BF%) as a continuous outcome and a pair of dichotomous variables; high or low adiposity, representing BF% >90th or <10th centile, respectively. Multivariable linear and logistic regression models were used to investigate the relationship between exercise and the respective outcomes. Results Crude analysis revealed no association between a changing level of exercise (since becoming pregnant) at 15 weeks’ gestation and any of the outcomes (BF%, low adiposity and high adiposity). At 20 weeks’ gestation, analyses revealed that relative to women who do not change their exercise level up to 20 weeks, those women who decreased their exercise level were more likely to give birth to a neonate with adiposity above the 90th centile (OR 1.62, 95% CI 1.07 to 2.46). This association was maintained after adjustment for putative confounders (OR 1.62, 95% CI 1.06 to 2.47). Conclusions We observed a possible critical period for the association between changing exercise levels and neonatal adiposity, with no association observed with exercise recall for the first 15 weeks of gestation, but an association with a decreasing level of exercise between 15 and 20 weeks. These results should be interpreted in line with the limitations of the study and further studies utilising objectively measured estimates of exercise are required in order to replicate these findings. Trial registration number NCT01498965. PMID:29196482

Acute Response of the Hippocampal Transcriptome Following Mild Traumatic Brain Injury After Controlled Cortical Impact in the Rat.

PubMed

Samal, Babru B; Waites, Cameron K; Almeida-Suhett, Camila; Li, Zheng; Marini, Ann M; Samal, Nihar R; Elkahloun, Abdel; Braga, Maria F M; Eiden, Lee E

2015-10-01

We have previously demonstrated that mild controlled cortical impact (mCCI) injury to rat cortex causes indirect, concussive injury to underlying hippocampus and other brain regions, providing a reproducible model for mild traumatic brain injury (mTBI) and its neurochemical, synaptic, and behavioral sequelae. Here, we extend a preliminary gene expression study of the hippocampus-specific events occurring after mCCI and identify 193 transcripts significantly upregulated, and 21 transcripts significantly downregulated, 24 h after mCCI. Fifty-three percent of genes altered by mCCI within 24 h of injury are predicted to be expressed only in the non-neuronal/glial cellular compartment, with only 13% predicted to be expressed only in neurons. The set of upregulated genes following mCCI was interrogated using Ingenuity Pathway Analysis (IPA) augmented with manual curation of the literature (190 transcripts accepted for analysis), revealing a core group of 15 first messengers, mostly inflammatory cytokines, predicted to account for >99% of the transcript upregulation occurring 24 h after mCCI. Convergent analysis of predicted transcription factors (TFs) regulating the mCCI target genes, carried out in IPA relative to the entire Affymetrix-curated transcriptome, revealed a high concordance with TFs regulated by the cohort of 15 cytokines/cytokine-like messengers independently accounting for upregulation of the mCCI transcript cohort. TFs predicted to regulate transcription of the 193-gene mCCI cohort also displayed a high degree of overlap with TFs predicted to regulate glia-, rather than neuron-specific genes in cortical tissue. We conclude that mCCI predominantly affects transcription of non-neuronal genes within the first 24 h after insult. This finding suggests that early non-neuronal events trigger later permanent neuronal changes after mTBI, and that early intervention after mTBI could potentially affect the neurochemical cascade leading to later reported synaptic and behavioral dysfunction.

Is the HAS-BLED score useful in predicting post-extraction bleeding in patients taking warfarin? A retrospective cohort study

PubMed Central

Kataoka, Toshiyuki; Hoshi, Keika; Ando, Tomohiro

2016-01-01

Objective Unexpected post-extraction bleeding is often experienced in clinical practice. Therefore, determining the risk of post-extraction bleeding in patients receiving anticoagulant therapy prior to surgery is beneficial. This study aimed to verify whether the HAS-BLED score was useful in predicting post-extraction bleeding in patients taking warfarin. Design Retrospective cohort study. Setting Department of Oral and Maxillofacial Surgery, Tokyo Women's Medical University. Participants Participants included 258 sequential cases (462 teeth) who had undergone tooth extraction between 1 January 2010 and 31 December 2012 while continuing warfarin therapy. Main outcome measure Post-extraction risk factors for bleeding. The following data were collected as the predicting variables for multivariate logistic analysis: the HAS-BLED score, extraction site, tooth type, stability of teeth, extraction procedure, prothrombin time-international normalised ratio value, platelet count and the use of concomitant antiplatelet agents. Results Post-extraction bleeding was noted in 21 (8.1%) of the 258 cases. Haemostasis was achieved with localised haemostatic procedures in all the cases of post-extraction bleeding. The HAS-BLED score was found to be insufficient in predicting post-extraction bleeding (area under the curve=0.548, p=0.867, multivariate analysis). The risk of post-extraction bleeding was approximately three times greater in patients taking concomitant oral antiplatelet agents (risk ratio=2.881, p=0.035, multivariate analysis). Conclusions The HAS-BLED score alone could not predict post-extraction bleeding. The concomitant use of oral antiplatelet agents was a risk factor for post-extraction bleeding. No episodes of post-extraction bleeding required more than local measures for haemostasis. However, because this was a retrospective study conducted at a single institution, large-scale prospective cohort studies, which include cases of outpatient tooth extraction, will be necessary in the future. PMID:26936909

Higher serum levels of vitamin D at diagnosis are associated with better survival in a prospective cohort of 1,666 women with breast cancer: A case-cohort analysis in the Pathways Study

PubMed Central

Yao, Song; Kwan, Marilyn L.; Ergas, Isaac J.; Roh, Janise M.; Cheng, Ting-Yuan David; Hong, Chi-Chen; McCann, Susan E.; Tang, Li; Davis, Warren; Liu, Song; Quesenberry, Charles P.; Lee, Marion M.; Ambrosone, Christine B.; Kushi, Lawrence H.

2017-01-01

Importance There are long-standing interests in the potential benefits of vitamin D for preventing breast cancer recurrence and mortality; yet data from prospective cohort studies are limited. Objective We investigated a serum biomarker of vitamin D status, 25-hydroxyvitamin D (25OHD) measured at the time of breast cancer diagnosis, with prognosis. Design The Pathways Study is a prospective cohort study of breast cancer survivors established in 2006. Enrollment was completed in 2013; follow up is ongoing. Setting The cohort was established in Kaiser Permanente Northern California (KPNC), a large integrated healthcare delivery system in San Francisco Bay Area and central valley, California. Participants Women diagnosed with incident invasive breast cancer were typically consented and enrolled within 2 months of diagnosis. The overall enrollment rate was 46%. Participants are followed for health outcomes and comorbidities at 12, 24, 48, 72 and 96 months after baseline interview. A case-cohort design was used for efficiency assay of 25OHD, selecting 1,666 cohort members with serum samples and ensuring representation in the sub-cohort of races and clinical subtypes. Main Outcome Measures Primary outcomes are breast cancer recurrence, second primary cancer (SPC), and death. Results Serum 25OHD concentrations were lower in women with advanced stage tumors, and the lowest in premenopausal women with triple-negative cancer. Levels were also inversely associated with hazards of disease progression and death. Compared with the lowest tertile (T1), women with the highest (T3) 25OHD levels had superior overall survival (OS). This association remained after adjustment for clinical prognostic factors [hazards ratio (HR)=0.72, 95% confidence interval (CI): 0.54, 0.98]. Among premenopausal women, the association with OS was stronger, and there were also associations with breast cancer-specific survival (BCSS) and invasive disease-free survival (IDFS) (OS: HR=0.45, 95% CI, 0.21–0.96; BCSS: HR=0.37, 95% CI, 0.15–0.93; IDFS: HR=0.58, 95% CI, 0.34–1.01; all after full adjustment.) Conclusions and Relevance Serum 25OHD levels were independently associated with breast cancer prognostic characteristics and patient prognosis, most prominently among premenopausal women. Our findings from a large, well-characterized prospective cohort provide compelling observational evidence on associations of vitamin D with lower risk of breast cancer morbidity and mortality. PMID:27832250

Differences in rates of switchbacks after switching from branded to authorized generic and branded to generic drug products: cohort study

PubMed Central

Sarpatwari, Ameet; Dejene, Sara; Khan, Nazleen F; Lii, Joyce; Rogers, James R; Dutcher, Sarah K; Raofi, Saeid; Bohn, Justin; Connolly, John; Fischer, Michael A; Kesselheim, Aaron S; Gagne, Joshua J

2018-01-01

Abstract Objectives To compare rates of switchbacks to branded drug products for patients switched from branded to authorized generic drug products, which have the same active ingredients, appearance, and excipients as the branded product, with patients switched from branded to generic drug products, which have the same active ingredients as the branded product but may differ in appearance and excipients. Design Observational cohort study. Setting Private (a large commercial health plan) and public (Medicaid) insurance programs in the US. Participants Beneficiaries of a large US commercial health insurer between 2004 and 2013 (primary cohort) and Medicaid beneficiaries between 2000 and 2010 (replication cohort). Main outcome measures Patients taking branded products for one of the study drugs (alendronate tablets, amlodipine tablets, amlodipine-benazepril capsules, calcitonin salmon nasal spray, escitalopram tablets, glipizide extended release tablets, quinapril tablets, and sertraline tablets) were identified when they switched to an authorized generic or a generic drug product after the date of market entry of generic drug products. These patients were followed for switchbacks to the branded drug product in the year after their switch to an authorized generic or a generic drug product. Cox proportional hazard models were used to estimate hazard ratios and 95% confidence intervals after adjusting for demographics, including age, sex, and calendar year. Inverse variance meta-analysis was used to pool adjusted hazard ratios across all drug products. Results A total of 94 909 patients switched from branded to authorized generic drug products and 116 017 patients switched from branded to generic drug products and contributed to the switchback analysis. Unadjusted incidence rates of switchback varied across drug products, ranging from a low of 3.8 per 100 person years (for alendronate tablets) to a high of 17.8 per 100 person years (for amlodipine-benazepril capsules), with an overall rate of 8.2 per 100 person years across all drug products. Adjusted switchback rates were consistently lower for patients who switched from branded to authorized generic drug products compared with branded to generic drug products in the primary cohort (pooled hazard ratio 0.72, 95% confidence interval 0.64 to 0.81). Similar results (0.75, 0.62 to 0.91) were observed in the replication cohort. Conclusion Switching from branded to authorized generic drug products was associated with lower switchback rates compared with switching from branded to generic drug products. PMID:29615391

High-Sensitivity C-Reactive Protein Complements Plasma Epstein-Barr Virus Deoxyribonucleic Acid Prognostication in Nasopharyngeal Carcinoma: A Large-Scale Retrospective and Prospective Cohort Study

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

Tang, Lin-Quan; Department of Nasopharyngeal Carcinoma, Sun Yat-sen University, Guangzhou; Li, Chao-Feng

Purpose: To evaluate the effects of combining the assessment of circulating high-sensitivity C-reactive protein (hs-CRP) with that of Epstein-Barr virus DNA (EBV DNA) in the pretherapy prognostication of nasopharyngeal carcinoma (NPC). Patients and Methods: Three independent cohorts of NPC patients (training set of n=3113, internal validation set of n=1556, and prospective validation set of n=1668) were studied. Determinants of disease-free survival, distant metastasis–free survival, and overall survival were assessed by multivariate analysis. Hazard ratios and survival probabilities of the patient groups, segregated by clinical stage (T1-2N0-1M0, T3-4N0-1M0, T1-2N2-3M0, and T3-4N2-3M0) and EBV DNA load (low or high) alone, and alsomore » according to hs-CRP level (low or high), were compared. Results: Elevated hs-CRP and EBV DNA levels were significantly correlated with poor disease-free survival, distant metastasis–free survival, and overall survival in both the training and validation sets. Associations were similar and remained significant after excluding patients with cardiovascular disease, diabetes, and chronic hepatitis B. Patients with advanced-stage disease were segregated by high EBV DNA levels and high hs-CRP level into a poorest-risk group, and participants with either high EBV DNA but low hs-CRP level or high hs-CRP but low EBV DNA values had poorer survival compared with the bottom values for both biomarkers. These findings demonstrate a significant improvement in the prognostic ability of conventional advanced NPC staging. Conclusion: Baseline plasma EBV DNA and serum hs-CRP levels were significantly correlated with survival in NPC patients. The combined interpretation of EBV DNA with hs-CRP levels led to refinement of the risks for the patient subsets, with improved risk discrimination in patients with advanced-stage disease.« less

Biostatistical analysis of mortality data for cohorts of cancer patients.

