Meta-analyses evaluating surrogate endpoints for overall survival in cancer randomized trials: A critical review.

PubMed

Savina, Marion; Gourgou, Sophie; Italiano, Antoine; Dinart, Derek; Rondeau, Virginie; Penel, Nicolas; Mathoulin-Pelissier, Simone; Bellera, Carine

2018-03-01

In cancer randomized controlled trials (RCT), alternative endpoints are increasingly being used in place of overall survival (OS) to reduce sample size, duration and cost of trials. It is necessary to ensure that these endpoints are valid surrogates for OS. Our aim was to identify meta-analyses that evaluated surrogate endpoints for OS and assess the strength of evidence for each meta-analysis (MA). We performed a systematic review to identify MA of cancer RCTs assessing surrogate endpoints for OS. We evaluated the strength of the association between the endpoints based on (i) the German Institute of Quality and Efficiency in Health Care guidelines and (ii) the Biomarker-Surrogate Evaluation Schema. Fifty-three publications reported on 164 MA, with heterogeneous statistical methods Disease-free survival (DFS) and progression-free survival (PFS) showed good surrogacy properties for OS in colorectal, lung and head and neck cancers. DFS was highly correlated to OS in gastric cancer. The statistical methodology used to evaluate surrogate endpoints requires consistency in order to facilitate the accurate interpretation of the results. Despite the limited number of clinical settings with validated surrogate endpoints for OS, there is evidence of good surrogacy for DFS and PFS in tumor types that account for a large proportion of cancer cases. Copyright © 2017 Elsevier B.V. All rights reserved.

Surrogate endpoints for clinical trials in primary sclerosing cholangitis: Review and results from an International PSC Study Group consensus process.

PubMed

Ponsioen, Cyriel Y; Chapman, Roger W; Chazouillères, Olivier; Hirschfield, Gideon M; Karlsen, Tom H; Lohse, Ansgar W; Pinzani, Massimo; Schrumpf, Erik; Trauner, Michael; Gores, Gregory J

2016-04-01

Primary sclerosing cholangitis (PSC) is a rare, but serious, cholestatic disease for which, to date, no effective therapy exists to halt disease progression toward end-stage liver disease. Clinical trial design to study drugs that improve prognosis is hampered by the relatively low event rate of clinically relevant endpoints. To overcome this shortcoming, there is an urgent need to identify appropriate surrogate endpoints. At present, there are no established surrogate endpoints. This article provides a critical review and describes the results of a consensus process initiated by the International PSC Study Group to delineate appropriate candidate surrogate endpoints at present for clinical trials in this frequently dismal disease. The consensus process resulted in a shortlist of five candidates as surrogate endpoints for measuring disease progression: alkaline phosphatase (ALP); transient elastography (TE); histology; combination of ALP+histology; and bilirubin. Of these, histology, ALP, and TE came out as the most promising. However, the expert panel concluded that no biomarker currently exceeds level 3 validation. Combining multiple endpoints is advisable. At present, there are insufficient data to support level 2 validation for any surrogate endpoint in PSC. Concerted efforts by all stakeholders are highly needed. Novel, promising noninvasive biomarkers are under study and should be incorporated as exploratory endpoints in clinical trials. © 2015 by the American Association for the Study of Liver Diseases.

Review of meta-analyses evaluating surrogate endpoints for overall survival in oncology.

PubMed

Sherrill, Beth; Kaye, James A; Sandin, Rickard; Cappelleri, Joseph C; Chen, Connie

2012-01-01

Overall survival (OS) is the gold standard in measuring the treatment effect of new drug therapies for cancer. However, practical factors may preclude the collection of unconfounded OS data, and surrogate endpoints are often used instead. Meta-analyses have been widely used for the validation of surrogate endpoints, specifically in oncology. This research reviewed published meta-analyses on the types of surrogate measures used in oncology studies and examined the extent of correlation between surrogate endpoints and OS for different cancer types. A search was conducted in October 2010 to compile available published evidence in the English language for the validation of disease progression-related endpoints as surrogates of OS, based on meta-analyses. We summarize published meta-analyses that quantified the correlation between progression-based endpoints and OS for multiple advanced solid-tumor types. We also discuss issues that affect the interpretation of these findings. Progression-free survival is the most commonly used surrogate measure in studies of advanced solid tumors, and correlation with OS is reported for a limited number of cancer types. Given the increased use of crossover in trials and the availability of second-/third-line treatment options available to patients after progression, it will become increasingly more difficult to establish correlation between effects on progression-free survival and OS in additional tumor types.

Defining Surrogate Endpoints for Clinical Trials in Severe Falciparum Malaria

PubMed Central

Plewes, Katherine; Maude, Richard J.; Hanson, Josh; Herdman, M. Trent; Leopold, Stije J.; Ngernseng, Thatsanun; Charunwatthana, Prakaykaew; Phu, Nguyen Hoan; Ghose, Aniruddha; Hasan, M. Mahtab Uddin; Fanello, Caterina I.; Faiz, Md Abul; Hien, Tran Tinh; Day, Nicholas P. J.; White, Nicholas J.; Dondorp, Arjen M.

2017-01-01

Background Clinical trials in severe falciparum malaria require a large sample size to detect clinically meaningful differences in mortality. This means few interventions can be evaluated at any time. Using a validated surrogate endpoint for mortality would provide a useful alternative allowing a smaller sample size. Here we evaluate changes in coma score and plasma lactate as surrogate endpoints for mortality in severe falciparum malaria. Methods Three datasets of clinical studies in severe malaria were re-evaluated: studies from Chittagong, Bangladesh (adults), the African ‘AQUAMAT’ trial comparing artesunate and quinine (children), and the Vietnamese ‘AQ’ study (adults) comparing artemether with quinine. The absolute change, relative change, slope of the normalization over time, and time to normalization were derived from sequential measurements of plasma lactate and coma score, and validated for their use as surrogate endpoint, including the proportion of treatment effect on mortality explained (PTE) by these surrogate measures. Results Improvements in lactate concentration or coma scores over the first 24 hours of admission, were strongly prognostic for survival in all datasets. In hyperlactataemic patients in the AQ study (n = 173), lower mortality with artemether compared to quinine closely correlated with faster reduction in plasma lactate concentration, with a high PTE of the relative change in plasma lactate at 8 and 12 hours of 0.81 and 0.75, respectively. In paediatric patients enrolled in the ‘AQUAMAT’ study with cerebral malaria (n = 785), mortality was lower with artesunate compared to quinine, but this was not associated with faster coma recovery. Conclusions The relative changes in plasma lactate concentration assessed at 8 or 12 hours after admission are valid surrogate endpoints for severe malaria studies on antimalarial drugs or adjuvant treatments aiming at improving the microcirculation. Measures of coma recovery are not valid surrogate endpoints for mortality. PMID:28052109

Defining Surrogate Endpoints for Clinical Trials in Severe Falciparum Malaria.

PubMed

Jeeyapant, Atthanee; Kingston, Hugh W; Plewes, Katherine; Maude, Richard J; Hanson, Josh; Herdman, M Trent; Leopold, Stije J; Ngernseng, Thatsanun; Charunwatthana, Prakaykaew; Phu, Nguyen Hoan; Ghose, Aniruddha; Hasan, M Mahtab Uddin; Fanello, Caterina I; Faiz, Md Abul; Hien, Tran Tinh; Day, Nicholas P J; White, Nicholas J; Dondorp, Arjen M

2017-01-01

Clinical trials in severe falciparum malaria require a large sample size to detect clinically meaningful differences in mortality. This means few interventions can be evaluated at any time. Using a validated surrogate endpoint for mortality would provide a useful alternative allowing a smaller sample size. Here we evaluate changes in coma score and plasma lactate as surrogate endpoints for mortality in severe falciparum malaria. Three datasets of clinical studies in severe malaria were re-evaluated: studies from Chittagong, Bangladesh (adults), the African 'AQUAMAT' trial comparing artesunate and quinine (children), and the Vietnamese 'AQ' study (adults) comparing artemether with quinine. The absolute change, relative change, slope of the normalization over time, and time to normalization were derived from sequential measurements of plasma lactate and coma score, and validated for their use as surrogate endpoint, including the proportion of treatment effect on mortality explained (PTE) by these surrogate measures. Improvements in lactate concentration or coma scores over the first 24 hours of admission, were strongly prognostic for survival in all datasets. In hyperlactataemic patients in the AQ study (n = 173), lower mortality with artemether compared to quinine closely correlated with faster reduction in plasma lactate concentration, with a high PTE of the relative change in plasma lactate at 8 and 12 hours of 0.81 and 0.75, respectively. In paediatric patients enrolled in the 'AQUAMAT' study with cerebral malaria (n = 785), mortality was lower with artesunate compared to quinine, but this was not associated with faster coma recovery. The relative changes in plasma lactate concentration assessed at 8 or 12 hours after admission are valid surrogate endpoints for severe malaria studies on antimalarial drugs or adjuvant treatments aiming at improving the microcirculation. Measures of coma recovery are not valid surrogate endpoints for mortality.

A rank test for bivariate time-to-event outcomes when one event is a surrogate

PubMed Central

Shaw, Pamela A.; Fay, Michael P.

2016-01-01

In many clinical settings, improving patient survival is of interest but a practical surrogate, such as time to disease progression, is instead used as a clinical trial’s primary endpoint. A time-to-first endpoint (e.g. death or disease progression) is commonly analyzed but may not be adequate to summarize patient outcomes if a subsequent event contains important additional information. We consider a surrogate outcome very generally, as one correlated with the true endpoint of interest. Settings of interest include those where the surrogate indicates a beneficial outcome so that the usual time-to-first endpoint of death or surrogate event is nonsensical. We present a new two-sample test for bivariate, interval-censored time-to-event data, where one endpoint is a surrogate for the second, less frequently observed endpoint of true interest. This test examines whether patient groups have equal clinical severity. If the true endpoint rarely occurs, the proposed test acts like a weighted logrank test on the surrogate; if it occurs for most individuals, then our test acts like a weighted logrank test on the true endpoint. If the surrogate is a useful statistical surrogate, our test can have better power than tests based on the surrogate that naively handle the true endpoint. In settings where the surrogate is not valid (treatment affects the surrogate but not the true endpoint), our test incorporates the information regarding the lack of treatment effect from the observed true endpoints and hence is expected to have a dampened treatment effect compared to tests based on the surrogate alone. PMID:27059817

A perfect correlate does not a surrogate make

PubMed Central

Baker, Stuart G; Kramer, Barnett S

2003-01-01

Background There is common belief among some medical researchers that if a potential surrogate endpoint is highly correlated with a true endpoint, then a positive (or negative) difference in potential surrogate endpoints between randomization groups would imply a positive (or negative) difference in unobserved true endpoints between randomization groups. We investigate this belief when the potential surrogate and unobserved true endpoints are perfectly correlated within each randomization group. Methods We use a graphical approach. The vertical axis is the unobserved true endpoint and the horizontal axis is the potential surrogate endpoint. Perfect correlation within each randomization group implies that, for each randomization group, potential surrogate and true endpoints are related by a straight line. In this scenario the investigator does not know the slopes or intercepts. We consider a plausible example where the slope of the line is higher for the experimental group than for the control group. Results In our example with unknown lines, a decrease in mean potential surrogate endpoints from control to experimental groups corresponds to an increase in mean true endpoint from control to experimental groups. Thus the potential surrogate endpoints give the wrong inference. Similar results hold for binary potential surrogate and true outcomes (although the notion of correlation does not apply). The potential surrogate endpointwould give the correct inference if either (i) the unknown lines for the two group coincided, which means that the distribution of true endpoint conditional on potential surrogate endpoint does not depend on treatment group, which is called the Prentice Criterion or (ii) if one could accurately predict the lines based on data from prior studies. Conclusion Perfect correlation between potential surrogate and unobserved true outcomes within randomized groups does not guarantee correct inference based on a potential surrogate endpoint. Even in early phase trials, investigators should not base conclusions on potential surrogate endpoints in which the only validation is high correlation with the true endpoint within a group. PMID:12962545

Surrogate Endpoint Evaluation: Principal Stratification Criteria and the Prentice Definition.

PubMed

Gilbert, Peter B; Gabriel, Erin E; Huang, Ying; Chan, Ivan S F

2015-09-01

A common problem of interest within a randomized clinical trial is the evaluation of an inexpensive response endpoint as a valid surrogate endpoint for a clinical endpoint, where a chief purpose of a valid surrogate is to provide a way to make correct inferences on clinical treatment effects in future studies without needing to collect the clinical endpoint data. Within the principal stratification framework for addressing this problem based on data from a single randomized clinical efficacy trial, a variety of definitions and criteria for a good surrogate endpoint have been proposed, all based on or closely related to the "principal effects" or "causal effect predictiveness (CEP)" surface. We discuss CEP-based criteria for a useful surrogate endpoint, including (1) the meaning and relative importance of proposed criteria including average causal necessity (ACN), average causal sufficiency (ACS), and large clinical effect modification; (2) the relationship between these criteria and the Prentice definition of a valid surrogate endpoint; and (3) the relationship between these criteria and the consistency criterion (i.e., assurance against the "surrogate paradox"). This includes the result that ACN plus a strong version of ACS generally do not imply the Prentice definition nor the consistency criterion, but they do have these implications in special cases. Moreover, the converse does not hold except in a special case with a binary candidate surrogate. The results highlight that assumptions about the treatment effect on the clinical endpoint before the candidate surrogate is measured are influential for the ability to draw conclusions about the Prentice definition or consistency. In addition, we emphasize that in some scenarios that occur commonly in practice, the principal strata sub-populations for inference are identifiable from the observable data, in which cases the principal stratification framework has relatively high utility for the purpose of effect modification analysis, and is closely connected to the treatment marker selection problem. The results are illustrated with application to a vaccine efficacy trial, where ACN and ACS for an antibody marker are found to be consistent with the data and hence support the Prentice definition and consistency.

Surrogate Endpoint Evaluation: Principal Stratification Criteria and the Prentice Definition

PubMed Central

Gilbert, Peter B.; Gabriel, Erin E.; Huang, Ying; Chan, Ivan S.F.