PubMed Central

Pauling, L

1989-01-01

The Hardin Jones principle states that for a homogeneous cohort of cancer patients the logarithm of the fraction surviving at time t has a constant slope. With use of this principle, the survival times of the members of a heterogeneous cohort can be analyzed to divide the cohort into subcohorts with different mortality rate constants. Probable values of the additional survival time can be estimated for members surviving at the closing date of a clinical trial, permitting them to be included in the biostatistical analysis of the results of the trial in a more significant way than through Kaplan-Meier renormalization. PMID:2726729

The neural correlates of morphological complexity processing: Detecting structure in pseudowords.

PubMed

Schuster, Swetlana; Scharinger, Mathias; Brooks, Colin; Lahiri, Aditi; Hartwigsen, Gesa

2018-06-01

Morphological complexity is a highly debated issue in visual word recognition. Previous neuroimaging studies have shown that speakers are sensitive to degrees of morphological complexity. Two-step derived complex words (bridging through bridge N  > bridge V  > bridging) led to more enhanced activation in the left inferior frontal gyrus than their 1-step derived counterparts (running through run V  > running). However, it remains unclear whether sensitivity to degrees of morphological complexity extends to pseudowords. If this were the case, it would indicate that abstract knowledge of morphological structure is independent of lexicality. We addressed this question by investigating the processing of two sets of pseudowords in German. Both sets contained morphologically viable two-step derived pseudowords differing in the number of derivational steps required to access an existing lexical representation and therefore the degree of structural analysis expected during processing. Using a 2 × 2 factorial design, we found lexicality effects to be distinct from processing signatures relating to structural analysis in pseudowords. Semantically-driven processes such as lexical search showed a more frontal distribution while combinatorial processes related to structural analysis engaged more parietal parts of the network. Specifically, more complex pseudowords showed increased activation in parietal regions (right superior parietal lobe and left precuneus) relative to pseudowords that required less structural analysis to arrive at an existing lexical representation. As the two sets were matched on cohort size and surface form, these results highlight the role of internal levels of morphological structure even in forms that do not possess a lexical representation. © 2018 Wiley Periodicals, Inc.

The MANGUA Project: A Population-Based HIV Cohort in Guatemala

PubMed Central

García, Juan Ignacio; Samayoa, Blanca; Sabidó, Meritxell; Prieto, Luis Alberto; Nikiforov, Mikhail; Pinzón, Rodolfo; Santa Marina de León, Luis Roberto; Ortiz, José Fernando; Ponce, Ernesto; Mejía, Carlos Rodolfo; Arathoon, Eduardo; Casabona, Jordi; Study Group, The Mangua Cohort

2015-01-01

Introduction. The MANGUA cohort is an ongoing multicenter, observational study of people living with HIV/AIDS in Guatemala. The cohort is based on the MANGUA application which is an electronic database to capture essential data from the medical records of HIV patients in care. Methods. The cohort enrolls HIV-positive adults ≥16 years of age. A predefined set of sociodemographic, behavioral, clinical, and laboratory data are registered at entry to the cohort study. Results. As of October 1st, 2012, 21 697 patients had been included in the MANGUA cohort (median age: 33 years, 40.3% female). At enrollment 74.1% had signs of advanced HIV infection and only 56.3% had baseline CD4 cell counts. In the first 12 months after starting antiretroviral treatment 26.9% (n = 3938) of the patients were lost to the program. Conclusions. The implementation of a cohort of HIV-positive patients in care in Guatemala is feasible and has provided national HIV indicators to monitor and evaluate the HIV epidemic. The identified percentages of late presenters and high rates of LTFU will help the Ministry to target their current efforts in improving access to diagnosis and care. PMID:26425365

The MANGUA Project: A Population-Based HIV Cohort in Guatemala.

PubMed

García, Juan Ignacio; Samayoa, Blanca; Sabidó, Meritxell; Prieto, Luis Alberto; Nikiforov, Mikhail; Pinzón, Rodolfo; Santa Marina de León, Luis Roberto; Ortiz, José Fernando; Ponce, Ernesto; Mejía, Carlos Rodolfo; Arathoon, Eduardo; Casabona, Jordi; Study Group, The Mangua Cohort

2015-01-01

Introduction. The MANGUA cohort is an ongoing multicenter, observational study of people living with HIV/AIDS in Guatemala. The cohort is based on the MANGUA application which is an electronic database to capture essential data from the medical records of HIV patients in care. Methods. The cohort enrolls HIV-positive adults ≥16 years of age. A predefined set of sociodemographic, behavioral, clinical, and laboratory data are registered at entry to the cohort study. Results. As of October 1st, 2012, 21 697 patients had been included in the MANGUA cohort (median age: 33 years, 40.3% female). At enrollment 74.1% had signs of advanced HIV infection and only 56.3% had baseline CD4 cell counts. In the first 12 months after starting antiretroviral treatment 26.9% (n = 3938) of the patients were lost to the program. Conclusions. The implementation of a cohort of HIV-positive patients in care in Guatemala is feasible and has provided national HIV indicators to monitor and evaluate the HIV epidemic. The identified percentages of late presenters and high rates of LTFU will help the Ministry to target their current efforts in improving access to diagnosis and care.

Evidence based management for paediatric burn: new approaches and improved scar outcomes.

PubMed

Kishikova, Lyudmila; Smith, Matthew D; Cubison, Tania C S

2014-12-01

Little evidence has been produced on the best practice for managing paediatric burns. We set out to develop a formal approach based on the finding that hypertrophic scarring is related to healing-time, with durations under 21 days associated with improved scar outcome. Incorporating new advances in burn care, we compared outcomes under the new approach to a cohort treated previously. Our study was a retrospective cross-sectional case note study, with demographic, treatment and outcome information collected. The management and outcome of each case was assessed and compared against another paediatric burns cohort from 2006. 181 burns presenting across a six month period were analysed (2010 cohort) and compared to 337 children from a previous cohort from 2006. Comparison of patients between cohorts showed an overall shift towards shorter healing-times in the 2010 cohort. A lower overall rate of hypertrophic scarring was seen in the 2010 cohort, and for corresponding healing-times after injury, hypertrophic scarring rates were halved in comparison to the 2006 cohort. We demonstrate that the use of a structured approach for paediatric burns has improved outcomes with regards to healing-time and hypertrophic scarring rate. This approach allows maximisation of healing potential and implements aggressive prophylactic measures. Copyright © 2014 Elsevier Ltd and ISBI. All rights reserved.

An Optimized Set of Fluorescence In Situ Hybridization Probes for Detection of Pancreatobiliary Tract Cancer in Cytology Brush Samples.

PubMed

Barr Fritcher, Emily G; Voss, Jesse S; Brankley, Shannon M; Campion, Michael B; Jenkins, Sarah M; Keeney, Matthew E; Henry, Michael R; Kerr, Sarah M; Chaiteerakij, Roongruedee; Pestova, Ekaterina V; Clayton, Amy C; Zhang, Jun; Roberts, Lewis R; Gores, Gregory J; Halling, Kevin C; Kipp, Benjamin R

2015-12-01

Pancreatobiliary cancer is detected by fluorescence in situ hybridization (FISH) of pancreatobiliary brush samples with UroVysion probes, originally designed to detect bladder cancer. We designed a set of new probes to detect pancreatobiliary cancer and compared its performance with that of UroVysion and routine cytology analysis. We tested a set of FISH probes on tumor tissues (cholangiocarcinoma or pancreatic carcinoma) and non-tumor tissues from 29 patients. We identified 4 probes that had high specificity for tumor vs non-tumor tissues; we called this set of probes pancreatobiliary FISH. We performed a retrospective analysis of brush samples from 272 patients who underwent endoscopic retrograde cholangiopancreatography for evaluation of malignancy at the Mayo Clinic; results were available from routine cytology and FISH with UroVysion probes. Archived residual specimens were retrieved and used to evaluate the pancreatobiliary FISH probes. Cutoff values for FISH with the pancreatobiliary probes were determined using 89 samples and validated in the remaining 183 samples. Clinical and pathologic evidence of malignancy in the pancreatobiliary tract within 2 years of brush sample collection was used as the standard; samples from patients without malignancies were used as negative controls. The validation cohort included 85 patients with malignancies (46.4%) and 114 patients with primary sclerosing cholangitis (62.3%). Samples containing cells above the cutoff for polysomy (copy number gain of ≥2 probes) were classified as positive in FISH with the UroVysion and pancreatobiliary probes. Multivariable logistic regression was used to estimate associations between clinical and pathology findings and results from FISH. The combination of FISH probes 1q21, 7p12, 8q24, and 9p21 identified cancer cells with 93% sensitivity and 100% specificity in pancreatobiliary tissue samples and were therefore included in the pancreatobiliary probe set. In the validation cohort of brush samples, pancreatobiliary FISH identified samples from patients with malignancy with a significantly higher level of sensitivity (64.7%) than the UroVysion probes (45.9%) (P < .001) or routine cytology analysis (18.8%) (P < .001), but similar specificity (92.9%, 90.8%, and 100.0% respectively). Factors significantly associated with detection of carcinoma, in adjusted analyses, included detection of polysomy by pancreatobiliary FISH (P < .001), a mass by cross-sectional imaging (P < .001), cancer cells by routine cytology (overall P = .003), as well as absence of primary sclerosing cholangitis (P = .011). We identified a set of FISH probes that detects cancer cells in pancreatobiliary brush samples from patients with and without primary sclerosing cholangitis with higher levels of sensitivity than UroVysion probes. Cytologic brushing test results and clinical features were independently associated with detection of cancer and might be used to identify patients with pancreatobiliary cancers. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

Liposomal cytarabine in the prophylaxis and treatment of CNS lymphoma: toxicity analysis in a retrospective case series study conducted at Polish Lymphoma Research Group Centers.

PubMed

Jurczak, Wojciech; Kroll-Balcerzak, Renata; Giebel, Sebastian; Machaczka, Maciej; Giza, Agnieszka; Ogórka, Tomasz; Fornagiel, Szymon; Rybka, Justyna; Wróbel, Tomasz; Kumiega, Beata; Skotnicki, Aleksander B; Komarnicki, Mieczysław

2015-04-01

Lymphomas with primary or secondary involvement of central nervous system (CNS) have poor prognosis despite specific treatment protocols which include whole brain radiotherapy and high-dose systemic and/or intrathecal chemotherapy. Toxicity of intrathecal liposomal cytarabine-based regimens collected between November 2006 and January 2012 was assessed retrospectively. Data from 120 adult lymphoma patients with, or at high risk of CNS involvement who received intrathecal liposomal cytarabine-based regimens at six Polish Lymphoma Research Group centres between November 2006 and January 2012 were assessed retrospectively. Patients were divided into three cohorts: A (high risk of CNS disease, n = 88), B (cerebrospinal fluid pleocytosis without neurological symptoms or pathological imaging findings, n = 7), and C (CNS disease/neurological involvement; n = 25). In all examined groups, toxicity of treatment was found to be acceptable (including the prophylactic setting). None of the patients in cohorts A or B who took intrathecal liposomal cytarabine 50 mg, repeated every 2-4 weeks (mean 3.8 doses) had experienced a CNS relapse at a median follow-up time of 3 years. Patients in cohort C had a 76 % overall neurological response rate (including a 40 % complete response rate) and median overall survival of 4.8 years. Regimens incorporating liposomal cytarabine seem to be safe and effective treatments for lymphomas with CNS involvement.

Predicting the Necessity for Extracorporeal Circulation During Lung Transplantation: A Feasibility Study.

PubMed

Hinske, Ludwig Christian; Hoechter, Dominik Johannes; Schröeer, Eva; Kneidinger, Nikolaus; Schramm, René; Preissler, Gerhard; Tomasi, Roland; Sisic, Alma; Frey, Lorenz; von Dossow, Vera; Scheiermann, Patrick

2017-06-01

The factors leading to the implementation of unplanned extracorporeal circulation during lung transplantation are poorly defined. Consequently, the authors aimed to identify patients at risk for unplanned extracorporeal circulation during lung transplantation. Retrospective data analysis. Single-center university hospital. A development data set of 170 consecutive patients and an independent validation cohort of 52 patients undergoing lung transplantation. The authors investigated a cohort of 170 consecutive patients undergoing single or sequential bilateral lung transplantation without a priori indication for extracorporeal circulation and evaluated the predictive capability of distinct preoperative and intraoperative variables by using automated model building techniques at three clinically relevant time points (preoperatively, after endotracheal intubation, and after establishing single-lung ventilation). Preoperative mean pulmonary arterial pressure was the strongest predictor for unplanned extracorporeal circulation. A logistic regression model based on preoperative mean pulmonary arterial pressure and lung allocation score achieved an area under the receiver operating characteristic curve of 0.85. Consequently, the authors developed a novel 3-point scoring system based on preoperative mean pulmonary arterial pressure and lung allocation score, which identified patients at risk for unplanned extracorporeal circulation and validated this score in an independent cohort of 52 patients undergoing lung transplantation. The authors showed that patients at risk for unplanned extracorporeal circulation during lung transplantation could be identified by their novel 3-point score. Copyright © 2017 Elsevier Inc. All rights reserved.

Smoking and hemorrhagic stroke mortality in a prospective cohort study of older Chinese.

PubMed

Xu, Lin; Schooling, Catherine Mary; Chan, Wai Man; Lee, Siu Yin; Leung, Gabriel M; Lam, Tai Hing

2013-08-01

Hemorrhagic stroke is more common in non-Western settings and does not always share risk factors with other cardiovascular diseases. The association of smoking with hemorrhagic stroke subtypes has not been established. We examined the association of cigarette smoking with hemorrhagic stroke, by subtype (intracerebral hemorrhage and subarachnoid hemorrhage), in a large cohort of older Chinese from Hong Kong. Multivariable Cox regression analysis was used to assess the adjusted associations of smoking at baseline with death from hemorrhagic stroke and its subtypes, using a population-based prospective cohort of 66 820 Chinese aged>65 years enrolled from July 1998 to December 2001 at all the 18 Elderly Health Centers of the Hong Kong Government Department of Health and followed until May 31, 2012. After follow-up for an average of 10.9 years (SD=3.1), 648 deaths from hemorrhagic stroke had occurred, of which 530 (82%) were intracerebral hemorrhage. Current smoking was associated with a higher risk of hemorrhagic stroke (hazard ratio, 2.19; 95% confidence interval, 1.49-3.22), intracerebral hemorrhage (1.94; 1.25-3.01), and subarachnoid hemorrhage (3.58; 1.62-7.94), adjusted for age, sex, education, public assistance, housing type, monthly expenditure, alcohol use, and exercise. Further adjustment for hypertension and body mass index slightly changed the estimates. Smoking is strongly associated with hemorrhagic stroke mortality, particularly for subarachnoid hemorrhage.

A New Approach to Age-Period-Cohort Analysis Using Partial Least Squares Regression: The Trend in Blood Pressure in the Glasgow Alumni Cohort

PubMed Central

Tu, Yu-Kang; Davey Smith, George; Gilthorpe, Mark S.

2011-01-01

Due to a problem of identification, how to estimate the distinct effects of age, time period and cohort has been a controversial issue in the analysis of trends in health outcomes in epidemiology. In this study, we propose a novel approach, partial least squares (PLS) analysis, to separate the effects of age, period, and cohort. Our example for illustration is taken from the Glasgow Alumni cohort. A total of 15,322 students (11,755 men and 3,567 women) received medical screening at the Glasgow University between 1948 and 1968. The aim is to investigate the secular trends in blood pressure over 1925 and 1950 while taking into account the year of examination and age at examination. We excluded students born before 1925 or aged over 25 years at examination and those with missing values in confounders from the analyses, resulting in 12,546 and 12,516 students for analysis of systolic and diastolic blood pressure, respectively. PLS analysis shows that both systolic and diastolic blood pressure increased with students' age, and students born later had on average lower blood pressure (SBP: −0.17 mmHg/per year [95% confidence intervals: −0.19 to −0.15] for men and −0.25 [−0.28 to −0.22] for women; DBP: −0.14 [−0.15 to −0.13] for men; −0.09 [−0.11 to −0.07] for women). PLS also shows a decreasing trend in blood pressure over the examination period. As identification is not a problem for PLS, it provides a flexible modelling strategy for age-period-cohort analysis. More emphasis is then required to clarify the substantive and conceptual issues surrounding the definitions and interpretations of age, period and cohort effects. PMID:21556329

An economic evaluation of an integrated care pathway in geriatric rehabilitation for older patients with complex health problems

PubMed Central

van Haastregt, Jolanda C. M.; Evers, Silvia M. A. A.; Kempen, Gertrudis I. J. M.; Schols, Jos M. G. A.

2018-01-01

Background Integrated care pathways which cover multiple care settings are increasingly used as a tool to structure care, enhance coordination and improve transitions between care settings. However, little is known about their economic impact. The objective of this study is to determine the cost-effectiveness and cost-utility of an integrated care pathway designed for patients with complex health problems transferring from the hospital, a geriatric rehabilitation facility and primary care. Methods This economic evaluation was performed from a societal perspective alongside a prospective cohort study with two cohorts of patients. The care as usual cohort was included before implementation of the pathway and the care pathway cohort after implementation of the pathway. Both cohorts were measured over nine months, during which intervention costs, healthcare costs, patient and family costs were identified. The outcome measures were dependence in activities of daily living (measured with the KATZ-15) and quality adjusted life years (EQ-5D-3L). Costs and effects were bootstrapped and various sensitivity analyses were performed to assess robustness of the results. Results After nine months, the average societal costs were significantly lower for patients in the care pathway cohort (€50,791) versus patients in the care as usual cohort (€62,170; CI = -22,090, -988). Patients in the care pathway cohort had better scores on the KATZ-15 (1.04), indicating cost-effectiveness. No significant differences were found between the two groups on QALY scores (0.01). Conclusions The results of this study indicate that the integrated care pathway is a cost-effective intervention. Therefore, dissemination of the integrated care pathway on a wider scale could be considered. This would provide us the opportunity to confirm the findings of our study in larger economic evaluations. When looking at QALYs, no effects were found. Therefore, it is also recommended to explore if therapy in geriatric rehabilitation could also pay attention to other quality of life-related domains, such as mood and social participation. PMID:29489820

Cohort profile: seek, test, treat and retain United States criminal justice cohort.

PubMed

Chandler, Redonna; Gordon, Michael S; Kruszka, Bridget; Strand, Lauren N; Altice, Frederick L; Beckwith, Curt G; Biggs, Mary L; Cunningham, William; Chris Delaney, J A; Flynn, Patrick M; Golin, Carol E; Knight, Kevin; Kral, Alex H; Kuo, Irene; Lorvick, Jennifer; Nance, Robin M; Ouellet, Lawrence J; Rich, Josiah D; Sacks, Stanley; Seal, David; Spaulding, Anne; Springer, Sandra A; Taxman, Faye; Wohl, David; Young, Jeremy D; Young, Rebekah; Crane, Heidi M

2017-05-16

The STTR treatment cascade provides a framework for research aimed at improving the delivery of services, care and outcomes of PLWH. The development of effective approaches to increase HIV diagnoses and engage PLWH in subsequent steps of the treatment cascade could lead to earlier and sustained ART treatment resulting in viral suppression. There is an unmet need for research applying the treatment cascade to improve outcomes for those with criminal justice involvement. The Seek, Test, Treat, and Retain (STTR) criminal justice (CJ) cohort combines data from 11 studies across the HIV treatment cascade that focused on persons involved in the criminal justice system, often but not exclusively for reasons related to substance use. The studies were conducted in a variety of CJ settings and collected information across 11 pre-selected domains: demographic characteristics, CJ involvement, HIV risk behaviors, HIV and/or Hepatitis C infections, laboratory measures of CD4 T-cell count (CD4) and HIV RNA viral load (VL), mental illness, health related quality of life (QoL), socioeconomic status, health care access, substance use, and social support. The STTR CJ cohort includes data on 11,070 individuals with and without HIV infection who range in age from 18 to 77 years, with a median age at baseline of 37 years. The cohort reflects racial, ethnic and gender distributions in the U.S. CJ system, and 64% of participants are African-American, 12% are Hispanic and 83% are men. Cohort members reported a wide range of HIV risk behaviors including history of injection drug use and, among those who reported on pre-incarceration sexual behaviors, the prevalence of unprotected sexual intercourse ranged across studies from 4% to 79%. Across all studies, 53% percent of the STTR CJ cohort reported recent polysubstance use. The STTR CJ cohort is comprised of participants from a wide range of CJ settings including jail, prison, and community supervision who report considerable diversity in their characteristics and behavioral practices. We have developed harmonized measures, where feasible, to improve the integration of these studies together to answer questions that cannot otherwise be addressed.

Statistical Models for the Analysis of Zero-Inflated Pain Intensity Numeric Rating Scale Data.