2015-01-01

A common problem of interest within a randomized clinical trial is the evaluation of an inexpensive response endpoint as a valid surrogate endpoint for a clinical endpoint, where a chief purpose of a valid surrogate is to provide a way to make correct inferences on clinical treatment effects in future studies without needing to collect the clinical endpoint data. Within the principal stratification framework for addressing this problem based on data from a single randomized clinical efficacy trial, a variety of definitions and criteria for a good surrogate endpoint have been proposed, all based on or closely related to the “principal effects” or “causal effect predictiveness (CEP)” surface. We discuss CEP-based criteria for a useful surrogate endpoint, including (1) the meaning and relative importance of proposed criteria including average causal necessity (ACN), average causal sufficiency (ACS), and large clinical effect modification; (2) the relationship between these criteria and the Prentice definition of a valid surrogate endpoint; and (3) the relationship between these criteria and the consistency criterion (i.e., assurance against the “surrogate paradox”). This includes the result that ACN plus a strong version of ACS generally do not imply the Prentice definition nor the consistency criterion, but they do have these implications in special cases. Moreover, the converse does not hold except in a special case with a binary candidate surrogate. The results highlight that assumptions about the treatment effect on the clinical endpoint before the candidate surrogate is measured are influential for the ability to draw conclusions about the Prentice definition or consistency. In addition, we emphasize that in some scenarios that occur commonly in practice, the principal strata sub-populations for inference are identifiable from the observable data, in which cases the principal stratification framework has relatively high utility for the purpose of effect modification analysis, and is closely connected to the treatment marker selection problem. The results are illustrated with application to a vaccine efficacy trial, where ACN and ACS for an antibody marker are found to be consistent with the data and hence support the Prentice definition and consistency. PMID:26722639

Review of meta-analyses evaluating surrogate endpoints for overall survival in oncology

PubMed Central

Sherrill, Beth; Kaye, James A; Sandin, Rickard; Cappelleri, Joseph C; Chen, Connie

2012-01-01

Overall survival (OS) is the gold standard in measuring the treatment effect of new drug therapies for cancer. However, practical factors may preclude the collection of unconfounded OS data, and surrogate endpoints are often used instead. Meta-analyses have been widely used for the validation of surrogate endpoints, specifically in oncology. This research reviewed published meta-analyses on the types of surrogate measures used in oncology studies and examined the extent of correlation between surrogate endpoints and OS for different cancer types. A search was conducted in October 2010 to compile available published evidence in the English language for the validation of disease progression-related endpoints as surrogates of OS, based on meta-analyses. We summarize published meta-analyses that quantified the correlation between progression-based endpoints and OS for multiple advanced solid-tumor types. We also discuss issues that affect the interpretation of these findings. Progression-free survival is the most commonly used surrogate measure in studies of advanced solid tumors, and correlation with OS is reported for a limited number of cancer types. Given the increased use of crossover in trials and the availability of second-/third-line treatment options available to patients after progression, it will become increasingly more difficult to establish correlation between effects on progression-free survival and OS in additional tumor types. PMID:23109809

On the relationship between the causal-inference and meta-analytic paradigms for the validation of surrogate endpoints.

PubMed

Alonso, Ariel; Van der Elst, Wim; Molenberghs, Geert; Buyse, Marc; Burzykowski, Tomasz

2015-03-01

The increasing cost of drug development has raised the demand for surrogate endpoints when evaluating new drugs in clinical trials. However, over the years, it has become clear that surrogate endpoints need to be statistically evaluated and deemed valid, before they can be used as substitutes of "true" endpoints in clinical studies. Nowadays, two paradigms, based on causal-inference and meta-analysis, dominate the scene. Nonetheless, although the literature emanating from these paradigms is wide, till now the relationship between them has largely been left unexplored. In the present work, we discuss the conceptual framework underlying both approaches and study the relationship between them using theoretical elements and the analysis of a real case study. Furthermore, we show that the meta-analytic approach can be embedded within a causal-inference framework on the one hand and that it can be heuristically justified why surrogate endpoints successfully evaluated using this approach will often be appealing from a causal-inference perspective as well, on the other. A newly developed and user friendly R package Surrogate is provided to carry out the evaluation exercise. © 2014, The International Biometric Society.

Validated surrogate endpoints needed for peri-implantitis.

PubMed

Lee, Dong Won

2011-01-01

Pubmed, Cochrane and Lilac databases, Google, Google Scholar, hand searching of websites of major dental journals. The reference list of five recently published systematic reviews on peri-implantitis treatment were also screened for potential studies. Randomised controlled trials and non-randomised studies in English, German, French, Spanish and Italian on peri-implantitis treatment in humans were included. Case series, case reports and cross sectional or non-therapy studies were excluded from the assessment of endpoints. No minimum follow up time was set for studies that were included. Data were extracted in duplicate by two reviewers and disagreements were resolved by consensus. True endpoints for peri-implantitis treatment were considered only if they provided evidence of tangible benefit to the patient. The outcome variables regarded as true endpoints were implant failure, aesthetic assessment and variables related to quality of life, but these were only considered if they were clearly identified as an objective of the research, not as an outcome of treatment. Surrogate endpoints were considered as those measurements of clinical outcomes such as probing pocket depth and clinical attachment level. Fourteen studies were included in this review with data on implant failure presented solely as consequence of peri-implantitis therapy. No true endpoint was described for any study on peri-implantitis. Mean pocket probing depth, clinical attachment level and bleeding on probing were the three surrogate endpoints cited most often in the literature. All endpoints used in the trials reviewed are surrogates of clinical events, such as implant failure. Clinical surrogate endpoints should be validated to assess the real effect of these measures on true endpoints.

Surrogate endpoints in clinical trials of chronic kidney disease progression: moving from single to multiple risk marker response scores.

PubMed

Schievink, Bauke; Mol, Peter G M; Lambers Heerspink, Hiddo J

2015-11-01

There is increased interest in developing surrogate endpoints for clinical trials of chronic kidney disease progression, as the established clinically meaningful endpoint end-stage renal disease requires large and lengthy trials to assess drug efficacy. We describe recent developments in the search for novel surrogate endpoints. Declines in estimated glomerular filtration rate (eGFR) of 30% or 40% and albuminuria have been proposed as surrogates for end-stage renal disease. However, changes in eGFR or albuminuria may not be valid under all circumstances as drugs always have effects on multiple renal risk markers. Changes in each of these other 'off-target' risk markers can alter renal risk (either beneficially or adversely), and can thereby confound the relationship between surrogates that are based on single risk markers and renal outcome. Risk algorithms that integrate the short-term drug effects on multiple risk markers to predict drug effects on hard renal outcomes may therefore be more accurate. The validity of these risk algorithms is currently investigated. Given that drugs affect multiple renal risk markers, risk scores that integrate these effects are a promising alternative to using eGFR decline or albuminuria. Proper validation is required before these risk scores can be implemented.

Surrogate endpoints for overall survival in digestive oncology trials: which candidates? A questionnaires survey among clinicians and methodologists.

PubMed

Methy, Nicolas; Bedenne, Laurent; Bonnetain, Franck

2010-06-10

Overall survival (OS) is the gold standard for the demonstration of a clinical benefit in cancer trials. Replacement of OS by a surrogate endpoint allows to reduce trial duration. To date, few surrogate endpoints have been validated in digestive oncology. The aim of this study was to draw up an ordered list of potential surrogate endpoints for OS in digestive cancer trials, by way of a survey among clinicians and methodologists. Secondary objective was to obtain their opinion on surrogacy and quality of life (QoL). In 2007 and 2008, self administered sequential questionnaires were sent to a panel of French clinicians and methodologists involved in the conduct of cancer clinical trials. In the first questionnaire, panellists were asked to choose the most important characteristics defining a surrogate among six proposals, to give advantages and drawbacks of the surrogates, and to answer questions about their validation and use. Then they had to suggest potential surrogate endpoints for OS in each of the following tumour sites: oesophagus, stomach, liver, pancreas, biliary tract, lymphoma, colon, rectum, and anus. They finally gave their opinion on QoL as surrogate endpoint. In the second questionnaire, they had to classify the previously proposed candidate surrogates from the most (position #1) to the least relevant in their opinion.Frequency at which the endpoints were chosen as first, second or third most relevant surrogates was calculated and served as final ranking. Response rate was 30% (24/80) in the first round and 20% (16/80) in the second one. Participants highlighted key points concerning surrogacy. In particular, they reminded that a surrogate endpoint is expected to predict clinical benefit in a well-defined therapeutic situation. Half of them thought it was not relevant to study QoL as surrogate for OS.DFS, in the neoadjuvant settings or early stages, and PFS, in the non operable or metastatic settings, were ranked first, with a frequency of more than 69% in 20 out of 22 settings. PFS was proposed in association with QoL in metastatic primary liver and stomach cancers (both 81%). This composite endpoint was ranked second in metastatic oesophageal (69%), colorectal (56%) and anal (56%) cancers, whereas QoL alone was also suggested in most metastatic situations.Other endpoints frequently suggested were R0 resection in the neoadjuvant settings (oesophagus (69%), stomach (56%), pancreas (75%) and biliary tract (63%)) and response. An unexpected endpoint was metastatic PFS in non operable oesophageal (31%) and pancreatic (44%) cancers. Quality and results of surgical procedures like sphincter preservation were also cited as eligible surrogate endpoints in rectal (19%) and anal (50% in case of localized disease) cancers. Except for alpha-FP kinetic in hepatocellular carcinoma (13%) and CA19-9 decline (6%) in pancreas, few endpoints based on biological or tumour markers were proposed. The overall results should help prioritise the endpoints to be statistically evaluated as surrogate for OS, so that trialists and clinicians can rely on endpoints that ensure relevant clinical benefit to the patient.

Surrogate endpoints for overall survival in digestive oncology trials: which candidates? A questionnaires survey among clinicians and methodologists

PubMed Central

2010-01-01

Background Overall survival (OS) is the gold standard for the demonstration of a clinical benefit in cancer trials. Replacement of OS by a surrogate endpoint allows to reduce trial duration. To date, few surrogate endpoints have been validated in digestive oncology. The aim of this study was to draw up an ordered list of potential surrogate endpoints for OS in digestive cancer trials, by way of a survey among clinicians and methodologists. Secondary objective was to obtain their opinion on surrogacy and quality of life (QoL). Methods In 2007 and 2008, self administered sequential questionnaires were sent to a panel of French clinicians and methodologists involved in the conduct of cancer clinical trials. In the first questionnaire, panellists were asked to choose the most important characteristics defining a surrogate among six proposals, to give advantages and drawbacks of the surrogates, and to answer questions about their validation and use. Then they had to suggest potential surrogate endpoints for OS in each of the following tumour sites: oesophagus, stomach, liver, pancreas, biliary tract, lymphoma, colon, rectum, and anus. They finally gave their opinion on QoL as surrogate endpoint. In the second questionnaire, they had to classify the previously proposed candidate surrogates from the most (position #1) to the least relevant in their opinion. Frequency at which the endpoints were chosen as first, second or third most relevant surrogates was calculated and served as final ranking. Results Response rate was 30% (24/80) in the first round and 20% (16/80) in the second one. Participants highlighted key points concerning surrogacy. In particular, they reminded that a surrogate endpoint is expected to predict clinical benefit in a well-defined therapeutic situation. Half of them thought it was not relevant to study QoL as surrogate for OS. DFS, in the neoadjuvant settings or early stages, and PFS, in the non operable or metastatic settings, were ranked first, with a frequency of more than 69% in 20 out of 22 settings. PFS was proposed in association with QoL in metastatic primary liver and stomach cancers (both 81%). This composite endpoint was ranked second in metastatic oesophageal (69%), colorectal (56%) and anal (56%) cancers, whereas QoL alone was also suggested in most metastatic situations. Other endpoints frequently suggested were R0 resection in the neoadjuvant settings (oesophagus (69%), stomach (56%), pancreas (75%) and biliary tract (63%)) and response. An unexpected endpoint was metastatic PFS in non operable oesophageal (31%) and pancreatic (44%) cancers. Quality and results of surgical procedures like sphincter preservation were also cited as eligible surrogate endpoints in rectal (19%) and anal (50% in case of localized disease) cancers. Except for alpha-FP kinetic in hepatocellular carcinoma (13%) and CA19-9 decline (6%) in pancreas, few endpoints based on biological or tumour markers were proposed. Conclusion The overall results should help prioritise the endpoints to be statistically evaluated as surrogate for OS, so that trialists and clinicians can rely on endpoints that ensure relevant clinical benefit to the patient. PMID:20537166

Biomarkers and Surrogate Endpoints in Drug Development: A European Regulatory View.

PubMed

Wickström, Kerstin; Moseley, Jane

2017-05-01

To give a European regulatory overview of the requirements on and the use of biomarkers or surrogate endpoints in the development of drugs for ocular disease. Definitions, methods to validate new markers, and circumstances where surrogate endpoints can be appropriate are summarized. The key endpoints that have been used in registration studies so far are based on visual acuity, signs, and symptoms, or on surrogate endpoints. In some ocular conditions, established outcome measures such as those based on visual acuity or visual field are not feasible (as with slowly progressing diseases), or lack relevance (e.g., when central visual acuity may be preserved even though the patient is legally blind owing to a severely restricted visual field, or vice versa). There are several ocular conditions for which there is an unmet medical need. In some of these conditions, surrogate endpoints as well as new clinical endpoints are needed to help speed up patient access to new medicines. Interaction with European regulators through the pathway specific for the development of biomarkers or novel methods is encouraged.

Considerations for development of surrogate endpoints for antifracture efficacy of new treatments in osteoporosis: a perspective.

PubMed

Bouxsein, Mary L; Delmas, Pierre D

2008-08-01

Because of the broad availability of efficacious osteoporosis therapies, conduct of placebo-controlled trials in subjects at high risk for fracture is becoming increasing difficult. Alternative trial designs include placebo-controlled trials in patients at low risk for fracture or active comparator studies, both of which would require enormous sample sizes and associated financial resources. Another more attractive alternative is to develop and validate surrogate endpoints for fracture. In this perspective, we review the concept of surrogate endpoints as it has been developed in other fields of medicine and discuss how it could be applied in clinical trials of osteoporosis. We outline a stepwise approach and possible study designs to qualify a biomarker as a surrogate endpoint in osteoporosis and review the existing data for several potential surrogate endpoints to assess their success in meeting the proposed criteria. Finally, we suggest a research agenda needed to advance the development of biomarkers as surrogate endpoints for fracture in osteoporosis trials. To ensure optimal development and best use of biomarkers to accelerate drug development, continuous dialog among the health professionals, industry, and regulators is of paramount importance.

Surrogate endpoints for overall survival in lung cancer trials: a review.

PubMed

Fiteni, Frédéric; Westeel, Virginie; Bonnetain, Franck

2017-05-01

Intermediate endpoints are often used as primary endpoints instead of overall survival (OS) in lung cancer trials but they are not systematically validated as surrogate endpoints for OS. Areas covered: The aim of the study was to review the studies which assessed potential surrogate endpoints for OS in lung cancer trials. Expert commentary: Twenty studies were identified. In operable non-small cell lung cancer (NSCLC) (adjuvant trials) and locally advanced NSCLC (radiotherapy trials), one individual-patient data meta-analysis found a high correlation of disease-free survival (DFS) and progression-free survival (PFS) with OS at patient and trial level. In trials of adjuvant chemotherapy, correlation between disease-free survival DFS and OS were 0.83 at the individual level (95% CI 0.83-0.83) and 0.92 at trial level (95% CI 0.88-0.95). In locally advanced disease, correlation between PFS and OS was 0.77 to 0.85 at the individual level, and 0.89 to 0.97 at trial level. This study provides a 'proof' of the surrogacy of PFS and DFS on OS according to the IQWiG framework and the surrogacy of PFS and DFS on OS was classified level 2 according to Fleming hierarchy. In all the other setting, no endpoint was judged to be valid surrogate for OS.

A unified framework for the evaluation of surrogate endpoints in mental-health clinical trials.

PubMed

Molenberghs, Geert; Burzykowski, Tomasz; Alonso, Ariel; Assam, Pryseley; Tilahun, Abel; Buyse, Marc

2010-06-01

For a number of reasons, surrogate endpoints are considered instead of the so-called true endpoint in clinical studies, especially when such endpoints can be measured earlier, and/or with less burden for patient and experimenter. Surrogate endpoints may occur more frequently than their standard counterparts. For these reasons, it is not surprising that the use of surrogate endpoints in clinical practice is increasing. Building on the seminal work of Prentice(1) and Freedman et al.,(2) Buyse et al. (3) framed the evaluation exercise within a meta-analytic setting, in an effort to overcome difficulties that necessarily surround evaluation efforts based on a single trial. In this article, we review the meta-analytic approach for continuous outcomes, discuss extensions to non-normal and longitudinal settings, as well as proposals to unify the somewhat disparate collection of validation measures currently on the market. Implications for design and for predicting the effect of treatment in a new trial, based on the surrogate, are discussed. A case study in schizophrenia is analysed.

Is Suicide Ideation a Surrogate Endpoint for Geriatric Suicide?

ERIC Educational Resources Information Center

Links, Paul S.; Heisel, Marnin J.; Quastel, Adam

2005-01-01

The present study explored the validity of treating suicide ideation as a surrogate endpoint that can serve as a proxy for suicide in clinical intervention research with suicidal seniors. Two criteria; that suicide ideation is modulated by the proposed intervention and that modulation of suicide ideation leads to a quantitative reduction in…

Surrogate endpoints for overall survival in advanced colorectal cancer: a clinician's perspective.

PubMed

Piedbois, Pascal; Miller Croswell, Jennifer

2008-10-01

Surrogate endpoints in oncology research and practice have garnered increasing attention over the past two decades. This activity has largely been driven by the promise surrogate endpoints appear to hold: the potential to get new therapies to seriously ill patients more rapidly. However, uncertainties abound. Even agreeing upon a definition of a "valid" surrogate endpoint has not been a straightforward exercise; this article begins by highlighting differences in how this term has been previously captured and applied, as well as laying out the basic criteria essential for its application in advanced colorectal cancer. Ideally, these elements include (but are not limited to) ease of measurement, rapid indication of treatment effect, and, most importantly, reliable and consistent prediction of the true impact of a treatment on the ultimate outcome of interest: overall survival. The strengths and weaknesses of current potential surrogate endpoints in advanced colorectal cancer, including performance status, carcinoembryonic antigen plasma level, overall response rate, time to progression, and disease-free survival, are each considered in turn. Finally, limitations of surrogate endpoints in the clinical setting, including challenges in extrapolation to new therapies, and the incomplete provision of information about potential adverse effects, are discussed. Work remains to be done between physicians and statisticians to bridge the gap between that which is statistically demonstrable and that which will be clinically useful.The term ;surrogate endpoint' was virtually unknown by most oncologists 15 years ago. A search in PubMed [http://www.ncbi.nlm.nih.gov] based on the words ;surrogate and cancer' shows that more than 2000 papers were published in medical journals in the last 20 years, with a dramatic increase of interest in the last five years. Interestingly, the same trend is observed when the words ;surrogate and heart' are entered into PubMed, suggesting that the issue of surrogate endpoints goes beyond the field of oncology, although the frequency of discussion varies (Figure 1; note different y-axis scales for oncology and cardiology).The goal of the present paper is to discuss the main issues surrounding surrogate endpoints from a clinician's point of view, using as an example surrogate endpoints of overall survival (OS) in advanced colorectal cancer (ACC).

Predicting treatment effect from surrogate endpoints and historical trials: an extrapolation involving probabilities of a binary outcome or survival to a specific time

PubMed Central

Sargent, Daniel J.; Buyse, Marc; Burzykowski, Tomasz

2011-01-01

SUMMARY Using multiple historical trials with surrogate and true endpoints, we consider various models to predict the effect of treatment on a true endpoint in a target trial in which only a surrogate endpoint is observed. This predicted result is computed using (1) a prediction model (mixture, linear, or principal stratification) estimated from historical trials and the surrogate endpoint of the target trial and (2) a random extrapolation error estimated from successively leaving out each trial among the historical trials. The method applies to either binary outcomes or survival to a particular time that is computed from censored survival data. We compute a 95% confidence interval for the predicted result and validate its coverage using simulation. To summarize the additional uncertainty from using a predicted instead of true result for the estimated treatment effect, we compute its multiplier of standard error. Software is available for download. PMID:21838732

Implications of the Institute of Medicine Report: Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease.

PubMed

Wagner, J A; Ball, J R

2015-07-01

The Institute of Medicine (IOM) released a groundbreaking 2010 report, Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease. Key recommendations included a harmonized scientific process and a general framework for biomarker evaluation with three interrelated steps: (1) Analytical validation -- is the biomarker measurement accurate? (2) Qualification -- is the biomarker associated with the clinical endpoint of concern? (3) Utilization -- what is the specific context of the proposed use? © 2015 American Society for Clinical Pharmacology and Therapeutics.

Improved design of prodromal Alzheimer's disease trials through cohort enrichment and surrogate endpoints.

PubMed

Macklin, Eric A; Blacker, Deborah; Hyman, Bradley T; Betensky, Rebecca A

2013-01-01

Alzheimer's disease (AD) trials initiated during or before the prodrome are costly and lengthy because patients are enrolled long before clinical symptoms are apparent, when disease progression is slow. We hypothesized that design of such trials could be improved by: 1) selecting individuals at moderate near-term risk of progression to AD dementia (the current clinical standard) and 2) by using short-term surrogate endpoints that predict progression to AD dementia. We used a longitudinal cohort of older, initially non-demented, community-dwelling participants (n = 358) to derive selection criteria and surrogate endpoints and tested them in an independent national data set (n = 6,243). To identify a "mid-risk" subgroup, we applied conditional tree-based survival models to Clinical Dementia Rating (CDR) scale scores and common neuropsychological tests. In the validation cohort, a time-to-AD dementia trial applying these mid-risk selection criteria to a pool of all non-demented individuals could achieve equivalent power with 47% fewer participants than enrolling at random from that pool. We evaluated surrogate endpoints measureable over two years of follow-up based on cross-validated concordance between predictions from Cox models and observed time to AD dementia. The best performing surrogate, rate of change in CDR sum-of-boxes, did not reduce the trial duration required for equivalent power using estimates from the validation cohort, but alternative surrogates with better ability to predict time to AD dementia should be able to do so. The approach tested here might improve efficiency of prodromal AD trials using other potential measures and could be generalized to other diseases with long prodromal phases.

Improved design of prodromal Alzheimer’s disease trials through cohort enrichment and surrogate endpoints

PubMed Central

Macklin, Eric A.; Blacker, Deborah; Hyman, Bradley T.; Betensky, Rebecca A.

2013-01-01

Summary Alzheimer’s disease (AD) trials initiated during or before the prodrome are costly and lengthy because patients are enrolled long before clinical symptoms are apparent, when disease progression is slow. We hypothesized that design of such trials could be improved by: (1) selecting individuals at moderate near-term risk of progression to AD dementia (the current clinical standard) and (2) by using short-term surrogate endpoints that predict progression to AD dementia. We used a longitudinal cohort of older, initially non-demented, community-dwelling participants (n=358) to derive selection criteria and surrogate endpoints and tested them in an independent national data set (n=6,243). To identify a “mid-risk” subgroup, we applied conditional tree-based survival models to Clinical Dementia Rating (CDR) scale scores and common neuropsychological tests. In the validation cohort, a time-to-AD dementia trial applying these mid-risk selection criteria to a pool of all non-demented individuals could achieve equivalent power with 47% fewer participants than enrolling at random from that pool. We evaluated surrogate endpoints measureable over two years of follow-up based on cross-validated concordance between predictions from Cox models and observed time to AD dementia. The best performing surrogate, rate of change in CDR sum-of-boxes, did not reduce the trial duration required for equivalent power using estimates from the validation cohort, but alternative surrogates with better ability to predict time to AD dementia should be able to do so. The approach tested here might improve efficiency of prodromal AD trials using other potential measures and could be generalized to other diseases with long prodromal phases. PMID:23629586

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

PubMed

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

2015-12-01

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

Surrogate endpoints in oncology: when are they acceptable for regulatory and clinical decisions, and are they currently overused?

PubMed

Kemp, Robert; Prasad, Vinay

2017-07-21

Surrogate outcomes are not intrinsically beneficial to patients, but are designed to be easier and faster to measure than clinically meaningful outcomes. The use of surrogates as an endpoint in clinical trials and basis for regulatory approval is common, and frequently exceeds the guidance given by regulatory bodies. In this article, we demonstrate that the use of surrogates in oncology is widespread and increasing. At the same time, the strength of association between the surrogates used and clinically meaningful outcomes is often unknown or weak. Attempts to validate surrogates are rarely undertaken. When this is done, validation relies on only a fraction of available data, and often concludes that the surrogate is poor. Post-marketing studies, designed to ensure drugs have meaningful benefits, are often not performed. Alternatively, if a drug fails to improve quality of life or overall survival, market authorization is rarely revoked. We suggest this reliance on surrogates, and the imprecision surrounding their acceptable use, means that numerous drugs are now approved based on small yet statistically significant increases in surrogates of questionable reliability. In turn, this means the benefits of many approved drugs are uncertain. This is an unacceptable situation for patients and professionals, as prior experience has shown that such uncertainty can be associated with significant harm. The use of surrogate outcomes should be limited to situations where a surrogate has demonstrated robust ability to predict meaningful benefits, or where cases are dire, rare or with few treatment options. In both cases, surrogates must be used only when continuing studies examining hard endpoints have been fully recruited.

Cardiac magnetic resonance imaging parameters as surrogate endpoints in clinical trials of acute myocardial infarction

PubMed Central

2011-01-01

Cardiac magnetic resonance (CMR) offers a variety of parameters potentially suited as surrogate endpoints in clinical trials of acute myocardial infarction such as infarct size, myocardial salvage, microvascular obstruction or left ventricular volumes and ejection fraction. The present article reviews each of these parameters with regard to the pathophysiological basis, practical aspects, validity, reliability and its relative value (strengths and limitations) as compared to competitive modalities. Randomized controlled trials of acute myocardial infarction which have used CMR parameters as a primary endpoint are presented. PMID:21917147

The Biomarker-Surrogacy Evaluation Schema: a review of the biomarker-surrogate literature and a proposal for a criterion-based, quantitative, multidimensional hierarchical levels of evidence schema for evaluating the status of biomarkers as surrogate endpoints.

PubMed

Lassere, Marissa N

2008-06-01

There are clear advantages to using biomarkers and surrogate endpoints, but concerns about clinical and statistical validity and systematic methods to evaluate these aspects hinder their efficient application. Section 2 is a systematic, historical review of the biomarker-surrogate endpoint literature with special reference to the nomenclature, the systems of classification and statistical methods developed for their evaluation. In Section 3 an explicit, criterion-based, quantitative, multidimensional hierarchical levels of evidence schema - Biomarker-Surrogacy Evaluation Schema - is proposed to evaluate and co-ordinate the multiple dimensions (biological, epidemiological, statistical, clinical trial and risk-benefit evidence) of the biomarker clinical endpoint relationships. The schema systematically evaluates and ranks the surrogacy status of biomarkers and surrogate endpoints using defined levels of evidence. The schema incorporates the three independent domains: Study Design, Target Outcome and Statistical Evaluation. Each domain has items ranked from zero to five. An additional category called Penalties incorporates additional considerations of biological plausibility, risk-benefit and generalizability. The total score (0-15) determines the level of evidence, with Level 1 the strongest and Level 5 the weakest. The term ;surrogate' is restricted to markers attaining Levels 1 or 2 only. Surrogacy status of markers can then be directly compared within and across different areas of medicine to guide individual, trial-based or drug-development decisions. This schema would facilitate communication between clinical, researcher, regulatory, industry and consumer participants necessary for evaluation of the biomarker-surrogate-clinical endpoint relationship in their different settings.

Potential surrogate endpoints for overall survival in locoregionally advanced nasopharyngeal carcinoma: an analysis of a phase III randomized trial

PubMed Central

Chen, Yu-Pei; Chen, Yong; Zhang, Wen-Na; Liang, Shao-Bo; Zong, Jing-Feng; Chen, Lei; Mao, Yan-Ping; Tang, Ling-Long; Li, Wen-Fei; Liu, Xu; Guo, Ying; Lin, Ai-Hua; Liu, Meng-Zhong; Sun, Ying; Ma, Jun

2015-01-01

The gold standard endpoint in trials of locoregionally advanced nasopharyngeal carcinoma (NPC) is overall survival (OS). Using data from a phase III randomized trial, we evaluated whether progression-free survival (PFS), failure-free survival (FFS), distant failure-free survival (D-FFS) or locoregional failure-free survival (LR-FFS) could be reliable surrogate endpoints for OS. Between July 2002 and September 2005, 316 eligible patients with stage III-IVB NPC were randomly assigned to receive either radiotherapy alone or chemoradiotherapy. 2- and 3-year PFS, FFS, D-FFS, and LR-FFS were tested as surrogate endpoints for 5-year OS using Prentice’s four criteria. The Spearman’s rank correlation coefficient was calculated to assess the strength of the associations. After a median follow-up time of 5.8 years, 2- and 3-year D-FFS and LR-FFS were not significantly different between treatment arms, in rejection of Prentice’s second criterion. Being consistent with all Prentice’s criteria, 2- and 3-year PFS and FFS were valid surrogate endpoints for 5-year OS; the rank correlation coefficient was highest (0.84) between 3-year PFS and 5-year OS. In conclusion, PFS and FFS at 2 and 3 years may be candidate surrogate endpoints for OS at 5 years; 3-year PFS may be more appropriate for early assessment of long-term survival. PMID:26219568

Potential surrogate endpoints for overall survival in locoregionally advanced nasopharyngeal carcinoma: an analysis of a phase III randomized trial.