PubMed

Goulet, Joseph L; Buta, Eugenia; Bathulapalli, Harini; Gueorguieva, Ralitza; Brandt, Cynthia A

2017-03-01

Pain intensity is often measured in clinical and research settings using the 0 to 10 numeric rating scale (NRS). NRS scores are recorded as discrete values, and in some samples they may display a high proportion of zeroes and a right-skewed distribution. Despite this, statistical methods for normally distributed data are frequently used in the analysis of NRS data. We present results from an observational cross-sectional study examining the association of NRS scores with patient characteristics using data collected from a large cohort of 18,935 veterans in Department of Veterans Affairs care diagnosed with a potentially painful musculoskeletal disorder. The mean (variance) NRS pain was 3.0 (7.5), and 34% of patients reported no pain (NRS = 0). We compared the following statistical models for analyzing NRS scores: linear regression, generalized linear models (Poisson and negative binomial), zero-inflated and hurdle models for data with an excess of zeroes, and a cumulative logit model for ordinal data. We examined model fit, interpretability of results, and whether conclusions about the predictor effects changed across models. In this study, models that accommodate zero inflation provided a better fit than the other models. These models should be considered for the analysis of NRS data with a large proportion of zeroes. We examined and analyzed pain data from a large cohort of veterans with musculoskeletal disorders. We found that many reported no current pain on the NRS on the diagnosis date. We present several alternative statistical methods for the analysis of pain intensity data with a large proportion of zeroes. Published by Elsevier Inc.

Estimating hazard ratios in cohort data with missing disease information due to death.

PubMed

Binder, Nadine; Herrnböck, Anne-Sophie; Schumacher, Martin

2017-03-01

In clinical and epidemiological studies information on the primary outcome of interest, that is, the disease status, is usually collected at a limited number of follow-up visits. The disease status can often only be retrieved retrospectively in individuals who are alive at follow-up, but will be missing for those who died before. Right-censoring the death cases at the last visit (ad-hoc analysis) yields biased hazard ratio estimates of a potential risk factor, and the bias can be substantial and occur in either direction. In this work, we investigate three different approaches that use the same likelihood contributions derived from an illness-death multistate model in order to more adequately estimate the hazard ratio by including the death cases into the analysis: a parametric approach, a penalized likelihood approach, and an imputation-based approach. We investigate to which extent these approaches allow for an unbiased regression analysis by evaluating their performance in simulation studies and on a real data example. In doing so, we use the full cohort with complete illness-death data as reference and artificially induce missing information due to death by setting discrete follow-up visits. Compared to an ad-hoc analysis, all considered approaches provide less biased or even unbiased results, depending on the situation studied. In the real data example, the parametric approach is seen to be too restrictive, whereas the imputation-based approach could almost reconstruct the original event history information. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Association between expression of random gene sets and survival is evident in multiple cancer types and may be explained by sub-classification.

PubMed

Shimoni, Yishai

2018-02-01

One of the goals of cancer research is to identify a set of genes that cause or control disease progression. However, although multiple such gene sets were published, these are usually in very poor agreement with each other, and very few of the genes proved to be functional therapeutic targets. Furthermore, recent findings from a breast cancer gene-expression cohort showed that sets of genes selected randomly can be used to predict survival with a much higher probability than expected. These results imply that many of the genes identified in breast cancer gene expression analysis may not be causal of cancer progression, even though they can still be highly predictive of prognosis. We performed a similar analysis on all the cancer types available in the cancer genome atlas (TCGA), namely, estimating the predictive power of random gene sets for survival. Our work shows that most cancer types exhibit the property that random selections of genes are more predictive of survival than expected. In contrast to previous work, this property is not removed by using a proliferation signature, which implies that proliferation may not always be the confounder that drives this property. We suggest one possible solution in the form of data-driven sub-classification to reduce this property significantly. Our results suggest that the predictive power of random gene sets may be used to identify the existence of sub-classes in the data, and thus may allow better understanding of patient stratification. Furthermore, by reducing the observed bias this may allow more direct identification of biologically relevant, and potentially causal, genes.

Association between expression of random gene sets and survival is evident in multiple cancer types and may be explained by sub-classification

PubMed Central

2018-01-01

One of the goals of cancer research is to identify a set of genes that cause or control disease progression. However, although multiple such gene sets were published, these are usually in very poor agreement with each other, and very few of the genes proved to be functional therapeutic targets. Furthermore, recent findings from a breast cancer gene-expression cohort showed that sets of genes selected randomly can be used to predict survival with a much higher probability than expected. These results imply that many of the genes identified in breast cancer gene expression analysis may not be causal of cancer progression, even though they can still be highly predictive of prognosis. We performed a similar analysis on all the cancer types available in the cancer genome atlas (TCGA), namely, estimating the predictive power of random gene sets for survival. Our work shows that most cancer types exhibit the property that random selections of genes are more predictive of survival than expected. In contrast to previous work, this property is not removed by using a proliferation signature, which implies that proliferation may not always be the confounder that drives this property. We suggest one possible solution in the form of data-driven sub-classification to reduce this property significantly. Our results suggest that the predictive power of random gene sets may be used to identify the existence of sub-classes in the data, and thus may allow better understanding of patient stratification. Furthermore, by reducing the observed bias this may allow more direct identification of biologically relevant, and potentially causal, genes. PMID:29470520

Systems Genetics Analysis of GWAS reveals Novel Associations between Key Biological Processes and Coronary Artery Disease

PubMed Central

Ghosh, Sujoy; Vivar, Juan; Nelson, Christopher P; Willenborg, Christina; Segrè, Ayellet V; Mäkinen, Ville-Petteri; Nikpay, Majid; Erdmann, Jeannette; Blankenberg, Stefan; O'Donnell, Christopher; März, Winfried; Laaksonen, Reijo; Stewart, Alexandre FR; Epstein, Stephen E; Shah, Svati H; Granger, Christopher B; Hazen, Stanley L; Kathiresan, Sekar; Reilly, Muredach P; Yang, Xia; Quertermous, Thomas; Samani, Nilesh J; Schunkert, Heribert; Assimes, Themistocles L; McPherson, Ruth

2016-01-01

Objective Genome-wide association (GWA) studies have identified multiple genetic variants affecting the risk of coronary artery disease (CAD). However, individually these explain only a small fraction of the heritability of CAD and for most, the causal biological mechanisms remain unclear. We sought to obtain further insights into potential causal processes of CAD by integrating large-scale GWA data with expertly curated databases of core human pathways and functional networks. Approaches and Results Employing pathways (gene sets) from Reactome, we carried out a two-stage gene set enrichment analysis strategy. From a meta-analyzed discovery cohort of 7 CADGWAS data sets (9,889 cases/11,089 controls), nominally significant gene-sets were tested for replication in a meta-analysis of 9 additional studies (15,502 cases/55,730 controls) from the CARDIoGRAM Consortium. A total of 32 of 639 Reactome pathways tested showed convincing association with CAD (replication p<0.05). These pathways resided in 9 of 21 core biological processes represented in Reactome, and included pathways relevant to extracellular matrix integrity, innate immunity, axon guidance, and signaling by PDRF, NOTCH, and the TGF-β/SMAD receptor complex. Many of these pathways had strengths of association comparable to those observed in lipid transport pathways. Network analysis of unique genes within the replicated pathways further revealed several interconnected functional and topologically interacting modules representing novel associations (e.g. semaphorin regulated axonal guidance pathway) besides confirming known processes (lipid metabolism). The connectivity in the observed networks was statistically significant compared to random networks (p<0.001). Network centrality analysis (‘degree’ and ‘betweenness’) further identified genes (e.g. NCAM1, FYN, FURIN etc.) likely to play critical roles in the maintenance and functioning of several of the replicated pathways. Conclusions These findings provide novel insights into how genetic variation, interpreted in the context of biological processes and functional interactions among genes, may help define the genetic architecture of CAD. PMID:25977570

Effectiveness and Persistence of Liraglutide Treatment Among Patients with Type 2 Diabetes Treated in Primary Care and Specialist Settings: A Subgroup Analysis from the EVIDENCE Study, a Prospective, 2-Year Follow-up, Observational, Post-Marketing Study.

PubMed

Martinez, Luc; Penfornis, Alfred; Gautier, Jean-Francois; Eschwège, Eveline; Charpentier, Guillaume; Bouzidi, Amira; Gourdy, Pierre

2017-03-01

The objective of this subgroup analysis is to investigate the effectiveness of liraglutide in people with type 2 diabetes (T2D) treated within the primary care physician (PCP) and specialist care settings. EVIDENCE is a prospective, observational study of 3152 adults with T2D recently starting or about to start liraglutide treatment in France. We followed patients in the PCP and specialist settings for 2 years to evaluate the effectiveness of liraglutide in glycemic control and body weight reduction. Furthermore, we evaluated the changes in combined antihyperglycemic treatments, the reasons for prescribing liraglutide, patient satisfaction, and safety of liraglutide in these two treatment settings. After 2 years of follow-up, 477 out of 1209 (39.0%) of PCP and 297 out of 1398 (21.2%) of specialist-treated patients still used liraglutide and maintained the glycated hemoglobin (HbA 1c ) target of <7.0%. Significant reductions from baseline were observed in both PCP- and specialist-treated cohorts in mean HbA 1c (-1.22% and -0.8%, respectively), fasting plasma glucose (FPG) concentration (-39 and -23 mg/dL), body weight (-4.4 and -3.8 kg), and body mass index (BMI) (-1.5 and -1.4 kg/m 2 ), all p < 0.0001. Reductions in HbA 1c and FPG were significantly greater among PCP- compared with specialist-treated patients, p < 0.0001 for both. Patient treatment satisfaction was also significantly increased in both cohorts. Reported gastrointestinal adverse events were less frequent among PCP-treated patients compared with specialist-treated patients (4.5% vs. 16.1%). Despite differences in demography and clinical characteristics of patients treated for T2D in PCP and specialty care, greater reduction in HbA 1c and increased glycemic control durability were observed with liraglutide in primary care, compared with specialist care. These data suggest that liraglutide treatment could benefit patients in primary care by delaying the need for further treatment intensification. ClinicalTrials.gov identifier, NCT01226966. Novo Nordisk A/S.

Vitamin D status in chronic fatigue syndrome/myalgic encephalomyelitis: a cohort study from the North-West of England

PubMed Central

Earl, Kate E; Sakellariou, Giorgos K; Sinclair, Melanie; Fenech, Manuel; Croden, Fiona; Owens, Daniel J; Tang, Jonathan; Miller, Alastair; Lawton, Clare; Dye, Louise; Close, Graeme L; Fraser, William D; McArdle, Anne; Beadsworth, Michael B J

2017-01-01

Objective Severe vitamin D deficiency is a recognised cause of skeletal muscle fatigue and myopathy. The aim of this study was to examine whether chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated with altered circulating vitamin D metabolites. Design Cohort study. Setting UK university hospital, recruiting from April 2014 to April 2015. Participants Ninety-two patients with CFS/ME and 94 age-matched healthy controls (HCs). Main outcome measures The presence of a significant association between CFS/ME, fatigue and vitamin D measures. Results No evidence of a deficiency in serum total 25(OH) vitamin D (25(OH)D2 and 25(OH)D3 metabolites) was evident in individuals with CFS/ME. Liquid chromatography tandem mass spectrometry (LC–MS/MS) analysis revealed that total 25(OH)D was significantly higher (p=0.001) in serum of patients with CFS/ME compared with HCs (60.2 and 47.3 nmol/L, respectively). Analysis of food/supplement diaries with WinDiets revealed that the higher total 25(OH) vitamin D concentrations observed in the CFS/ME group were associated with increased vitamin D intake through use of supplements compared with the control group. Analysis of Chalder Fatigue Questionnaire data revealed no association between perceived fatigue and vitamin D levels. Conclusions Low serum concentrations of total 25(OH)D do not appear to be a contributing factor to the level of fatigue of CFS/ME. PMID:29118054

Utility of blood pressure genetic risk score in admixed Hispanic samples.