PubMed

Chen, Yu-Pei; Chen, Yong; Zhang, Wen-Na; Liang, Shao-Bo; Zong, Jing-Feng; Chen, Lei; Mao, Yan-Ping; Tang, Ling-Long; Li, Wen-Fei; Liu, Xu; Guo, Ying; Lin, Ai-Hua; Liu, Meng-Zhong; Sun, Ying; Ma, Jun

2015-07-29

The gold standard endpoint in trials of locoregionally advanced nasopharyngeal carcinoma (NPC) is overall survival (OS). Using data from a phase III randomized trial, we evaluated whether progression-free survival (PFS), failure-free survival (FFS), distant failure-free survival (D-FFS) or locoregional failure-free survival (LR-FFS) could be reliable surrogate endpoints for OS. Between July 2002 and September 2005, 316 eligible patients with stage III-IVB NPC were randomly assigned to receive either radiotherapy alone or chemoradiotherapy. 2- and 3-year PFS, FFS, D-FFS, and LR-FFS were tested as surrogate endpoints for 5-year OS using Prentice's four criteria. The Spearman's rank correlation coefficient was calculated to assess the strength of the associations. After a median follow-up time of 5.8 years, 2- and 3-year D-FFS and LR-FFS were not significantly different between treatment arms, in rejection of Prentice's second criterion. Being consistent with all Prentice's criteria, 2- and 3-year PFS and FFS were valid surrogate endpoints for 5-year OS; the rank correlation coefficient was highest (0.84) between 3-year PFS and 5-year OS. In conclusion, PFS and FFS at 2 and 3 years may be candidate surrogate endpoints for OS at 5 years; 3-year PFS may be more appropriate for early assessment of long-term survival.

Is blood pressure reduction a valid surrogate endpoint for stroke prevention? an analysis incorporating a systematic review of randomised controlled trials, a by-trial weighted errors-in-variables regression, the surrogate threshold effect (STE) and the biomarker-surrogacy (BioSurrogate) evaluation schema (BSES)

PubMed Central

2012-01-01

Background Blood pressure is considered to be a leading example of a valid surrogate endpoint. The aims of this study were to (i) formally evaluate systolic and diastolic blood pressure reduction as a surrogate endpoint for stroke prevention and (ii) determine what blood pressure reduction would predict a stroke benefit. Methods We identified randomised trials of at least six months duration comparing any pharmacologic anti-hypertensive treatment to placebo or no treatment, and reporting baseline blood pressure, on-trial blood pressure, and fatal and non-fatal stroke. Trials with fewer than five strokes in at least one arm were excluded. Errors-in-variables weighted least squares regression modelled the reduction in stroke as a function of systolic blood pressure reduction and diastolic blood pressure reduction respectively. The lower 95% prediction band was used to determine the minimum systolic blood pressure and diastolic blood pressure difference, the surrogate threshold effect (STE), below which there would be no predicted stroke benefit. The STE was used to generate the surrogate threshold effect proportion (STEP), a surrogacy metric, which with the R-squared trial-level association was used to evaluate blood pressure as a surrogate endpoint for stroke using the Biomarker-Surrogacy Evaluation Schema (BSES3). Results In 18 qualifying trials representing all pharmacologic drug classes of antihypertensives, assuming a reliability coefficient of 0.9, the surrogate threshold effect for a stroke benefit was 7.1 mmHg for systolic blood pressure and 2.4 mmHg for diastolic blood pressure. The trial-level association was 0.41 and 0.64 and the STEP was 66% and 78% for systolic and diastolic blood pressure respectively. The STE and STEP were more robust to measurement error in the independent variable than R-squared trial-level associations. Using the BSES3, assuming a reliability coefficient of 0.9, systolic blood pressure was a B + grade and diastolic blood pressure was an A grade surrogate endpoint for stroke prevention. In comparison, using the same stroke data sets, no STEs could be estimated for cardiovascular (CV) mortality or all-cause mortality reduction, although the STE for CV mortality approached 25 mmHg for systolic blood pressure. Conclusions In this report we provide the first surrogate threshold effect (STE) values for systolic and diastolic blood pressure. We suggest the STEs have face and content validity, evidenced by the inclusivity of trial populations, subject populations and pharmacologic intervention populations in their calculation. We propose that the STE and STEP metrics offer another method of evaluating the evidence supporting surrogate endpoints. We demonstrate how surrogacy evaluations are strengthened if formally evaluated within specific-context evaluation frameworks using the Biomarker- Surrogate Evaluation Schema (BSES3), and we discuss the implications of our evaluation of blood pressure on other biomarkers and patient-reported instruments in relation to surrogacy metrics and trial design. PMID:22409774

An Evaluation of Culture Results during Treatment for Tuberculosis as Surrogate Endpoints for Treatment Failure and Relapse

PubMed Central

Phillips, Patrick P. J.; Fielding, Katherine; Nunn, Andrew J.

2013-01-01

It is widely acknowledged that new regimens are urgently needed for the treatment of tuberculosis. The primary endpoint in the Phase III trials is a composite outcome of failure at the end of treatment or relapse after stopping treatment. Such trials are usually both long and expensive. Valid surrogate endpoints measured during or at the end of treatment could dramatically reduce both the time and cost of assessing the effectiveness of new regimens. The objective of this study was to evaluate sputum culture results on solid media during treatment as surrogate endpoints for poor outcome. Data were obtained from twelve randomised controlled trials conducted by the British Medical Research Council in the 1970s and 80s in East Africa and East Asia, consisting of 6974 participants and 49 different treatment regimens. The month two culture result was shown to be a poor surrogate in East Africa but a good surrogate in Hong Kong. In contrast, the month three culture was a good surrogate in trials conducted in East Africa but not in Hong Kong. As well as differences in location, ethnicity and probable strain of Mycobacteria tuberculosis, Hong Kong trials more often evaluated regimens with rifampicin throughout and intermittent regimens, and patients in East African trials more often presented with extensive cavitation and were slower to convert to culture negative during treatment. An endpoint that is a summary measure of the longitudinal profile of culture results over time or that is able to detect the presence of M. tuberculosis later in treatment is more likely to be a better endpoint for a phase II trial than a culture result at a single time point and may prove to be an acceptable surrogate. More data are needed before any endpoint can be used as a surrogate in a confirmatory phase III trial. PMID:23667677

An evaluation of culture results during treatment for tuberculosis as surrogate endpoints for treatment failure and relapse.

PubMed

Phillips, Patrick P J; Fielding, Katherine; Nunn, Andrew J

2013-01-01

It is widely acknowledged that new regimens are urgently needed for the treatment of tuberculosis. The primary endpoint in the Phase III trials is a composite outcome of failure at the end of treatment or relapse after stopping treatment. Such trials are usually both long and expensive. Valid surrogate endpoints measured during or at the end of treatment could dramatically reduce both the time and cost of assessing the effectiveness of new regimens. The objective of this study was to evaluate sputum culture results on solid media during treatment as surrogate endpoints for poor outcome. Data were obtained from twelve randomised controlled trials conducted by the British Medical Research Council in the 1970s and 80s in East Africa and East Asia, consisting of 6974 participants and 49 different treatment regimens. The month two culture result was shown to be a poor surrogate in East Africa but a good surrogate in Hong Kong. In contrast, the month three culture was a good surrogate in trials conducted in East Africa but not in Hong Kong. As well as differences in location, ethnicity and probable strain of Mycobacteria tuberculosis, Hong Kong trials more often evaluated regimens with rifampicin throughout and intermittent regimens, and patients in East African trials more often presented with extensive cavitation and were slower to convert to culture negative during treatment. An endpoint that is a summary measure of the longitudinal profile of culture results over time or that is able to detect the presence of M. tuberculosis later in treatment is more likely to be a better endpoint for a phase II trial than a culture result at a single time point and may prove to be an acceptable surrogate. More data are needed before any endpoint can be used as a surrogate in a confirmatory phase III trial.

Evaluating principal surrogate endpoints with time-to-event data accounting for time-varying treatment efficacy.

PubMed

Gabriel, Erin E; Gilbert, Peter B

2014-04-01

Principal surrogate (PS) endpoints are relatively inexpensive and easy to measure study outcomes that can be used to reliably predict treatment effects on clinical endpoints of interest. Few statistical methods for assessing the validity of potential PSs utilize time-to-event clinical endpoint information and to our knowledge none allow for the characterization of time-varying treatment effects. We introduce the time-dependent and surrogate-dependent treatment efficacy curve, ${\\mathrm {TE}}(t|s)$, and a new augmented trial design for assessing the quality of a biomarker as a PS. We propose a novel Weibull model and an estimated maximum likelihood method for estimation of the ${\\mathrm {TE}}(t|s)$ curve. We describe the operating characteristics of our methods via simulations. We analyze data from the Diabetes Control and Complications Trial, in which we find evidence of a biomarker with value as a PS.

Hard, harder, hardest: principal stratification, statistical identifiability, and the inherent difficulty of finding surrogate endpoints.

PubMed

Wolfson, Julian; Henn, Lisa

2014-01-01

In many areas of clinical investigation there is great interest in identifying and validating surrogate endpoints, biomarkers that can be measured a relatively short time after a treatment has been administered and that can reliably predict the effect of treatment on the clinical outcome of interest. However, despite dramatic advances in the ability to measure biomarkers, the recent history of clinical research is littered with failed surrogates. In this paper, we present a statistical perspective on why identifying surrogate endpoints is so difficult. We view the problem from the framework of causal inference, with a particular focus on the technique of principal stratification (PS), an approach which is appealing because the resulting estimands are not biased by unmeasured confounding. In many settings, PS estimands are not statistically identifiable and their degree of non-identifiability can be thought of as representing the statistical difficulty of assessing the surrogate value of a biomarker. In this work, we examine the identifiability issue and present key simplifying assumptions and enhanced study designs that enable the partial or full identification of PS estimands. We also present example situations where these assumptions and designs may or may not be feasible, providing insight into the problem characteristics which make the statistical evaluation of surrogate endpoints so challenging.

Hard, harder, hardest: principal stratification, statistical identifiability, and the inherent difficulty of finding surrogate endpoints

PubMed Central

2014-01-01

In many areas of clinical investigation there is great interest in identifying and validating surrogate endpoints, biomarkers that can be measured a relatively short time after a treatment has been administered and that can reliably predict the effect of treatment on the clinical outcome of interest. However, despite dramatic advances in the ability to measure biomarkers, the recent history of clinical research is littered with failed surrogates. In this paper, we present a statistical perspective on why identifying surrogate endpoints is so difficult. We view the problem from the framework of causal inference, with a particular focus on the technique of principal stratification (PS), an approach which is appealing because the resulting estimands are not biased by unmeasured confounding. In many settings, PS estimands are not statistically identifiable and their degree of non-identifiability can be thought of as representing the statistical difficulty of assessing the surrogate value of a biomarker. In this work, we examine the identifiability issue and present key simplifying assumptions and enhanced study designs that enable the partial or full identification of PS estimands. We also present example situations where these assumptions and designs may or may not be feasible, providing insight into the problem characteristics which make the statistical evaluation of surrogate endpoints so challenging. PMID:25342953

Potential surrogate endpoints for prostate cancer survival: analysis of a phase III randomized trial.

PubMed

Ray, Michael E; Bae, Kyounghwa; Hussain, Maha H A; Hanks, Gerald E; Shipley, William U; Sandler, Howard M

2009-02-18

The identification of surrogate endpoints for prostate cancer-specific survival may shorten the length of clinical trials for prostate cancer. We evaluated distant metastasis and general clinical treatment failure as potential surrogates for prostate cancer-specific survival by use of data from the Radiation Therapy and Oncology Group 92-02 randomized trial. Patients (n = 1554 randomly assigned and 1521 evaluable for this analysis) with locally advanced prostate cancer had been treated with 4 months of neoadjuvant and concurrent androgen deprivation therapy with external beam radiation therapy and then randomly assigned to no additional therapy (control arm) or 24 additional months of androgen deprivation therapy (experimental arm). Data from landmark analyses at 3 and 5 years for general clinical treatment failure (defined as documented local disease progression, regional or distant metastasis, initiation of androgen deprivation therapy, or a prostate-specific antigen level of 25 ng/mL or higher after radiation therapy) and/or distant metastasis were tested as surrogate endpoints for prostate cancer-specific survival at 10 years by use of Prentice's four criteria. All statistical tests were two-sided. At 3 years, 1364 patients were alive and contributed data for analysis. Both distant metastasis and general clinical treatment failure at 3 years were consistent with all four of Prentice's criteria for being surrogate endpoints for prostate cancer-specific survival at 10 years. At 5 years, 1178 patients were alive and contributed data for analysis. Although prostate cancer-specific survival was not statistically significantly different between treatment arms at 5 years (P = .08), both endpoints were consistent with Prentice's remaining criteria. Distant metastasis and general clinical treatment failure at 3 years may be candidate surrogate endpoints for prostate cancer-specific survival at 10 years. These endpoints, however, must be validated in other datasets.