PubMed

Beecham, A H; Wang, L; Vasudeva, N; Liu, Z; Dong, C; Goldschmidt-Clermont, P J; Pericak-Vance, M A; Rundek, T; Seo, D; Blanton, S H; Sacco, R L; Beecham, G W

2016-12-01

Hypertension is strongly influenced by genetic factors. Although hypertension prevalence in some Hispanic sub-populations is greater than in non-Hispanic whites, genetic studies on hypertension have focused primarily on samples of European descent. A recent meta-analysis of 200 000 individuals of European descent identified 29 common genetic variants that influence blood pressure, and a genetic risk score derived from the 29 variants has been proposed. We sought to evaluate the utility of this genetic risk score in Hispanics. The sample set consists of 1994 Hispanics from 2 cohorts: the Northern Manhattan Study (primarily Dominican/Puerto Rican) and the Miami Cardiovascular Registry (primarily Cuban/South American). Risk scores for systolic and diastolic blood pressure were computed as a weighted sum of the risk alleles, with the regression coefficients reported in the European meta-analysis used as weights. Association of risk score with blood pressure was tested within each cohort, adjusting for age, age 2 , sex and body mass index. Results were combined using an inverse-variance meta-analysis. The risk score was significantly associated with blood pressure in our combined sample (P=5.65 × 10 -4 for systolic and P=1.65 × 10 -3 for diastolic) but the magnitude of the effect sizes varied by degree of European, African and Native American admixture. Further studies among other Hispanic sub-populations are needed to elucidate the role of these 29 variants and identify additional genetic and environmental factors contributing to blood pressure variability in Hispanics.

The 'lost tribe' reconsidered: Teenagers and young adults treated for cancer in adult settings in the UK.

PubMed

Marshall, Steve; Grinyer, Anne; Limmer, Mark

2018-04-01

Although the UK has pioneered the development of specialist adolescent cancer units, the majority of teenagers and young adults (TYAs) continue to be treated at their local hospital or at a cancer centre alongside adults of all ages. This study aimed to elicit young people's views on this experience of having cancer treatment in an adult setting. Seventeen participants who had been treated for cancer in an adult hospital between the ages of 15 and 24 were recruited via cancer charities and social media. Telephone interviews were conducted with the participants and the resulting data were analysed using thematic analysis. Already feeling out of sync as a TYA with cancer, participants felt out of place in the adult setting. Four factors contributed to this negative experience: a lack of affinity with older patients; the challenging issues in the adult setting; the absence of empathy towards TYAs by staff; and the unsuitability of the environment for adolescents. Staff working with TYAs with cancer in the adult setting should be aware of the potentially detrimental impact of this environment on this cohort of patients, and consider ways of adapting and modifying their approach. Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.

Risk Factors of Clinical and Immunological Failure in South Indian Cohort on Generic Antiretroviral Therapy.

PubMed

Sadashiv, Mucheli Shravan; Rupali, Priscilla; Manesh, Abi; Kannangai, Rajesh; Abraham, Ooriapadickal Cherian; Pulimood, Susanne A; Karthik, Rajiv; Rajkumar, S; Thomas, Kurien

2017-12-01

Since the time of NACO Antiretroviral (ART) roll-out, generic ART has been the mainstay of therapy. There are many studies documenting the efficacy of generic ART but with the passage of time, failure of therapy is on the rise. As institution of second line ART has significant financial implications both for a program and for an individual it is imperative that we determine factors which contribute towards treatment failure in a cohort of patients on generic antiretroviral therapy. This was a nested matched case-control study assessing the predictors for treatment failure in our cohort who had been on Anti-retroviral therapy for at least a year. We identified 42 patients (Cases) with documented treatment failure out of our cohort of 823 patients and 42 sex, age and duration of therapy-matched controls. Using a structured proforma, we collected information from the out-patient and in-patient charts of the Infectious Diseases clinic Cohort in CMC, Vellore. A set of predetermined variables were studied as potential risk factors for treatment failure on ART. Univariate analysis showed significant association with 1) Self-reported nonadherence<95% [OR 12.81 (95%CI 1.54-281.45)]. 2) Treatment interruptions in adherent cases (OR 9.56 (95% CI 1.11-213.35)]. 3) Past inappropriate therapies [OR 9.65 (95% CI 1.12-215.94)]. 4) Diarrhoea [OR 16.40 (95% CI 2.02-3.55.960]. 5) GI opportunistic infections (OR 11.06 (95% CI 1.31 -244.27)] and 6) Drug Toxicity [OR 3.69 (95% CI 1.15-12.35).In multiple logistic regression analysis, we found independent risk factors of treatment failure to be: Self-reported non-adherence (<95%) with OR 15.46(95%CI 1.55 - 154.08), drug toxicity - OR 4.13(95%CI 1.095 - 15.534) and history of diarrhoea - OR 23.446(95%CI 2.572 - 213.70). This study reveals that besides adherence to therapy, presence of diarrhoea and occurrence of drug toxicity are significant risk factors associated with failure of anti-retroviral therapy. There is a need for further prospective studies to assess their role in development of treatment failure on ART and thus help development of targeted interventions.

Characteristics of Real-World Metastatic Non-Small Cell Lung Cancer Patients Treated with Nivolumab and Pembrolizumab During the Year Following Approval.

PubMed

Khozin, Sean; Abernethy, Amy P; Nussbaum, Nathan C; Zhi, Jizu; Curtis, Melissa D; Tucker, Melisa; Lee, Shannon E; Light, David E; Gossai, Anala; Sorg, Rachael A; Torres, Aracelis Z; Patel, Payal; Blumenthal, Gideon Michael; Pazdur, Richard

2018-03-01

Evidence from cancer clinical trials can be difficult to generalize to real-world patient populations, but can be complemented by real-world evidence to optimize personalization of care. Further, real-world usage patterns of programmed cell death protein 1 (PD-1) inhibitors following approval can inform future studies of subpopulations underrepresented in clinical trials. We performed a multicenter analysis using electronic health record data collected during routine care of patients treated in community cancer care clinics in the Flatiron Health network. Real-world metastatic non-small cell lung cancer (NSCLC) patients who received nivolumab or pembrolizumab in the metastatic setting ( n  = 1,344) were selected from a starting random sample of 55,969 NSCLC patients with two or more documented visits from January 1, 2011, through March 31, 2016. The primary study outcome measurement was demographic and treatment characteristics of the cohort. Median age at PD-1 inhibitor initiation was 69 years (interquartile range 61-75). Patients were 56% male, 88% smokers, 65% nonsquamous histology, and 64% diagnosed at stage IV. Of 1,344 patients, 112 (8%) were tested for programmed death-ligand 1 expression. Overall, 50% received nivolumab or pembrolizumab in the second line, with a substantial proportion of third and later line use that began to decline in Q4 2015. During the year following U.S. regulatory approval of PD-1 inhibitors for treatment of NSCLC, real-world patients receiving nivolumab or pembrolizumab were older at treatment initiation and more had smoking history relative to clinical trial cohorts. Studies of outcomes in underrepresented subgroups are needed to inform real-world treatment decisions. Evidence gathered in conventional clinical trials used to assess safety and efficacy of new therapies is not necessarily generalizable to real-world patients receiving these drugs following regulatory approval. Real-world evidence derived from electronic health record data can yield complementary evidence to enable optimal clinical decisions. Examined here is a cohort of programmed cell death protein 1 inhibitor-treated metastatic non-small cell lung cancer patients in the first year following regulatory approval of these therapies in this indication. The analysis revealed how the real-world cohort differed from the clinical trial cohorts, which will inform which patients are underrepresented and warrant additional studies. © AlphaMed Press 2018.

Preliminary Rural Analysis of the Early Childhood Longitudinal Study--Kindergarten Cohort. Rural Early Childhood Brief Number 2

ERIC Educational Resources Information Center

National Center for Rural Early Childhood Learning Initiatives - Mississippi State University Early Childhood Institute, 2005

2005-01-01

This brief introduces the first results from a rural analysis of selected national datasets. Provided are key findings concerning kindergarten readiness of rural children from an analysis of the Kindergarten Cohort of the Early Childhood Longitudinal Study (ECLS). Future briefs will summarize the findings concerning the health of the Kindergarten…

Master Maker: Understanding Gaming Skill Through Practice and Habit From Gameplay Behavior.

PubMed

Huang, Jeff; Yan, Eddie; Cheung, Gifford; Nagappan, Nachiappan; Zimmermann, Thomas

2017-04-01

The study of expertise is difficult to do in a laboratory environment due to the challenge of finding people at different skill levels and the lack of time for participants to acquire mastery. In this paper, we report on two studies that analyze naturalistic gameplay data using cohort analysis to better understand how skill relates to practice and habit. Two cohorts are analyzed, each from two different games (Halo Reach and StarCraft 2). Our work follows skill progression through 7 months of Halo matches for a holistic perspective, but also explores low-level in-game habits when controlling game units in StarCraft 2. Players who played moderately frequently without long breaks were able to gain skill the most efficiently. What set the highest performers apart was their ability to gain skill more rapidly and without dips compared to other players. At the beginning of matches, top players habitually warmed up by selecting and re-selecting groups of units repeatedly in a meaningless cycle. They exhibited unique routines during their play that aided them when under pressure. Copyright © 2017 Cognitive Science Society, Inc.

ProteinSeq: High-Performance Proteomic Analyses by Proximity Ligation and Next Generation Sequencing

PubMed Central

Vänelid, Johan; Siegbahn, Agneta; Ericsson, Olle; Fredriksson, Simon; Bäcklin, Christofer; Gut, Marta; Heath, Simon; Gut, Ivo Glynne; Wallentin, Lars; Gustafsson, Mats G.; Kamali-Moghaddam, Masood; Landegren, Ulf

2011-01-01

Despite intense interest, methods that provide enhanced sensitivity and specificity in parallel measurements of candidate protein biomarkers in numerous samples have been lacking. We present herein a multiplex proximity ligation assay with readout via realtime PCR or DNA sequencing (ProteinSeq). We demonstrate improved sensitivity over conventional sandwich assays for simultaneous analysis of sets of 35 proteins in 5 µl of blood plasma. Importantly, we observe a minimal tendency to increased background with multiplexing, compared to a sandwich assay, suggesting that higher levels of multiplexing are possible. We used ProteinSeq to analyze proteins in plasma samples from cardiovascular disease (CVD) patient cohorts and matched controls. Three proteins, namely P-selectin, Cystatin-B and Kallikrein-6, were identified as putative diagnostic biomarkers for CVD. The latter two have not been previously reported in the literature and their potential roles must be validated in larger patient cohorts. We conclude that ProteinSeq is promising for screening large numbers of proteins and samples while the technology can provide a much-needed platform for validation of diagnostic markers in biobank samples and in clinical use. PMID:21980495

From "Sooo excited!!!" to "So proud": using language to study development.

PubMed

Kern, Margaret L; Eichstaedt, Johannes C; Schwartz, H Andrew; Park, Gregory; Ungar, Lyle H; Stillwell, David J; Kosinski, Michal; Dziurzynski, Lukasz; Seligman, Martin E P

2014-01-01

We introduce a new method, differential language analysis (DLA), for studying human development in which computational linguistics are used to analyze the big data available through online social media in light of psychological theory. Our open vocabulary DLA approach finds words, phrases, and topics that distinguish groups of people based on 1 or more characteristics. Using a data set of over 70,000 Facebook users, we identify how word and topic use vary as a function of age and compile cohort specific words and phrases into visual summaries that are face valid and intuitively meaningful. We demonstrate how this methodology can be used to test developmental hypotheses, using the aging positivity effect (Carstensen & Mikels, 2005) as an example. While in this study we focused primarily on common trends across age-related cohorts, the same methodology can be used to explore heterogeneity within developmental stages or to explore other characteristics that differentiate groups of people. Our comprehensive list of words and topics is available on our web site for deeper exploration by the research community. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Update on causes of premature death in people with convulsive epilepsy in rural West China.

PubMed

Si, Yang; Chen, Deng; Tian, Linyu; Mu, Jie; Chen, Tao; Liu, Ling; Deng, Ying; He, Jun; Li, You; He, Li; Zhou, Dong

2016-06-01

This longitudinal prospective study updated a previous report on premature mortality and focused on the risk factors among patients with convulsive epilepsy in resource-poor settings. The present cohort size (7,231) and follow-up (mean 33.4 months) were expanded. The basic epidemiologic aspects of this cohort were similar to the original report (case fatality: 3.26% vs. 2.97%, respectively; injury contributed more than half of the deaths). Cox regression analysis suggested that male patients, late ages of onset (>45 years old), short duration of epilepsy (<10 years), and high convulsive seizure frequency (>2 per month) were independent risk factors for overall premature death. Male patients with late ages of onset and high seizure frequency had a higher risk of injury-specific death. This study emphasizes the preventable nature of injuries that are leading putative causes of death among people with convulsive epilepsy in rural West China. Education on specific populations and efficient seizure control are of paramount importance in reducing the risk of premature mortality. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

Benign Breast Disease: Toward Molecular Prediction of Breast Cancer Risk

DTIC Science & Technology

2006-06-01

with benign breast disease ( BBD ) (1967-1991); 2) the application of potential biomarkers of risk to this archival tissue set; and 3) the discovery...of new, potentially relevant biomarkers of risk in fresh and frozen specimens of BBD . The Center includes a multi-institutional team of basic...State). I. Task 1: Establish Retrospective Cohort of BBD and Nested Case-Control Study A. Complete cohort follow-up We provide here an update of

Longitudinal Effects of Class Size Reductions on Attainment: Results from Hong Kong Primary Classrooms

ERIC Educational Resources Information Center

Galton, Maurice; Pell, Tony

2012-01-01

In a four-year study of the effect of class size on pupil outcomes in a sample of 36 primary schools in Hong Kong, it has been found that there are few positive differences in attainment between classes set at less than 25 pupils and those of normal size averaging 38. Three cohorts of pupils were studied. In Cohort 1 pupils spent 3 years in small…

Serum antibodies in mares and foals to Actinobacillus equuli whole cells, outer membrane proteins, and Aqx toxin.

PubMed

Holyoak, G R; Smith, C M; Boyette, R; Montelongo, M; Wray, J H; Ayalew, S; Duggan, V E; Confer, A W

2007-08-15

Actinobacillus equuli is carried in the alimentary tract of mares and can cause severe septicemia of neonatal foals. A hemolytic subspecies, A. equuli subsp. haemolyticus, and a non-hemolytic subspecies, A. equuli subsp. equuli, have been identified. Hemolytic strains produce the RTX toxin Aqx. The purpose of this study was to demonstrate sequentially in two sets of mare-foal pairs antibodies to A. equuli whole bacterial cells, outer membrane proteins, and recombinant Aqx and to compare the transfer of antibodies to these antigens between mares and their foals. Two mare/foal sets of sera were evaluated. Cohort A consisted of 18 mare-foal pairs obtained in the spring of 2005. Cohort B consisted of 10 mare-foal pairs obtained in the spring of 2006. For both sets, mare and foal sera were obtained immediately after foaling and prior to nursing (time 0) as well as at 12 and 24h and daily thereafter for 7 days. For Cohort B, sera were also obtained 30 days after birth. At parturition all mares had detectable antibodies to A. equuli whole cells and outer membranes; however, of those mares, two in Cohort A had undetectable antibodies to Aqx and their foals likewise had undetectable anti-Aqx antibodies. Antibodies against whole cells, outer membrane proteins, and Aqx were readily transferred from mares to foals. In most cases, there were significant correlations (p<0.05) between antibodies against whole cells, outer membrane proteins, and Aqx in mares' sera at the time of parturition and foal sera 24 after birth. Antibodies against the three antigen preparations had declined insignificantly (p>0.05) by day 30.

Gene expression analysis of TIL rich HPV-driven head and neck tumors reveals a distinct B-cell signature when compared to HPV independent tumors.

PubMed

Wood, Oliver; Woo, Jeongmin; Seumois, Gregory; Savelyeva, Natalia; McCann, Katy J; Singh, Divya; Jones, Terry; Peel, Lailah; Breen, Michael S; Ward, Matthew; Garrido Martin, Eva; Sanchez-Elsner, Tilman; Thomas, Gareth; Vijayanand, Pandurangan; Woelk, Christopher H; King, Emma; Ottensmeier, Christian

2016-08-30

Human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) has a better prognosis than it's HPV negative (HPV(-)) counterpart. This may be due to the higher numbers of tumor-infiltrating lymphocytes (TILs) in HPV positive (HPV(+)) tumors. RNA-Sequencing (RNA-Seq) was used to evaluate whether the differences in clinical behaviour simply reflect a numerical difference in TILs or whether there is a fundamental behavioural difference between TILs in these two settings. Thirty-nine HNSCC tumors were scored for TIL density by immunohistochemistry. After the removal of 16 TILlow tumors, RNA-Seq analysis was performed on 23 TILhigh/med tumors (HPV(+) n=10 and HPV(-) n=13). Using EdgeR, differentially expressed genes (DEG) were identified. Immune subset analysis was performed using Functional Analysis of Individual RNA-Seq/ Microarray Expression (FAIME) and immune gene RNA transcript count analysis. In total, 1,634 DEGs were identified, with a dominant immune signature observed in HPV(+) tumors. After normalizing the expression profiles to account for differences in B- and T-cell number, 437 significantly DEGs remained. A B-cell associated signature distinguished HPV(+) from HPV(-) tumors, and included the DEGs CD200, GGA2, ADAM28, STAG3, SPIB, VCAM1, BCL2 and ICOSLG; the immune signal relative to T-cells was qualitatively similar between TILs of both tumor cohorts. Our findings were validated and confirmed in two independent cohorts using TCGA data and tumor-infiltrating B-cells from additional HPV(+) HNSCC patients. A B-cell associated signal segregated tumors relative to HPV status. Our data suggests that the role of B-cells in the adaptive immune response to HPV(+) HNSCC requires re-assessment.

Gene expression analysis of TIL rich HPV-driven head and neck tumors reveals a distinct B-cell signature when compared to HPV independent tumors

PubMed Central

Savelyeva, Natalia; McCann, Katy J.; Singh, Divya; Jones, Terry; Peel, Lailah; Breen, Michael S.; Ward, Matthew; Martin, Eva Garrido

2016-01-01

Human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) has a better prognosis than it's HPV negative (HPV(−)) counterpart. This may be due to the higher numbers of tumor-infiltrating lymphocytes (TILs) in HPV positive (HPV(+)) tumors. RNA-Sequencing (RNA-Seq) was used to evaluate whether the differences in clinical behaviour simply reflect a numerical difference in TILs or whether there is a fundamental behavioural difference between TILs in these two settings. Thirty-nine HNSCC tumors were scored for TIL density by immunohistochemistry. After the removal of 16 TILlow tumors, RNA-Seq analysis was performed on 23 TILhigh/med tumors (HPV(+) n=10 and HPV(−) n=13). Using EdgeR, differentially expressed genes (DEG) were identified. Immune subset analysis was performed using Functional Analysis of Individual RNA-Seq/ Microarray Expression (FAIME) and immune gene RNA transcript count analysis. In total, 1,634 DEGs were identified, with a dominant immune signature observed in HPV(+) tumors. After normalizing the expression profiles to account for differences in B- and T-cell number, 437 significantly DEGs remained. A B-cell associated signature distinguished HPV(+) from HPV(−) tumors, and included the DEGs CD200, GGA2, ADAM28, STAG3, SPIB, VCAM1, BCL2 and ICOSLG; the immune signal relative to T-cells was qualitatively similar between TILs of both tumor cohorts. Our findings were validated and confirmed in two independent cohorts using TCGA data and tumor-infiltrating B-cells from additional HPV(+) HNSCC patients. A B-cell associated signal segregated tumors relative to HPV status. Our data suggests that the role of B-cells in the adaptive immune response to HPV(+) HNSCC requires re-assessment. PMID:27462861

Perinatal and maternal outcomes in planned home and obstetric unit births in women at ‘higher risk’ of complications: secondary analysis of the Birthplace national prospective cohort study

PubMed Central

Li, Y; Townend, J; Rowe, R; Brocklehurst, P; Knight, M; Linsell, L; Macfarlane, A; McCourt, C; Newburn, M; Marlow, N; Pasupathy, D; Redshaw, M; Sandall, J; Silverton, L; Hollowell, J

2015-01-01

Objective To explore and compare perinatal and maternal outcomes in women at ‘higher risk’ of complications planning home versus obstetric unit (OU) birth. Design Prospective cohort study. Setting OUs and planned home births in England. Population 8180 ‘higher risk’ women in the Birthplace cohort. Methods We used Poisson regression to calculate relative risks adjusted for maternal characteristics. Sensitivity analyses explored possible effects of differences in risk between groups and alternative outcome measures. Main outcome measures Composite perinatal outcome measure encompassing ‘intrapartum related mortality and morbidity’ (intrapartum stillbirth, early neonatal death, neonatal encephalopathy, meconium aspiration syndrome, brachial plexus injury, fractured humerus or clavicle) and neonatal admission within 48 hours for more than 48 hours. Two composite maternal outcome measures capturing intrapartum interventions/adverse maternal outcomes and straightforward birth. Results The risk of ‘intrapartum related mortality and morbidity’ or neonatal admission for more than 48 hours was lower in planned home births than planned OU births [adjusted relative risks (RR) 0.50, 95% CI 0.31–0.81]. Adjustment for clinical risk factors did not materially affect this finding. The direction of effect was reversed for the more restricted outcome measure ‘intrapartum related mortality and morbidity’ (RR adjusted for parity 1.92, 95% CI 0.97–3.80). Maternal interventions were lower in planned home births. Conclusions The babies of ‘higher risk’ women who plan birth in an OU appear more likely to be admitted to neonatal care than those whose mothers plan birth at home, but it is unclear if this reflects a real difference in morbidity. Rates of intrapartum related morbidity and mortality did not differ statistically significantly between settings at the 5% level but a larger study would be required to rule out a clinically important difference between the groups. PMID:25603762

Can Contrast-Enhanced Sonography Detect Bowel Wall Fibrosis in Mixed Inflammatory and Fibrotic Crohn Disease Lesions in an Animal Model?