Uncertainty in the Bayesian meta-analysis of normally distributed surrogate endpoints

PubMed Central

Thompson, John R; Spata, Enti; Abrams, Keith R

2015-01-01

We investigate the effect of the choice of parameterisation of meta-analytic models and related uncertainty on the validation of surrogate endpoints. Different meta-analytical approaches take into account different levels of uncertainty which may impact on the accuracy of the predictions of treatment effect on the target outcome from the treatment effect on a surrogate endpoint obtained from these models. A range of Bayesian as well as frequentist meta-analytical methods are implemented using illustrative examples in relapsing–remitting multiple sclerosis, where the treatment effect on disability worsening is the primary outcome of interest in healthcare evaluation, while the effect on relapse rate is considered as a potential surrogate to the effect on disability progression, and in gastric cancer, where the disease-free survival has been shown to be a good surrogate endpoint to the overall survival. Sensitivity analysis was carried out to assess the impact of distributional assumptions on the predictions. Also, sensitivity to modelling assumptions and performance of the models were investigated by simulation. Although different methods can predict mean true outcome almost equally well, inclusion of uncertainty around all relevant parameters of the model may lead to less certain and hence more conservative predictions. When investigating endpoints as candidate surrogate outcomes, a careful choice of the meta-analytical approach has to be made. Models underestimating the uncertainty of available evidence may lead to overoptimistic predictions which can then have an effect on decisions made based on such predictions. PMID:26271918

Uncertainty in the Bayesian meta-analysis of normally distributed surrogate endpoints.

PubMed

Bujkiewicz, Sylwia; Thompson, John R; Spata, Enti; Abrams, Keith R

2017-10-01

We investigate the effect of the choice of parameterisation of meta-analytic models and related uncertainty on the validation of surrogate endpoints. Different meta-analytical approaches take into account different levels of uncertainty which may impact on the accuracy of the predictions of treatment effect on the target outcome from the treatment effect on a surrogate endpoint obtained from these models. A range of Bayesian as well as frequentist meta-analytical methods are implemented using illustrative examples in relapsing-remitting multiple sclerosis, where the treatment effect on disability worsening is the primary outcome of interest in healthcare evaluation, while the effect on relapse rate is considered as a potential surrogate to the effect on disability progression, and in gastric cancer, where the disease-free survival has been shown to be a good surrogate endpoint to the overall survival. Sensitivity analysis was carried out to assess the impact of distributional assumptions on the predictions. Also, sensitivity to modelling assumptions and performance of the models were investigated by simulation. Although different methods can predict mean true outcome almost equally well, inclusion of uncertainty around all relevant parameters of the model may lead to less certain and hence more conservative predictions. When investigating endpoints as candidate surrogate outcomes, a careful choice of the meta-analytical approach has to be made. Models underestimating the uncertainty of available evidence may lead to overoptimistic predictions which can then have an effect on decisions made based on such predictions.

Identification of surrogate endpoints in patients with locoregionally advanced nasopharyngeal carcinoma receiving neoadjuvant chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone.

PubMed

Chen, Yu-Pei; Zhang, Wen-Na; Tang, Ling-Long; Mao, Yan-Ping; Liu, Xu; Chen, Lei; Zhou, Guan-Qun; Mai, Hai-Qiang; Shao, Jian-Yong; Jia, Wei-Hua; Kang, Tie-Bang; Zeng, Mu-Sheng; Sun, Ying; Ma, Jun

2015-11-24

In the era of intensity-modulated radiotherapy (IMRT), the efficacy of additional neoadjuvant chemotherapy (NACT) to concurrent chemoradiotherapy (CCRT) in locoregionally advanced nasopharyngeal carcinoma (NPC) is currently being investigated in ongoing trials. Overall survival (OS) is the gold standard endpoint in NPC trials. We performed this analysis to identify surrogate endpoints for OS, which could shorten follow-up duration and speed up assessment of treatment effects. We retrospectively analysed 208 matched-pair patients with locoregionally advanced NPC receiving NACT+CCRT or CCRT. Progression-free survival (PFS), failure-free survival (FFS), distant failure-free survival (D-FFS) and locoregional failure-free survival (LR-FFS) at 2 and 3 years were assessed as surrogates for 5-year OS according to Prentice's criteria. The strength of the associations were assessed using Spearman's rank correlation coefficient. No significant differences were observed between treatment arms for any surrogate endpoint at 2 years, which rejected Prentice's second criterion. In contrast, 3-year LR-FFS, PFS, FFS and D-FFS were consistent with all four of Prentice's criteria; the rank correlation coefficient (0.730) between 3-year PFS and 5-year OS was highest. 3-year PFS, FFS and D-FFS could be valid surrogate endpoints for 5-year OS; 3-year PFS may be the most accurate.

Risk estimates for persistent high-risk human papillomavirus infections as surrogate endpoints of progressive cervical disease critically depend on reference category: analysis of the combined prospective cohort of the New Independent States of the Former Soviet Union and Latin American Screening studies.

PubMed

Syrjänen, K; Shabalova, I; Naud, P; Kozachenko, V; Derchain, S; Zakharchenko, S; Roteli-Martins, C; Nerovjna, R; Longatto-Filho, A; Kljukina, L; Tatti, S; Branovskaja, M; Hammes, L S; Branca, M; Grunjberga, V; Eržen, M; Juschenko, A; Costa, S; Sarian, L; Podistov, J; Syrjänen, S

2011-06-01

To make feasible future clinical trials with new-generation human papillomavirus (HPV) vaccines, novel virological surrogate endpoints of progressive disease have been proposed, including high-risk HPV (HR-HPV) persistence for six months (6M+) or 12 months (12M+). The risk estimates (relative risks [RRs]) of these 'virological endpoints' are influenced by several variables, not yet validated adequately. We compared the impact of three referent groups: (i) HPV-negative, (ii) HPV-transient, (iii) HPV-mixed outcome on the risk estimates for 6M+ or 12M+ HR-HPV persistence as predictors of progressive disease. Generalized estimating equation models were used to estimate the strength of 6M+ and 12M+ HR-HPV persistence with disease progression to squamous intraepithelial lesions (SILs), cervical intraepithelial neoplasia (CIN) grade 1+, CIN2+, CIN/SIL endpoints, comparing three optional reference categories (i)-(iii) in a prospective sub-cohort of 1865 women from the combined New Independent States of the Former Soviet Union (NIS) and Latin American Screening (LAMS) studies cohort (n = 15,301). The RRs of these viral endpoints as predictors of progressive disease are affected by the length of viral persistence (6M+ or 12M+) and the surrogate endpoint (SIL, CIN1, CIN2, CIN/SIL). Most dramatic is the effect of the referent group used in risk estimates, with the HPV-negative referent group giving the highest and most consistent RRs for both 6M+ and 12M+ viral persistence, irrespective of which surrogate is used. In addition to deciding on whether to use 6M+ or 12M+ persistence criteria, and cytological, histological or combined surrogate endpoints, one should adopt the HPV-negative referent group as the gold standard in all future studies using viral persistence as the surrogate endpoint of progressive disease.

The current role and limitations of surrogate endpoints in advanced prostate cancer.

PubMed

Gomella, Leonard G; Oliver Sartor, A

2014-01-01

The identification of appropriate surrogate endpoints for evaluating cancer therapeutics has been of ongoing interest across various tumor types. Metastatic castrate-resistant prostate cancer (mCRPC) has been a particularly challenging area. As more targeted and novel therapies are being developed in this disease space, an urgent need exists to identify surrogate endpoints in mCRPC. The ability to discern patient benefit in the absence of patient death or other complications would facilitate both drug development and more appropriate patient care. We reviewed the available literature and guidelines used in the development and approval of recent agents for mCRPC. The majority of regulatory approvals of new medications have relied on overall survival (OS) or prevention of complications such as skeletal related events (SRE's). Progression-free survival measures, such as bone scans, computed tomography scans, and prostate-specific antigen related changes, have not been validated nor uniformly accepted as outcome surrogates. All of the successful recent pivotal Phase III trials designed to achieve regulatory approval in mCRPC have used either OS or SRE's as the primary endpoint. There are significant problematic issues that exist associated with defining and implementing surrogate markers in mCRPC beyond survival and complications. Suggestions are made as to how the current situation might be improved. Copyright © 2014 Elsevier Inc. All rights reserved.

Surrogate endpoints for overall survival in combined chemotherapy and radiotherapy trials in nasopharyngeal carcinoma: Meta-analysis of randomised controlled trials.

PubMed

Chen, Yu-Pei; Sun, Ying; Chen, Lei; Mao, Yan-Ping; Tang, Ling-Long; Li, Wen-Fei; Liu, Xu; Zhang, Wen-Na; Zhou, Guan-Qun; Guo, Rui; Lin, Ai-Hua; Ma, Jun

2015-08-01

We used a literature-based meta-analysis to assess whether failure-free survival (FFS) or progression-free survival (PFS) could be reliable surrogate endpoints for overall survival (OS) in trials of combined chemotherapy and radiotherapy for nasopharyngeal carcinoma (NPC). We identified randomised trials that evaluated combined chemoradiotherapy strategies, and reported FFS or PFS and OS in NPC. We analysed the treatment effects on FFS or PFS, and OS. We used the coefficient of determination (R(2)), and the surrogate threshold effect (STE) to assess the trial-level correlation. Twenty-one trials (5212 patients), with sixteen treatment-control comparisons for FFS, and nine for PFS, were analysed. FFS was strongly correlated with OS (R(2)=0.88, STE=0.84), as was PFS (R(2)=0.90, STE=0.88). Moreover, FFS and PFS at 3 years were still strongly correlated with 5-year OS (R(2)=0.80, STE=0.83; R(2)=0.85, STE=0.84). Both FFS and PFS could be valid surrogate endpoints for OS in trials of combined chemotherapy and radiotherapy for NPC; PFS may be a more acceptable surrogate endpoint compared with FFS. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Challenge of surrogate endpoints.

PubMed

Furgerson, James L; Hannah, William N; Thompson, Jennifer C

2012-03-01

Surrogate endpoints are biomarkers that are intended to substitute for clinical endpoints. They have been used to find novel therapeutic targets, improve the statistical power and shorten the duration of clinical trials, and control the cost of conducting research studies. The more generalized use of surrogate endpoints in clinical decision making can be hazardous and should be undertaken with great caution. This article reviews prior work with surrogate endpoints and highlights caveats and lessons learned from studies using surrogate endpoints.

Surrogacy assessment using principal stratification with multivariate normal and Gaussian copula models.

PubMed

Taylor, Jeremy M G; Conlon, Anna S C; Elliott, Michael R

2015-08-01

The validation of intermediate markers as surrogate markers (S) for the true outcome of interest (T) in clinical trials offers the possibility for trials to be run more quickly and cheaply by using the surrogate endpoint in place of the true endpoint. Working within a principal stratification framework, we propose causal quantities to evaluate surrogacy using a Gaussian copula model for an ordinal surrogate and time-to-event final outcome. The methods are applied to data from four colorectal cancer clinical trials, where S is tumor response and T is overall survival. For the Gaussian copula model, a Bayesian estimation strategy is used and, as some parameters are not identifiable from the data, we explore the use of informative priors that are consistent with reasonable assumptions in the surrogate marker setting to aid in estimation. While there is some bias in the estimation of the surrogacy quantities of interest, the estimation procedure does reasonably well at distinguishing between poor and good surrogate markers. Some of the parameters of the proposed model are not identifiable from the data, and therefore, assumptions must be made in order to aid in their estimation. The proposed quantities can be used in combination to provide evidence about the validity of S as a surrogate marker for T. © The Author(s) 2014.

When Progressive Disease Does Not Mean Treatment Failure: Reconsidering the Criteria for Progression

PubMed Central

2012-01-01

Although progression-based endpoints, such as progression-free survival, are often key clinical trial endpoints for anticancer agents, the clinical meaning of “objective progression” is much less certain. As scrutiny of progression-based endpoints in clinical trials increases, it should be remembered that the Response Evaluation Criteria In Solid Tumors (RECIST) progression criteria were not developed as a surrogate for survival. Now that progression-free survival has come to be an increasingly important trial endpoint, the criteria that define progression deserve critical evaluation to determine whether alternate definitions of progression might facilitate the development of stronger surrogate endpoints and more meaningful trial results. In this commentary, we review the genesis of the criteria for progression, highlight recent data that question their value as a marker of treatment failure, and advocate for several research strategies that could lay the groundwork for a clinically validated definition of disease progression in solid tumor oncology. PMID:22927506

Tumor response and progression-free survival as potential surrogate endpoints for overall survival in extensive stage small-cell lung cancer: findings on the basis of North Central Cancer Treatment Group trials.

PubMed

Foster, Nathan R; Qi, Yingwei; Shi, Qian; Krook, James E; Kugler, John W; Jett, James R; Molina, Julian R; Schild, Steven E; Adjei, Alex A; Mandrekar, Sumithra J

2011-03-15

The authors investigated the putative surrogate endpoints of best response, complete response (CR), confirmed response, and progression-free survival (PFS) for associations with overall survival (OS), and as possible surrogate endpoints for OS. Individual patient data from 870 untreated extensive stage small-cell lung cancer patients participating in 6 single-arm (274 patients) and 3 randomized trials (596 patients) were pooled. Patient-level associations between putative surrogate endpoints and OS were assessed by Cox models using landmark analyses. Trial-level surrogacy of putative surrogate endpoints were assessed by the association of treatment effects on OS and individual putative surrogate endpoints. Trial-level surrogacy measures included: R(2) from weighted least squares regression model, Spearman correlation coefficient, and R(2) from bivariate survival model (Copula R(2) ). Median OS and PFS were 9.6 (95% confidence interval [CI], 9.1-10.0) and 5.5 (95% CI, 5.2-5.9) months, respectively; best response, CR, and confirmed response rates were 44%, 22%, and 34%, respectively. Patient-level associations showed that PFS status at 4 months was a strong predictor of subsequent survival (hazard ratio [HR], 0.42; 95% CI, 0.35-0.51; concordance index 0.63; P < .01), with 6-month PFS being the strongest (HR, 0.41; 95% CI, 0.35-0.49; concordance index, 0.66, P < .01). At the trial level, PFS showed the highest level of surrogacy for OS (weighted least squares R(2) = 0.79; Copula R(2) = 0.80), explaining 79% of the variance in OS. Tumor response endpoints showed lower surrogacy levels (weighted least squares R(2) ≤0.48). PFS was strongly associated with OS at both the patient and trial levels. PFS also shows promise as a potential surrogate for OS, but further validation is needed using data from a larger number of randomized phase 3 trials. Copyright © 2010 American Cancer Society.

21 CFR 601.41 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 7 2014-04-01 2014-04-01 false Approval based on a surrogate endpoint or on an... Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or... uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical...

21 CFR 601.41 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 7 2013-04-01 2013-04-01 false Approval based on a surrogate endpoint or on an... Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or... uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical...

21 CFR 601.41 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 7 2012-04-01 2012-04-01 false Approval based on a surrogate endpoint or on an... Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or... uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical...