PubMed

Dillman, Jonathan R; Rubin, Jonathan M; Johnson, Laura A; Moons, David S; Higgins, Peter D R

2017-03-01

To determine whether contrast-enhanced sonographic quantitative perfusion parameters can detect bowel wall fibrosis in the setting of mixed inflammatory and fibrotic lesions in a Crohn disease animal model. This study was approved by the institutional Committee on the Use and Care of Animals. Multiple (range, 1-5) 2,4,6-trinitrobenzenesulfonic acid-ethanol enemas were used to create intestinal inflammatory lesions with variable fibrosis in female Lewis rats. Low-mechanical index contrast-enhanced sonography was performed 3 days after the final enema using a 0.2-mL bolus of sulfur hexafluoride microbubbles injected through a tail vein. Contrast-enhanced sonographic data were analyzed with software that converts video data into echo-power (linearized) data. Colorectal lesions were scored for histopathologic inflammation and fibrosis; bowel wall collagen was quantified by Western blotting. The Spearman correlation was used to assess associations between contrast-enhanced sonographic quantitative parameters and bowel wall collagen; the Kruskal-Wallis test was used to compare continuous results between histopathologic groups. Thirty-one animals were included in our analysis. Animals were placed into 3 histopathologic cohorts: (1) severe bowel wall inflammation/minimal or no fibrosis (n = 11); (2) severe bowel wall inflammation/moderate fibrosis (n = 9); and (3) severe bowel wall inflammation/severe fibrosis (n = 11). Western blotting showed a significant difference in bowel wall collagen between histopathologic cohorts (P = .0001). There was no correlation between any contrast-enhanced sonographic quantitative parameter and bowel wall collagen (P > .05). There was no difference between histopathologic cohorts for any contrast-enhanced sonographic quantitative parameter (P > .05). Contrast-enhanced sonographic quantitative perfusion parameters failed to effectively detect bowel wall fibrosis in the setting of superimposed inflammation in a Crohn disease animal model. © 2017 by the American Institute of Ultrasound in Medicine.

Does psychedelic drug use reduce risk of suicidality? Evidence from a longitudinal community-based cohort of marginalised women in a Canadian setting

PubMed Central

Argento, Elena; Strathdee, Steffanie A; Tupper, Kenneth; Braschel, Melissa; Wood, Evan; Shannon, Kate

2017-01-01

Objective This study aimed to longitudinally investigate whether ever having used a psychedelic drug can have a protective effect on incidence of suicidality among marginalised women. Design Longitudinal community-based cohort study. Setting Data were drawn from a prospective, community-based cohort of marginalised women in Metro Vancouver, Canada. Participants 766 women completed the baseline questionnaire between January 2010 and August 2014. Participants who did not report suicidality at baseline and who completed at least one follow-up visit were included. Main outcome measure Extended Cox regression was used to model predictors of new suicidality (suicide ideation or attempts) over 54-month follow-up. Results Nearly half (46%; n=355) of participants reported prior suicidality and were thus excluded from the present analyses. Of 290 women eligible at baseline, 11% (n=31) reported recent suicidality during follow-up, with an incidence density of 4.42 per 100 person-years (95% CI 3.10 to 6.30). In multivariable analysis, reported lifetime psychedelic drug use was associated with a 60% reduced hazard for suicidality (adjusted HR (AHR) 0.40; 95% CI 0.17 to 0.94). Crystal methamphetamine use (AHR 3.25; 95% CI 1.47 to 7.21) and childhood abuse (AHR 3.54; 95% CI 1.49 to 8.40) remained independent predictors of suicidality. Conclusion The high rate of suicidality identified in this study is of major concern. Alongside emerging evidence on the potential of psychedelic-assisted therapy to treat some mental illness and addiction issues, our findings demonstrate that naturalistic psychedelic drug use is independently associated with reduced suicidality, while other illicit drug use and childhood trauma predispose women to suicidality. While observational, this study supports calls for further investigation of the therapeutic utility of psychedelic drugs in treating poor mental health and promoting mental wellness. PMID:28939573

Protocol: systematic review and meta-analyses of birth outcomes for women who intend at the onset of labour to give birth at home compared to women of low obstetrical risk who intend to give birth in hospital.

PubMed

Hutton, Eileen K; Reitsma, Angela; Thorpe, Julia; Brunton, Ginny; Kaufman, Karyn

2014-05-29

There has been a renewed interest in the place of birth, including intended home birth, for low risk women. In the absence of adequately-sized randomised controlled trials, a recent Cochrane review recommended that a systematic review and meta-analysis, including observational studies, be undertaken to inform this topic. The objective of this review is to determine if women intending at the onset of labour to give birth at home are more or less likely to experience a foetal or neonatal loss compared to a cohort of women who are comparable to the home birth cohort on the absence of risk factors but who intend to give birth in a hospital setting. We will search using Embase, MEDLINE, CINAHL, AMED and the Cochrane Library to find studies published since 1990 that compare foetal, neonatal and maternal outcomes for women who intended at the onset of labour to give birth at home to a comparison cohort of low risk women who intended at the onset of labour to give birth in hospital. We will obtain pooled estimates of effect using Review Manager. Because of the likelihood of differences in outcomes in settings where home birth is integrated into the health care system, we will stratify our results according to jurisdictions that have a health care system that integrates home birth and those where home birth is provided outside the usual health care system. Since parity is known to be associated with birth outcomes, only studies that take parity into account will be included in the meta-analyses. We will provide results by parity to the extent possible. This protocol was registered with PROSPERO at http://www.crd.york.ac.uk/Prospero/ (Registration number: CRD42013004046).

Safety and efficacy of hysteroscopic sterilization compared with laparoscopic sterilization: an observational cohort study

PubMed Central

Mao, Jialin; Pfeifer, Samantha; Schlegel, Peter

2015-01-01

Objective To compare the safety and efficacy of hysteroscopic sterilization with the “Essure” device with laparoscopic sterilization in a large, all-inclusive, state cohort. Design Population based cohort study. Settings Outpatient interventional setting in New York State. Participants Women undergoing interval sterilization procedure, including hysteroscopic sterilization with Essure device and laparoscopic surgery, between 2005 and 2013. Main outcomes measures Safety events within 30 days of procedures; unintended pregnancies and reoperations within one year of procedures. Mixed model accounting for hospital clustering was used to compare 30 day and 1 year outcomes, adjusting for patient characteristics and other confounders. Time to reoperation was evaluated using frailty model for time to event analysis. Results We identified 8048 patients undergoing hysteroscopic sterilization and 44 278 undergoing laparoscopic sterilization between 2005 and 2013 in New York State. There was a significant increase in the use of hysteroscopic procedures during this period, while use of laparoscopic sterilization decreased. Patients undergoing hysteroscopic sterilization were older than those undergoing laparoscopic sterilization and were more likely to have a history of pelvic inflammatory disease (10.3% v 7.2%, P<0.01), major abdominal surgery (9.4% v 7.9%, P<0.01), and cesarean section (23.2% v 15.4%, P<0.01). At one year after surgery, hysteroscopic sterilization was not associated with a higher risk of unintended pregnancy (odds ratio 0.84 (95% CI 0.63 to 1.12)) but was associated with a substantially increased risk of reoperation (odds ratio 10.16 (7.47 to 13.81)) compared with laparoscopic sterilization. Conclusions Patients undergoing hysteroscopic sterilization have a similar risk of unintended pregnancy but a more than 10-fold higher risk of undergoing reoperation compared with patients undergoing laparoscopic sterilization. Benefits and risks of both procedures should be discussed with patients for informed decisions making. PMID:26462857

Impact of electronic health records on malpractice claims in a sample of physician offices in Colorado: a retrospective cohort study.

PubMed

Victoroff, Michael S; Drury, Barbara M; Campagna, Elizabeth J; Morrato, Elaine H

2013-05-01

Electronic health records (EHRs) might reduce medical liability claims and potentially justify premium credits from liability insurers, but the evidence is limited. To evaluate the association between EHR use and medical liability claims in a population of office-based physicians, including claims that could potentially be directly prevented by features available in EHRs ("EHR-sensitive" claims). Retrospective cohort study of medical liability claims and analysis of claim abstracts. The 26 % of Colorado office-based physicians insured through COPIC Insurance Company who responded to a survey on EHR use (894 respondents out of 3,502 invitees). Claims incidence rate ratio (IRR); prevalence of "EHR-sensitive" claims. 473 physicians (53 % of respondents) used an office-based EHR. After adjustment for sex, birth cohort, specialty, practice setting and use of an EHR in settings other than an office, IRR for all claims was not significantly different between EHR users and non-users (0.88, 95 % CI 0.52-1.46; p = 0.61), or for users after EHR implementation as compared to before (0.73, 95 % CI 0.41-1.29; p = 0.28). Of 1,569 claim abstracts reviewed, 3 % were judged "Plausibly EHR-sensitive," 82 % "Unlikely EHR-sensitive," and 15 % "Unable to determine." EHR-sensitive claims occurred in six out of 633 non-users and two out of 251 EHR users. Incidence rate ratios were 0.01 for both groups. Colorado physicians using office-based EHRs did not have significantly different rates of liability claims than non-EHR users; nor were rates different for EHR users before and after EHR implementation. The lack of significant effect may be due to a low prevalence of EHR-sensitive claims. Further research on EHR use and medical liability across a larger population of physicians is warranted.