21 CFR 601.41 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 7 2011-04-01 2010-04-01 true Approval based on a surrogate endpoint or on an... Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or... uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical...

21 CFR 601.41 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 7 2010-04-01 2010-04-01 false Approval based on a surrogate endpoint or on an... Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or... uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical...

Trends in Utilization of Surrogate Endpoints in Contemporary Cardiovascular Clinical Trials.

PubMed

Patel, Ravi B; Vaduganathan, Muthiah; Samman-Tahhan, Ayman; Kalogeropoulos, Andreas P; Georgiopoulou, Vasiliki V; Fonarow, Gregg C; Gheorghiade, Mihai; Butler, Javed

2016-06-01

Surrogate endpoints facilitate trial efficiency but are variably linked to clinical outcomes, and limited data are available exploring their utilization in cardiovascular clinical trials over time. We abstracted data regarding primary clinical, intermediate, and surrogate endpoints from all phase II to IV cardiovascular clinical trials from 2001 to 2012 published in the 8 highest Web of Science impact factor journals. Two investigators independently classified the type of primary endpoint. Of the 1,224 trials evaluated, 677 (55.3%) primary endpoints were clinical, 165 (13.5%) intermediate, and 382 (31.2%) surrogate. The relative proportions of these endpoints remained constant over time (p = 0.98). Trials using surrogate endpoints were smaller (187 vs 1,028 patients) and enrolled patients more expeditiously (1.4 vs 0.9 patients per site per month) compared with trials using clinical endpoints (p <0.001 for both comparisons). Surrogate endpoint trials were independently more likely to meet their primary endpoint compared to trials with clinical endpoints (adjusted odds ratio 1.56, 95% CI 1.05 to 2.34; p = 0.03). Rates of positive results in clinical endpoint trials have decreased over time from 66.1% in 2001 to 2003 to 47.2% in 2010 to 2012 (p = 0.001), whereas these rates have remained stable over the same period for surrogate (72.0% to 69.3%, p = 0.27) and intermediate endpoints (74.4% to 71.4%, p = 0.98). In conclusion, approximately a third of contemporary cardiovascular trials use surrogate endpoints. These trials are completed more expeditiously and are more likely to meet their primary outcomes. The overall scientific contribution of these surrogate endpoint trials requires further attention given their variable association with definitive outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

Trial endpoints for drug approval in oncology: Chemoprevention.

PubMed

Beitz, J

2001-04-01

As with other drugs, new drug applications for marketing approval of chemopreventive drugs must include data from adequate and well-controlled clinical trials that demonstrate effectiveness and safety for the intended use. This article summarizes the regulatory requirements for traditional marketing approval, as well as for approval under the accelerated approval regulations. Unlike traditional approval, accelerated approval is based on a surrogate endpoint that is reasonably likely to predict clinical benefit. Discussions with the Food and Drug Administration (FDA) regarding the validity of trial endpoints that may serve as surrogates for clinical benefit for accelerated approval should take place as early as possible in drug development. Meetings with the FDA to discuss these issues may be requested throughout the clinical development of a new drug.

Statistical evaluation of surrogate endpoints with examples from cancer clinical trials.

PubMed

Buyse, Marc; Molenberghs, Geert; Paoletti, Xavier; Oba, Koji; Alonso, Ariel; Van der Elst, Wim; Burzykowski, Tomasz

2016-01-01

A surrogate endpoint is intended to replace a clinical endpoint for the evaluation of new treatments when it can be measured more cheaply, more conveniently, more frequently, or earlier than that clinical endpoint. A surrogate endpoint is expected to predict clinical benefit, harm, or lack of these. Besides the biological plausibility of a surrogate, a quantitative assessment of the strength of evidence for surrogacy requires the demonstration of the prognostic value of the surrogate for the clinical outcome, and evidence that treatment effects on the surrogate reliably predict treatment effects on the clinical outcome. We focus on these two conditions, and outline the statistical approaches that have been proposed to assess the extent to which these conditions are fulfilled. When data are available from a single trial, one can assess the "individual level association" between the surrogate and the true endpoint. When data are available from several trials, one can additionally assess the "trial level association" between the treatment effect on the surrogate and the treatment effect on the true endpoint. In the latter case, the "surrogate threshold effect" can be estimated as the minimum effect on the surrogate endpoint that predicts a statistically significant effect on the clinical endpoint. All these concepts are discussed in the context of randomized clinical trials in oncology, and illustrated with two meta-analyses in gastric cancer. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

21 CFR 314.510 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Approval based on a surrogate endpoint or on an... Serious or Life-Threatening Illnesses § 314.510 Approval based on a surrogate endpoint or on an effect on... the drug product has an effect on a surrogate endpoint that is reasonably likely, based on...

21 CFR 314.510 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Approval based on a surrogate endpoint or on an... Serious or Life-Threatening Illnesses § 314.510 Approval based on a surrogate endpoint or on an effect on... the drug product has an effect on a surrogate endpoint that is reasonably likely, based on...

21 CFR 314.510 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Approval based on a surrogate endpoint or on an... Serious or Life-Threatening Illnesses § 314.510 Approval based on a surrogate endpoint or on an effect on... the drug product has an effect on a surrogate endpoint that is reasonably likely, based on...

21 CFR 314.510 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Approval based on a surrogate endpoint or on an... Serious or Life-Threatening Illnesses § 314.510 Approval based on a surrogate endpoint or on an effect on... the drug product has an effect on a surrogate endpoint that is reasonably likely, based on...

Surrogate marker evaluation from an information theory perspective.

PubMed

Alonso, Ariel; Molenberghs, Geert

2007-03-01

The last 20 years have seen lots of work in the area of surrogate marker validation, partly devoted to frame the evaluation in a multitrial framework, leading to definitions in terms of the quality of trial- and individual-level association between a potential surrogate and a true endpoint (Buyse et al., 2000, Biostatistics 1, 49-67). A drawback is that different settings have led to different measures at the individual level. Here, we use information theory to create a unified framework, leading to a definition of surrogacy with an intuitive interpretation, offering interpretational advantages, and applicable in a wide range of situations. Our method provides a better insight into the chances of finding a good surrogate endpoint in a given situation. We further show that some of the previous proposals follow as special cases of our method. We illustrate our methodology using data from a clinical study in psychiatry.

Exploring the relationship between the causal-inference and meta-analytic paradigms for the evaluation of surrogate endpoints.

PubMed

Van der Elst, Wim; Molenberghs, Geert; Alonso, Ariel

2016-04-15

Nowadays, two main frameworks for the evaluation of surrogate endpoints, based on causal-inference and meta-analysis, dominate the scene. Earlier work showed that the metrics of surrogacy introduced in both paradigms are related, although in a complex way that is difficult to study analytically. In the present work, this relationship is further examined using simulations and the analysis of a case study. The results indicate that the extent to which both paradigms lead to similar conclusions regarding the validity of the surrogate, depends on a complex interplay between multiple factors like the ratio of the between and within trial variability and the unidentifiable correlations between the potential outcomes. All the analyses were carried out using the newly developed R package Surrogate, which is freely available via CRAN. Copyright © 2015 John Wiley & Sons, Ltd.

A Poisson approach to the validation of failure time surrogate endpoints in individual patient data meta-analyses.

PubMed

Rotolo, Federico; Paoletti, Xavier; Burzykowski, Tomasz; Buyse, Marc; Michiels, Stefan

2017-01-01

Surrogate endpoints are often used in clinical trials instead of well-established hard endpoints for practical convenience. The meta-analytic approach relies on two measures of surrogacy: one at the individual level and one at the trial level. In the survival data setting, a two-step model based on copulas is commonly used. We present a new approach which employs a bivariate survival model with an individual random effect shared between the two endpoints and correlated treatment-by-trial interactions. We fit this model using auxiliary mixed Poisson models. We study via simulations the operating characteristics of this mixed Poisson approach as compared to the two-step copula approach. We illustrate the application of the methods on two individual patient data meta-analyses in gastric cancer, in the advanced setting (4069 patients from 20 randomized trials) and in the adjuvant setting (3288 patients from 14 randomized trials).

Evaluating principal surrogate endpoints with time-to-event data accounting for time-varying treatment efficacy

PubMed Central

Gabriel, Erin E.; Gilbert, Peter B.

2014-01-01

Principal surrogate (PS) endpoints are relatively inexpensive and easy to measure study outcomes that can be used to reliably predict treatment effects on clinical endpoints of interest. Few statistical methods for assessing the validity of potential PSs utilize time-to-event clinical endpoint information and to our knowledge none allow for the characterization of time-varying treatment effects. We introduce the time-dependent and surrogate-dependent treatment efficacy curve, \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{upgreek} \\usepackage{mathrsfs} \\setlength{\\oddsidemargin}{-69pt} \\begin{document} }{}${\\mathrm {TE}}(t|s)$\\end{document}, and a new augmented trial design for assessing the quality of a biomarker as a PS. We propose a novel Weibull model and an estimated maximum likelihood method for estimation of the \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{upgreek} \\usepackage{mathrsfs} \\setlength{\\oddsidemargin}{-69pt} \\begin{document} }{}${\\mathrm {TE}}(t|s)$\\end{document} curve. We describe the operating characteristics of our methods via simulations. We analyze data from the Diabetes Control and Complications Trial, in which we find evidence of a biomarker with value as a PS. PMID:24337534

Surrogate endpoints for overall survival in advanced non-small-cell lung cancer patients with mutations of the epidermal growth factor receptor gene.

PubMed

Yoshino, Reiko; Imai, Hisao; Mori, Keita; Takei, Kousuke; Tomizawa, Mai; Kaira, Kyoichi; Yoshii, Akihiro; Tomizawa, Yoshio; Saito, Ryusei; Yamada, Masanobu

2014-09-01

Subsequent therapies confound the ability to discern the effect of first-line chemotherapy on overall survival (OS). We investigated whether progression-free survival (PFS), post-progression survival (PPS) and tumor response were valid surrogate endpoints for OS following first-line chemotherapy in individual patients with advanced non-small-cell lung cancer (NSCLC) harboring sensitive epidermal growth factor receptor gene mutations. We retrospectively analyzed 35 patients with advanced NSCLC treated with first-line gefitinib. The associations of PFS, PPS and tumor response with OS were analyzed. PPS was found to be strongly correlated with OS, unlike PFS and tumor shrinkage. The factors significantly associated with PPS were performance status (PS) after first-line treatment, best response to second-line treatment and number of regimens used after disease progression. PPS may be a surrogate for OS in this patient population and further therapy after disease progression following first-line chemotherapy may significantly affect OS. However, a larger study is required to validate these results.

An information-theoretic approach for the evaluation of surrogate endpoints based on causal inference.

PubMed

Alonso, Ariel; Van der Elst, Wim; Molenberghs, Geert; Buyse, Marc; Burzykowski, Tomasz

2016-09-01

In this work a new metric of surrogacy, the so-called individual causal association (ICA), is introduced using information-theoretic concepts and a causal inference model for a binary surrogate and true endpoint. The ICA has a simple and appealing interpretation in terms of uncertainty reduction and, in some scenarios, it seems to provide a more coherent assessment of the validity of a surrogate than existing measures. The identifiability issues are tackled using a two-step procedure. In the first step, the region of the parametric space of the distribution of the potential outcomes, compatible with the data at hand, is geometrically characterized. Further, in a second step, a Monte Carlo approach is proposed to study the behavior of the ICA on the previous region. The method is illustrated using data from the Collaborative Initial Glaucoma Treatment Study. A newly developed and user-friendly R package Surrogate is provided to carry out the evaluation exercise. © 2016, The International Biometric Society.

21 CFR 314.510 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity. 314.510 Section 314.510 Food... Serious or Life-Threatening Illnesses § 314.510 Approval based on a surrogate endpoint or on an effect on...

Surrogate outcomes are associated with low methodological quality of studies of rheumatoid arthritis treated with antitumour necrosis factor agents: a systematic review.

PubMed

Nobre, Moacyr Roberto Cuce; da Costa, Frnanda Marques

2012-02-01

Surrogate endpoints may be used as substitutes for, but often do not predict clinically relevant events. Objective To assess the methodological quality of articles that present their conclusions based on clinically relevant or surrogate outcomes in a systematic review of randomised trials and cohort studies of patients with rheumatoid arthritis treated with antitumour necrosis factor (TNF) agents. PubMed, Embase and Cochrane databases were searched. The Jadad score, the percentage of Consolidated Standards Of Reporting Trials (CONSORT) statement items adequately reported and levels-of-evidence (Center for Evidence-based Medicine, Oxford) were used in a descriptive synthesis. Among 88 articles appraised, 27 had surrogate endpoints, mainly radiographic, and 44 were duplicate publications; 74% of articles with surrogate and 39% of articles with clinical endpoints (p=0.006). Fewer articles with surrogate endpoints represented a high level of evidence (Level 1b, 33% vs 62%, p=0.037) and the mean percentage of CONSORT statement items met was also lower for articles with surrogate endpoints (62.5 vs 70.7, p=0.026). Although fewer articles with surrogate endpoints were randomised trials (63% vs 74%, p=0.307) and articles with surrogate endpoints had lower Jadad scores (3.0 vs 3.2, p=0.538), these differences were not statistically significant. Studies of anti-TNF agents that report surrogate outcomes are of lesser methodological quality. As such, inclusion of such studies in evidence syntheses may bias results.

[Immunological surrogate endpoints to evaluate vaccine efficacy].

PubMed

Jin, Pengfei; Li, Jingxin; Zhou, Yang; Zhu, Fengcai

2015-12-01

An immunological surrogate endpoints is a vaccine-induced immune response (either humoral or cellular immune) that predicts protection against clinical endpoints (infection or disease), and can be used to evaluate vaccine efficacy in clinical vaccine trials. Compared with field efficacy trials observing clinical endpoints, immunological vaccine trials could reduce the sample size or shorten the duration of a trial, which promote the license and development of new candidate vaccines. For these reasons, establishing immunological surrogate endpoints is one of 14 Grand Challenges of Global Health of the National Institutes of Health (NIH) and the Bill and Melinda Gates Foundation. From two parts of definition and statistical methods for evaluation of surrogate endpoints, this review provides a more comprehensive description.