A qualitative study exploring the social and environmental context of recently acquired HIV infection among men who have sex with men in South-East England

PubMed Central

Gourlay, Annabelle; Fox, Julie; Gafos, Mitzy; Fidler, Sarah; Nwokolo, Nneka; Clarke, Amanda; Gilson, Richard; Orkin, Chloe; Collins, Simon; Porter, Kholoud; Hart, Graham

2017-01-01

Objectives A key UK public health priority is to reduce HIV incidence among gay and other men who have sex with men (MSM). This study aimed to explore the social and environmental context in which new HIV infections occurred among MSM in London and Brighton in 2015. Design A qualitative descriptive study, comprising in-depth interviews, was carried out as a substudy to the UK Register of HIV Seroconverters cohort: an observational cohort of individuals whose date of HIV seroconversion was well estimated. An inductive thematic analysis was conducted in NVivo, guided by a socio-ecological framework. Setting Participants were recruited from six HIV clinics in London and Brighton. Fieldwork was conducted between January and April 2015. Participants All MSM eligible for the UK Register Seroconverter cohort (an HIV-positive antibody test result within 12 months of their last documented HIV-negative test or other laboratory evidence of HIV seroconversion) diagnosed within the past 12 months and aged ≥18 were eligible for the qualitative substudy. 21 MSM participated, aged 22–61 years and predominantly white. Results A complex interplay of factors, operating at different levels, influenced risk behaviours and HIV acquisition. Participants saw risk as multi-factorial, but the relative importance of factors varied for each person. Individual psycho-social factors, including personal history, recent life stressors and mental health, enhanced vulnerability towards higher risk situations, while features of the social environment, such as chemsex and social media, and prevalent community beliefs regarding treatment and HIV normalisation, encouraged risk taking. Conclusions Recently acquired HIV infection among MSM reflects a complex web of factors operating at different levels. These findings point to the need for multi-level interventions to reduce the risk of HIV acquisition among high-risk MSM in the UK and similar settings. PMID:28851787

MO-DE-207B-03: Improved Cancer Classification Using Patient-Specific Biological Pathway Information Via Gene Expression Data

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

Young, M; Craft, D

Purpose: To develop an efficient, pathway-based classification system using network biology statistics to assist in patient-specific response predictions to radiation and drug therapies across multiple cancer types. Methods: We developed PICS (Pathway Informed Classification System), a novel two-step cancer classification algorithm. In PICS, a matrix m of mRNA expression values for a patient cohort is collapsed into a matrix p of biological pathways. The entries of p, which we term pathway scores, are obtained from either principal component analysis (PCA), normal tissue centroid (NTC), or gene expression deviation (GED). The pathway score matrix is clustered using both k-means and hierarchicalmore » clustering, and a clustering is judged by how well it groups patients into distinct survival classes. The most effective pathway scoring/clustering combination, per clustering p-value, thus generates various ‘signatures’ for conventional and functional cancer classification. Results: PICS successfully regularized large dimension gene data, separated normal and cancerous tissues, and clustered a large patient cohort spanning six cancer types. Furthermore, PICS clustered patient cohorts into distinct, statistically-significant survival groups. For a suboptimally-debulked ovarian cancer set, the pathway-classified Kaplan-Meier survival curve (p = .00127) showed significant improvement over that of a prior gene expression-classified study (p = .0179). For a pancreatic cancer set, the pathway-classified Kaplan-Meier survival curve (p = .00141) showed significant improvement over that of a prior gene expression-classified study (p = .04). Pathway-based classification confirmed biomarkers for the pyrimidine, WNT-signaling, glycerophosphoglycerol, beta-alanine, and panthothenic acid pathways for ovarian cancer. Despite its robust nature, PICS requires significantly less run time than current pathway scoring methods. Conclusion: This work validates the PICS method to improve cancer classification using biological pathways. Patients are classified with greater specificity and physiological relevance as compared to current gene-specific approaches. Focus now moves to utilizing PICS for pan-cancer patient-specific treatment response prediction.« less

Algorithm for predicting death among older adults in the home care setting: study protocol for the Risk Evaluation for Support: Predictions for Elder-life in the Community Tool (RESPECT)

PubMed Central

Manuel, Douglas G; Taljaard, Monica; Chalifoux, Mathieu; Bennett, Carol; Costa, Andrew P; Bronskill, Susan; Kobewka, Daniel; Tanuseputro, Peter

2016-01-01

Introduction Older adults living in the community often have multiple, chronic conditions and functional impairments. A challenge for healthcare providers working in the community is the lack of a predictive tool that can be applied to the broad spectrum of mortality risks observed and may be used to inform care planning. Objective To predict survival time for older adults in the home care setting. The final mortality risk algorithm will be implemented as a web-based calculator that can be used by older adults needing care and by their caregivers. Design Open cohort study using the Resident Assessment Instrument for Home Care (RAI-HC) data in Ontario, Canada, from 1 January 2007 to 31 December 2013. Participants The derivation cohort will consist of ∼437 000 older adults who had an RAI-HC assessment between 1 January 2007 and 31 December 2012. A split sample validation cohort will include ∼122 000 older adults with an RAI-HC assessment between 1 January and 31 December 2013. Main outcome measures Predicted survival from the time of an RAI-HC assessment. All deaths (n≈245 000) will be ascertained through linkage to a population-based registry that is maintained by the Ministry of Health in Ontario. Statistical analysis Proportional hazards regression will be estimated after assessment of assumptions. Predictors will include sociodemographic factors, social support, health conditions, functional status, cognition, symptoms of decline and prior healthcare use. Model performance will be evaluated for 6-month and 12-month predicted risks, including measures of calibration (eg, calibration plots) and discrimination (eg, c-statistics). The final algorithm will use combined development and validation data. Ethics and dissemination Research ethics approval has been granted by the Sunnybrook Health Sciences Centre Review Board. Findings will be disseminated through presentations at conferences and in peer-reviewed journals. Trial registration number NCT02779309, Pre-results. PMID:27909039

Predicting degree of benefit from adjuvant trastuzumab in NSABP trial B-31.

PubMed

Pogue-Geile, Katherine L; Kim, Chungyeul; Jeong, Jong-Hyeon; Tanaka, Noriko; Bandos, Hanna; Gavin, Patrick G; Fumagalli, Debora; Goldstein, Lynn C; Sneige, Nour; Burandt, Eike; Taniyama, Yusuke; Bohn, Olga L; Lee, Ahwon; Kim, Seung-Il; Reilly, Megan L; Remillard, Matthew Y; Blackmon, Nicole L; Kim, Seong-Rim; Horne, Zachary D; Rastogi, Priya; Fehrenbacher, Louis; Romond, Edward H; Swain, Sandra M; Mamounas, Eleftherios P; Wickerham, D Lawrence; Geyer, Charles E; Costantino, Joseph P; Wolmark, Norman; Paik, Soonmyung

2013-12-04

National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31 suggested the efficacy of adjuvant trastuzumab, even in HER2-negative breast cancer. This finding prompted us to develop a predictive model for degree of benefit from trastuzumab using archived tumor blocks from B-31. Case subjects with tumor blocks were randomly divided into discovery (n = 588) and confirmation cohorts (n = 991). A predictive model was built from the discovery cohort through gene expression profiling of 462 genes with nCounter assay. A predefined cut point for the predictive model was tested in the confirmation cohort. Gene-by-treatment interaction was tested with Cox models, and correlations between variables were assessed with Spearman correlation. Principal component analysis was performed on the final set of selected genes. All statistical tests were two-sided. Eight predictive genes associated with HER2 (ERBB2, c17orf37, GRB7) or ER (ESR1, NAT1, GATA3, CA12, IGF1R) were selected for model building. Three-dimensional subset treatment effect pattern plot using two principal components of these genes was used to identify a subset with no benefit from trastuzumab, characterized by intermediate-level ERBB2 and high-level ESR1 mRNA expression. In the confirmation set, the predefined cut points for this model classified patients into three subsets with differential benefit from trastuzumab with hazard ratios of 1.58 (95% confidence interval [CI] = 0.67 to 3.69; P = .29; n = 100), 0.60 (95% CI = 0.41 to 0.89; P = .01; n = 449), and 0.28 (95% CI = 0.20 to 0.41; P < .001; n = 442; P(interaction) between the model and trastuzumab < .001). We developed a gene expression-based predictive model for degree of benefit from trastuzumab and demonstrated that HER2-negative tumors belong to the moderate benefit group, thus providing justification for testing trastuzumab in HER2-negative patients (NSABP B-47).

Predicting Degree of Benefit From Adjuvant Trastuzumab in NSABP Trial B-31

PubMed Central

Pogue-Geile, Katherine L.; Kim, Chungyeul; Jeong, Jong-Hyeon; Tanaka, Noriko; Bandos, Hanna; Gavin, Patrick G.; Fumagalli, Debora; Goldstein, Lynn C.; Sneige, Nour; Burandt, Eike; Taniyama, Yusuke; Bohn, Olga L.; Lee, Ahwon; Kim, Seung-Il; Reilly, Megan L.; Remillard, Matthew Y.; Blackmon, Nicole L.; Kim, Seong-Rim; Horne, Zachary D.; Rastogi, Priya; Fehrenbacher, Louis; Romond, Edward H.; Swain, Sandra M.; Mamounas, Eleftherios P.; Wickerham, D. Lawrence; Geyer, Charles E.; Costantino, Joseph P.; Wolmark, Norman

2013-01-01

Background National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31 suggested the efficacy of adjuvant trastuzumab, even in HER2-negative breast cancer. This finding prompted us to develop a predictive model for degree of benefit from trastuzumab using archived tumor blocks from B-31. Methods Case subjects with tumor blocks were randomly divided into discovery (n = 588) and confirmation cohorts (n = 991). A predictive model was built from the discovery cohort through gene expression profiling of 462 genes with nCounter assay. A predefined cut point for the predictive model was tested in the confirmation cohort. Gene-by-treatment interaction was tested with Cox models, and correlations between variables were assessed with Spearman correlation. Principal component analysis was performed on the final set of selected genes. All statistical tests were two-sided. Results Eight predictive genes associated with HER2 (ERBB2, c17orf37, GRB7) or ER (ESR1, NAT1, GATA3, CA12, IGF1R) were selected for model building. Three-dimensional subset treatment effect pattern plot using two principal components of these genes was used to identify a subset with no benefit from trastuzumab, characterized by intermediate-level ERBB2 and high-level ESR1 mRNA expression. In the confirmation set, the predefined cut points for this model classified patients into three subsets with differential benefit from trastuzumab with hazard ratios of 1.58 (95% confidence interval [CI] = 0.67 to 3.69; P = .29; n = 100), 0.60 (95% CI = 0.41 to 0.89; P = .01; n = 449), and 0.28 (95% CI = 0.20 to 0.41; P < .001; n = 442; P interaction between the model and trastuzumab < .001). Conclusions We developed a gene expression–based predictive model for degree of benefit from trastuzumab and demonstrated that HER2-negative tumors belong to the moderate benefit group, thus providing justification for testing trastuzumab in HER2-negative patients (NSABP B-47). PMID:24262440

Increasing Use of Nonmedical Analgesics Among Younger Cohorts in the United States: A Birth Cohort Effect

PubMed Central

Miech, Richard; Bohnert, Amy; Heard, Kennon; Boardman, Jason

2017-01-01

Purpose Nonmedical use of prescription pain drugs (hereafter ‘analgesics’) has increased substantially in recent years. It is not known whether today’s youth are disproportionately driving this increase or, instead, the trend is a general one that has affected cohorts of all ages similarly. To address this question we present the first age-period-cohort analysis of nonmedical use of analgesics. Methods Data come from the National Survey on Drug Use and Health, a series of annual, nationally-representative, cross-sectional surveys of the U.S. civilian, non-institutionalized population. The analysis focuses on the years 1985 to 2009 and uses the recently developed ‘intrinsic estimator’ algorithm to disentangle age-period-cohort effects. Results Substantial increases in the prevalence of nonmedical analgesics use have occurred across all cohorts and ages in recent years, but this increase is significantly amplified among today’s adolescents. The odds of past-year, nonmedical analgesics use for today’s youngest cohort (born 1980–1994) are higher than would be expected on the basis of their age and broad, historical period influences that have increased use across people of all ages and cohorts. The independent influence of cohort on past-year, nonmedical analgesics use is about 40% higher for today’s youth cohort than any of the cohorts that came before them. This finding is present among men, women, non-Hispanic whites, non-Hispanic blacks, and Hispanics. Conclusions Although nonmedical use of analgesics is evident among all ages, cohorts, and periods, today’s younger cohorts warrant special attention for substance abuse policies and interventions targeted at reversing the increase in nonmedical analgesics use. PMID:23260832