The Role of Surrogate Endpoints in the Evaluation of Efficacy and Safety of Therapeutic Interventions in Diabetes Mellitus

PubMed Central

Wieczorek, Aleksandra; Rys, Przemyslaw; Skrzekowska-Baran, Iwona; Malecki, Maciej

2008-01-01

In this paper, we examine the concept of surrogate endpoints (i.e. substitute outcome measures) and review their use in clinical trials involving therapies for diabetes mellitus using the example of metformin. Trials such as DCCT and UKPDS, in which patient-important endpoints were evaluated, are relatively rare in diabetology. Clinical decisions, therefore, are often based on evidence obtained using surrogate outcomes, usually fasting or postprandial glycemia or glycated hemoglobin level. In contrast to patient-important endpoints, surrogates do not describe direct clinical benefit to the patient. However, a proven association between a surrogate and patient-important endpoint is essential to draw appropriate therapeutic conclusions. In the process of new drug development, the duration of follow-up, sample size and methodology of the studies initially available are often inadequate to demonstrate the effect of the intervention on patient-important endpoints. Evidence concerning the effect of an intervention on surrogate outcomes usually comes first, followed only later by reports describing its influence on patient-important endpoints. Metformin may serve as an example in several ways. The first publications reported beneficial effects on glycemic control and body weight. Outcomes from the subsequent UKPDS study suggested the patient-important efficacy of metformin measured as a reduction in mortality and a decrease in the incidence of diabetic complications, including myocardial infarction. This reasoning process worked for some but not all strategies. It is particularly questionable whether a change in surrogate endpoint was associated with a potential deterioration in patient-important outcomes. Defining the general relationship between surrogates widely used as measures of metabolic control and patient-important endpoints remains an important challenge in contemporary diabetology. PMID:19099084

The role of surrogate endpoints in the evaluation of efficacy and safety of therapeutic interventions in diabetes mellitus.

PubMed

Wieczorek, Aleksandra; Rys, Przemyslaw; Skrzekowska-Baran, Iwona; Malecki, Maciej

2008-01-01

In this paper, we examine the concept of surrogate endpoints (i.e. substitute outcome measures) and review their use in clinical trials involving therapies for diabetes mellitus using the example of metformin. Trials such as DCCT and UKPDS, in which patient-important endpoints were evaluated, are relatively rare in diabetology. Clinical decisions, therefore, are often based on evidence obtained using surrogate outcomes, usually fasting or postprandial glycemia or glycated hemoglobin level. In contrast to patient-important endpoints, surrogates do not describe direct clinical benefit to the patient. However, a proven association between a surrogate and patient-important endpoint is essential to draw appropriate therapeutic conclusions. In the process of new drug development, the duration of follow-up, sample size and methodology of the studies initially available are often inadequate to demonstrate the effect of the intervention on patient-important endpoints. Evidence concerning the effect of an intervention on surrogate outcomes usually comes first, followed only later by reports describing its influence on patient-important endpoints. Metformin may serve as an example in several ways. The first publications reported beneficial effects on glycemic control and body weight. Outcomes from the subsequent UKPDS study suggested the patient-important efficacy of metformin measured as a reduction in mortality and a decrease in the incidence of diabetic complications, including myocardial infarction. This reasoning process worked for some but not all strategies. It is particularly questionable whether a change in surrogate endpoint was associated with a potential deterioration in patient-important outcomes. Defining the general relationship between surrogates widely used as measures of metabolic control and patient-important endpoints remains an important challenge in contemporary diabetology.

Ultrasound and radiology surrogate endpoints in pharmacological studies.

PubMed

Agewall, S; DeGroot, E; Marcos-Alberca, P; Zamorano, J L; Barrero, A A; Badano, L P; Perrone-Filardi, P

2012-09-01

Cardiovascular studies investigating therapeutic intervention with clinical endpoints are costly due to the need for considerable duration and large number of patients, or both. Therefore, for evaluation of novel cardiovascular drug efficacy, surrogate endpoints are used. Cardiovascular imaging endpoints have proven their worth. Sometimes the relevance of imaging is questioned and other methods are suggested instead. There is also some confusion about the strengths of imaging endpoints. The aim of the present paper is to review ultrasound and radiology imaging techniques as surrogate endpoints in pharmacological trials. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

The role of imperfect surrogate endpoint information in drug approval and reimbursement decisions.

PubMed

Bognar, Katalin; Romley, John A; Bae, Jay P; Murray, James; Chou, Jacquelyn W; Lakdawalla, Darius N

2017-01-01

Approval of new drugs is increasingly reliant on "surrogate endpoints," which correlate with but imperfectly predict clinical benefits. Proponents argue surrogate endpoints allow for faster approval, but critics charge they provide inadequate evidence. We develop an economic framework that addresses the value of improvement in the predictive power, or "quality," of surrogate endpoints, and clarifies how quality can influence decisions by regulators, payers, and manufacturers. For example, the framework shows how lower-quality surrogates lead to greater misalignment of incentives between payers and regulators, resulting in more drugs that are approved for use but not covered by payers. Efficient price-negotiation in the marketplace can help align payer incentives for granting access based on surrogates. Higher-quality surrogates increase manufacturer profits and social surplus from early access to new drugs. Since the return on better quality is shared between manufacturers and payers, private incentives to invest in higher-quality surrogates are inefficiently low. Copyright © 2016 The Author(s). Published by Elsevier B.V. All rights reserved.

Selecting surrogate endpoints for estimating pesticide effects on avian reproductive success.

PubMed

Bennett, Richard S; Etterson, Matthew A

2013-10-01

A Markov chain nest productivity model (MCnest) has been developed for projecting the effects of a specific pesticide-use scenario on the annual reproductive success of avian species of concern. A critical element in MCnest is the use of surrogate endpoints, defined as measured endpoints from avian toxicity tests that represent specific types of effects possible in field populations at specific phases of a nesting attempt. In this article, we discuss the attributes of surrogate endpoints and provide guidance for selecting surrogates from existing avian laboratory tests as well as other possible sources. We also discuss some of the assumptions and uncertainties related to using surrogate endpoints to represent field effects. The process of explicitly considering how toxicity test results can be used to assess effects in the field helps identify uncertainties and data gaps that could be targeted in higher-tier risk assessments. © 2013 SETAC.

Evaluating Candidate Principal Surrogate Endpoints

PubMed Central

Gilbert, Peter B.; Hudgens, Michael G.

2009-01-01

Summary Frangakis and Rubin (2002, Biometrics 58, 21–29) proposed a new definition of a surrogate endpoint (a “principal” surrogate) based on causal effects. We introduce an estimand for evaluating a principal surrogate, the causal effect predictiveness (CEP) surface, which quantifies how well causal treatment effects on the biomarker predict causal treatment effects on the clinical endpoint. Although the CEP surface is not identifiable due to missing potential outcomes, it can be identified by incorporating a baseline covariate(s) that predicts the biomarker. Given case–cohort sampling of such a baseline predictor and the biomarker in a large blinded randomized clinical trial, we develop an estimated likelihood method for estimating the CEP surface. This estimation assesses the “surrogate value” of the biomarker for reliably predicting clinical treatment effects for the same or similar setting as the trial. A CEP surface plot provides a way to compare the surrogate value of multiple biomarkers. The approach is illustrated by the problem of assessing an immune response to a vaccine as a surrogate endpoint for infection. PMID:18363776

Surrogate endpoints and competing risk of death in cardiac arrest research.

PubMed

McCredie, Victoria A; Scales, Damon C

2016-06-29

We urgently need new therapies to improve outcomes after cardiac arrest. Initial studies typically target surrogate endpoints, and these studies help to inform subsequent larger trials that are powered to measure more patient-orientated clinical outcomes such as survival. The competing risk of death and premature assessment of neurological prognosis pose significant challenges to measuring these surrogate endpoints after cardiac arrest.

Biomarkers and surrogate endpoints in kidney disease.

PubMed

Hartung, Erum A

2016-03-01

Kidney disease and its related comorbidities impose a large public health burden. Despite this, the number of clinical trials in nephrology lags behind many other fields. An important factor contributing to the relatively slow pace of nephrology trials is that existing clinical endpoints have significant limitations. "Hard" endpoints for chronic kidney disease, such as progression to end-stage renal disease, may not be reached for decades. Traditional biomarkers, such as serum creatinine in acute kidney injury, may lack sensitivity and predictive value. Finding new biomarkers to serve as surrogate endpoints is therefore an important priority in kidney disease research and may help to accelerate nephrology clinical trials. In this paper, I first review key concepts related to the selection of clinical trial endpoints and discuss statistical and regulatory considerations related to the evaluation of biomarkers as surrogate endpoints. This is followed by a discussion of the challenges and opportunities in developing novel biomarkers and surrogate endpoints in three major areas of nephrology research: acute kidney injury, chronic kidney disease, and autosomal dominant polycystic kidney disease.

Center-Within-Trial Versus Trial-Level Evaluation of Surrogate Endpoints.

PubMed

Renfro, Lindsay A; Shi, Qian; Xue, Yuan; Li, Junlong; Shang, Hongwei; Sargent, Daniel J

2014-10-01

Evaluation of candidate surrogate endpoints using individual patient data from multiple clinical trials is considered the gold standard approach to validate surrogates at both patient and trial levels. However, this approach assumes the availability of patient-level data from a relatively large collection of similar trials, which may not be possible to achieve for a given disease application. One common solution to the problem of too few similar trials involves performing trial-level surrogacy analyses on trial sub-units (e.g., centers within trials), thereby artificially increasing the trial-level sample size for feasibility of the multi-trial analysis. To date, the practical impact of treating trial sub-units (centers) identically to trials in multi-trial surrogacy analyses remains unexplored, and conditions under which this ad hoc solution may in fact be reasonable have not been identified. We perform a simulation study to identify such conditions, and demonstrate practical implications using a multi-trial dataset of patients with early stage colon cancer.

Center-Within-Trial Versus Trial-Level Evaluation of Surrogate Endpoints

PubMed Central

Renfro, Lindsay A.; Shi, Qian; Xue, Yuan; Li, Junlong; Shang, Hongwei; Sargent, Daniel J.

2014-01-01

Evaluation of candidate surrogate endpoints using individual patient data from multiple clinical trials is considered the gold standard approach to validate surrogates at both patient and trial levels. However, this approach assumes the availability of patient-level data from a relatively large collection of similar trials, which may not be possible to achieve for a given disease application. One common solution to the problem of too few similar trials involves performing trial-level surrogacy analyses on trial sub-units (e.g., centers within trials), thereby artificially increasing the trial-level sample size for feasibility of the multi-trial analysis. To date, the practical impact of treating trial sub-units (centers) identically to trials in multi-trial surrogacy analyses remains unexplored, and conditions under which this ad hoc solution may in fact be reasonable have not been identified. We perform a simulation study to identify such conditions, and demonstrate practical implications using a multi-trial dataset of patients with early stage colon cancer. PMID:25061255

An investigation into the two-stage meta-analytic copula modelling approach for evaluating time-to-event surrogate endpoints which comprise of one or more events of interest.

PubMed

Dimier, Natalie; Todd, Susan

2017-09-01

Clinical trials of experimental treatments must be designed with primary endpoints that directly measure clinical benefit for patients. In many disease areas, the recognised gold standard primary endpoint can take many years to mature, leading to challenges in the conduct and quality of clinical studies. There is increasing interest in using shorter-term surrogate endpoints as substitutes for costly long-term clinical trial endpoints; such surrogates need to be selected according to biological plausibility, as well as the ability to reliably predict the unobserved treatment effect on the long-term endpoint. A number of statistical methods to evaluate this prediction have been proposed; this paper uses a simulation study to explore one such method in the context of time-to-event surrogates for a time-to-event true endpoint. This two-stage meta-analytic copula method has been extensively studied for time-to-event surrogate endpoints with one event of interest, but thus far has not been explored for the assessment of surrogates which have multiple events of interest, such as those incorporating information directly from the true clinical endpoint. We assess the sensitivity of the method to various factors including strength of association between endpoints, the quantity of data available, and the effect of censoring. In particular, we consider scenarios where there exist very little data on which to assess surrogacy. Results show that the two-stage meta-analytic copula method performs well under certain circumstances and could be considered useful in practice, but demonstrates limitations that may prevent universal use. Copyright © 2017 John Wiley & Sons, Ltd.

Bayesian meta-analytical methods to incorporate multiple surrogate endpoints in drug development process.

PubMed

Bujkiewicz, Sylwia; Thompson, John R; Riley, Richard D; Abrams, Keith R

2016-03-30

A number of meta-analytical methods have been proposed that aim to evaluate surrogate endpoints. Bivariate meta-analytical methods can be used to predict the treatment effect for the final outcome from the treatment effect estimate measured on the surrogate endpoint while taking into account the uncertainty around the effect estimate for the surrogate endpoint. In this paper, extensions to multivariate models are developed aiming to include multiple surrogate endpoints with the potential benefit of reducing the uncertainty when making predictions. In this Bayesian multivariate meta-analytic framework, the between-study variability is modelled in a formulation of a product of normal univariate distributions. This formulation is particularly convenient for including multiple surrogate endpoints and flexible for modelling the outcomes which can be surrogate endpoints to the final outcome and potentially to one another. Two models are proposed, first, using an unstructured between-study covariance matrix by assuming the treatment effects on all outcomes are correlated and second, using a structured between-study covariance matrix by assuming treatment effects on some of the outcomes are conditionally independent. While the two models are developed for the summary data on a study level, the individual-level association is taken into account by the use of the Prentice's criteria (obtained from individual patient data) to inform the within study correlations in the models. The modelling techniques are investigated using an example in relapsing remitting multiple sclerosis where the disability worsening is the final outcome, while relapse rate and MRI lesions are potential surrogates to the disability progression. © 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

On assessing surrogacy in a single trial setting using a semi-competing risks paradigm

PubMed Central

Ghosh, Debashis

2009-01-01

Summary There has been a recent emphasis on the identification of biomarkers and other biologic measures that may be potentially used as surrogate endpoints in clinical trials. We focus on the setting of data from a single clinical trial. In this paper, we consider a framework in which the surrogate must occur before the true endpoint. This suggests viewing the surrogate and true endpoints as semi-competing risks data; this approach is new to the literature on surrogate endpoints and leads to an asymmetrical treatment of the surrogate and true endpoints. However, such a data structure also conceptually complicates many of the previously considered measures of surrogacy in the literature. We propose novel estimation and inferential procedures for the relative effect and adjusted association quantities proposed by Buyse and Molenberghs (1998, Biometrics, 1014 – 1029). The proposed methodology is illustrated with application to simulated data, as well as to data from a leukemia study. PMID:18759839

Assessment of generalizability, applicability and predictability (GAP) for evaluating external validity in studies of universal family-based prevention of alcohol misuse in young people: systematic methodological review of randomized controlled trials.

PubMed

Fernandez-Hermida, Jose Ramon; Calafat, Amador; Becoña, Elisardo; Tsertsvadze, Alexander; Foxcroft, David R

2012-09-01

To assess external validity characteristics of studies from two Cochrane Systematic Reviews of the effectiveness of universal family-based prevention of alcohol misuse in young people. Two reviewers used an a priori developed external validity rating form and independently assessed three external validity dimensions of generalizability, applicability and predictability (GAP) in randomized controlled trials. The majority (69%) of the included 29 studies were rated 'unclear' on the reporting of sufficient information for judging generalizability from sample to study population. Ten studies (35%) were rated 'unclear' on the reporting of sufficient information for judging applicability to other populations and settings. No study provided an assessment of the validity of the trial end-point measures for subsequent mortality, morbidity, quality of life or other economic or social outcomes. Similarly, no study reported on the validity of surrogate measures using established criteria for assessing surrogate end-points. Studies evaluating the benefits of family-based prevention of alcohol misuse in young people are generally inadequate at reporting information relevant to generalizability of the findings or implications for health or social outcomes. Researchers, study authors, peer reviewers, journal editors and scientific societies should take steps to improve the reporting of information relevant to external validity in prevention trials. © 2012 The Authors. Addiction © 2012 Society for the Study of Addiction.

Surrogate Endpoints in Suicide Research

ERIC Educational Resources Information Center

Wortzel, Hal S.; Gutierrez, Peter M.; Homaifar, Beeta Y.; Breshears, Ryan E.; Harwood, Jeri E.

2010-01-01

Surrogate endpoints frequently substitute for rare outcomes in research. The ability to learn about completed suicides by investigating more readily available and proximate outcomes, such as suicide attempts, has obvious appeal. However, concerns with surrogates from the statistical science perspective exist, and mounting evidence from…

Surrogacy assessment using principal stratification when surrogate and outcome measures are multivariate normal.

PubMed

Conlon, Anna S C; Taylor, Jeremy M G; Elliott, Michael R

2014-04-01

In clinical trials, a surrogate outcome variable (S) can be measured before the outcome of interest (T) and may provide early information regarding the treatment (Z) effect on T. Using the principal surrogacy framework introduced by Frangakis and Rubin (2002. Principal stratification in causal inference. Biometrics 58, 21-29), we consider an approach that has a causal interpretation and develop a Bayesian estimation strategy for surrogate validation when the joint distribution of potential surrogate and outcome measures is multivariate normal. From the joint conditional distribution of the potential outcomes of T, given the potential outcomes of S, we propose surrogacy validation measures from this model. As the model is not fully identifiable from the data, we propose some reasonable prior distributions and assumptions that can be placed on weakly identified parameters to aid in estimation. We explore the relationship between our surrogacy measures and the surrogacy measures proposed by Prentice (1989. Surrogate endpoints in clinical trials: definition and operational criteria. Statistics in Medicine 8, 431-440). The method is applied to data from a macular degeneration study and an ovarian cancer study.

Surrogacy assessment using principal stratification when surrogate and outcome measures are multivariate normal

PubMed Central

Conlon, Anna S. C.; Taylor, Jeremy M. G.; Elliott, Michael R.

2014-01-01

In clinical trials, a surrogate outcome variable (S) can be measured before the outcome of interest (T) and may provide early information regarding the treatment (Z) effect on T. Using the principal surrogacy framework introduced by Frangakis and Rubin (2002. Principal stratification in causal inference. Biometrics 58, 21–29), we consider an approach that has a causal interpretation and develop a Bayesian estimation strategy for surrogate validation when the joint distribution of potential surrogate and outcome measures is multivariate normal. From the joint conditional distribution of the potential outcomes of T, given the potential outcomes of S, we propose surrogacy validation measures from this model. As the model is not fully identifiable from the data, we propose some reasonable prior distributions and assumptions that can be placed on weakly identified parameters to aid in estimation. We explore the relationship between our surrogacy measures and the surrogacy measures proposed by Prentice (1989. Surrogate endpoints in clinical trials: definition and operational criteria. Statistics in Medicine 8, 431–440). The method is applied to data from a macular degeneration study and an ovarian cancer study. PMID:24285772

Pathologic complete response and disease-free survival are not surrogate endpoints for 5-year survival in rectal cancer: an analysis of 22 randomized trials.

PubMed

Petrelli, Fausto; Borgonovo, Karen; Cabiddu, Mary; Ghilardi, Mara; Lonati, Veronica; Barni, Sandro

2017-02-01

We performed a literature-based analysis of randomized clinical trials to assess the pathologic complete response (pCR) (ypT0N0 after neoadjuvant therapy) and 3-year disease-free survival (DFS) as potential surrogate endpoints for 5-year overall survival (OS) in rectal cancer treated with neoadjuvant (chemo)radiotherapy (CT)RT. A systematic literature search of PubMed, EMBASE, the Web of Science, SCOPUS, CINAHL, and the Cochrane Library was performed. Treatment effects on 3-year DFS and 5-year OS were expressed as rates of patients alive (%), and those on pCR as differences in pCR rates (∆ pCR% ). A weighted regression analysis was performed at individual- and trial-level to test the association between treatment effects on surrogate (∆ pCR% and ∆ 3yDFS ) and the main clinical outcome (∆ 5yOS ). Twenty-two trials involving 10,050 patients, were included in the analysis. The individual level surrogacy showed that the pCR% and 3-year DFS were poorly correlated with 5-year OS (R=0.52; 95% CI, 0.31-0.91; P=0.002; and R=0.60; 95% CI, 0.36-1; P=0.002). The trial-level surrogacy analysis confirmed that the two treatment effects on surrogates (∆ pCR% and ∆ 3yDFS ) are not strong surrogates for treatment effects on 5-year OS % (R=0.2; 95% CI, -0.29-0.78; P=0.5 and R=0.64; 95% CI, 0.29-1; P=0.06). These findings were confirmed in neoadjuvant CTRT studies but not in phase III trials were 3-year DFS could still represent a valid surrogate. This analysis does not support the use of pCR and 3-year DFS% as appropriate surrogate endpoints for 5-year OS% in patients with rectal cancer treated with neoadjuvant therapy.

Surrogate marker analysis in cancer clinical trials through time-to-event mediation techniques.

PubMed

Vandenberghe, Sjouke; Duchateau, Luc; Slaets, Leen; Bogaerts, Jan; Vansteelandt, Stijn

2017-01-01

The meta-analytic approach is the gold standard for validation of surrogate markers, but has the drawback of requiring data from several trials. We refine modern mediation analysis techniques for time-to-event endpoints and apply them to investigate whether pathological complete response can be used as a surrogate marker for disease-free survival in the EORTC 10994/BIG 1-00 randomised phase 3 trial in which locally advanced breast cancer patients were randomised to either taxane or anthracycline based neoadjuvant chemotherapy. In the mediation analysis, the treatment effect is decomposed into an indirect effect via pathological complete response and the remaining direct effect. It shows that only 4.2% of the treatment effect on disease-free survival after five years is mediated by the treatment effect on pathological complete response. There is thus no evidence from our analysis that pathological complete response is a valuable surrogate marker to evaluate the effect of taxane versus anthracycline based chemotherapies on progression free survival of locally advanced breast cancer patients. The proposed analysis strategy is broadly applicable to mediation analyses of time-to-event endpoints, is easy to apply and outperforms existing strategies in terms of precision as well as robustness against model misspecification.

Health-related quality-of-life as co-primary endpoint in randomized clinical trials in oncology.

PubMed

Fiteni, Frédéric; Pam, Alhousseiny; Anota, Amélie; Vernerey, Dewi; Paget-Bailly, Sophie; Westeel, Virginie; Bonnetain, Franck

2015-01-01

Overall survival (OS) has been considered as the most relevant primary endpoint but trials using OS often require large numbers of patients and long-term follow-up. Therefore composite endpoints, which are assessed earlier, are frequently used as primary endpoint but suffer from important limitations specially a lack of validation as surrogate of OS. Therefore, Health-related quality of life (HRQoL) could be considered as an outcome to judge efficacy of a treatment. An alternative approach would be to combine HRQoL with composite endpoints as co-primary endpoint to ensure a clinical benefit for patients of a new therapy. The decision rules of such design, the procedure to control the Type I error and the determination of sample size remain questions to debate. Here, we discusses HRQoL as co-primary endpoints in randomized clinical trials in oncology and provide some solutions to promote such design.

surrosurv: An R package for the evaluation of failure time surrogate endpoints in individual patient data meta-analyses of randomized clinical trials.

PubMed

Rotolo, Federico; Paoletti, Xavier; Michiels, Stefan

2018-03-01

Surrogate endpoints are attractive for use in clinical trials instead of well-established endpoints because of practical convenience. To validate a surrogate endpoint, two important measures can be estimated in a meta-analytic context when individual patient data are available: the R indiv 2 or the Kendall's τ at the individual level, and the R trial 2 at the trial level. We aimed at providing an R implementation of classical and well-established as well as more recent statistical methods for surrogacy assessment with failure time endpoints. We also intended incorporating utilities for model checking and visualization and data generating methods described in the literature to date. In the case of failure time endpoints, the classical approach is based on two steps. First, a Kendall's τ is estimated as measure of individual level surrogacy using a copula model. Then, the R trial 2 is computed via a linear regression of the estimated treatment effects; at this second step, the estimation uncertainty can be accounted for via measurement-error model or via weights. In addition to the classical approach, we recently developed an approach based on bivariate auxiliary Poisson models with individual random effects to measure the Kendall's τ and treatment-by-trial interactions to measure the R trial 2 . The most common data simulation models described in the literature are based on: copula models, mixed proportional hazard models, and mixture of half-normal and exponential random variables. The R package surrosurv implements the classical two-step method with Clayton, Plackett, and Hougaard copulas. It also allows to optionally adjusting the second-step linear regression for measurement-error. The mixed Poisson approach is implemented with different reduced models in addition to the full model. We present the package functions for estimating the surrogacy models, for checking their convergence, for performing leave-one-trial-out cross-validation, and for plotting the results. We illustrate their use in practice on individual patient data from a meta-analysis of 4069 patients with advanced gastric cancer from 20 trials of chemotherapy. The surrosurv package provides an R implementation of classical and recent statistical methods for surrogacy assessment of failure time endpoints. Flexible simulation functions are available to generate data according to the methods described in the literature. Copyright © 2017 Elsevier B.V. All rights reserved.

[Selection of "surrogate" and "endpoints" evaluation of the efficacy of medical interventions].

PubMed

Lazebnik, L B; Gusein-Zade, M G; Efremov, L I

2011-01-01

With the advent of new medical technologies and medicines, as well as due to changes in disease patterns and demographic problems rises the need for continued increases in health spending. Increased costs can be totally inadequate, if it has been done without studying the effectiveness of medical interventions, based on the results of evidence-based medicine and economic of their feasibility. To evaluate the clinical effectiveness of medical interventions have been recently used specific criteria, so called points of clinical efficacy (surrogate and endpoints), that allow to conclude feasibility or harmfulness of the introduction or application of the intervention in clinical practice. The endpoint is reliable indicator the effectiveness of medical intervention. Surrogate point--is a biomarker that is intended to replace the endpoint and is a predictor of the effectiveness of medical intervention. The use of surrogate points has several advantages such as simple in identification and measurement, as well as more higher in compare with endpoints the vents frequency, that can significantly reduce the size of the selection and duration and cost of clinical trials, respectively. Finally, the surrogate points allow to evaluate treatment effect in situations where the use of endpoints is difficult or is unethical.

Comparison of treatment effect sizes from pivotal and postapproval trials of novel therapeutics approved by the FDA based on surrogate markers of disease: a meta-epidemiological study.

PubMed

Wallach, Joshua D; Ciani, Oriana; Pease, Alison M; Gonsalves, Gregg S; Krumholz, Harlan M; Taylor, Rod S; Ross, Joseph S

2018-03-21

The U.S. Food and Drug Administration (FDA) often approves new drugs based on trials that use surrogate markers for endpoints, which involve certain trade-offs and may risk making erroneous inferences about the medical product's actual clinical effect. This study aims to compare the treatment effects among pivotal trials supporting FDA approval of novel therapeutics based on surrogate markers of disease with those observed among postapproval trials for the same indication. We searched Drugs@FDA and PubMed to identify published randomized superiority design pivotal trials for all novel drugs initially approved by the FDA between 2005 and 2012 based on surrogate markers as primary endpoints and published postapproval trials using the same surrogate markers or patient-relevant outcomes as endpoints. Summary ratio of odds ratios (RORs) and difference between standardized mean differences (dSMDs) were used to quantify the average difference in treatment effects between pivotal and matched postapproval trials. Between 2005 and 2012, the FDA approved 88 novel drugs for 90 indications based on one or multiple pivotal trials using surrogate markers of disease. Of these, 27 novel drugs for 27 indications were approved based on pivotal trials using surrogate markers as primary endpoints that could be matched to at least one postapproval trial, for a total of 43 matches. For nine (75.0%) of the 12 matches using the same non-continuous surrogate markers as trial endpoints, pivotal trials had larger treatment effects than postapproval trials. On average, treatment effects were 50% higher (more beneficial) in the pivotal than the postapproval trials (ROR 1.5; 95% confidence interval CI 1.01-2.23). For 17 (54.8%) of the 31 matches using the same continuous surrogate markers as trial endpoints, pivotal trials had larger treatment effects than the postapproval trials. On average, there was no difference in treatment effects between pivotal and postapproval trials (dSMDs 0.01; 95% CI -0.15-0.16). Many postapproval drug trials are not directly comparable to previously published pivotal trials, particularly with respect to endpoint selection. Although treatment effects from pivotal trials supporting FDA approval of novel therapeutics based on non-continuous surrogate markers of disease are often larger than those observed among postapproval trials using surrogate markers as trial endpoints, there is no evidence of difference between pivotal and postapproval trials using continuous surrogate markers.

Biomarkers and surrogate endpoints in kidney disease

PubMed Central

2015-01-01

Kidney disease and its related comorbidities impose a large public health burden. Despite this, the number of clinical trials in nephrology lags behind many other fields. An important factor contributing to the relatively slow pace of nephrology trials is that existing clinical endpoints have significant limitations. “Hard” endpoints for chronic kidney disease, such as progression to end-stage renal disease, may not be reached for decades. Traditional biomarkers, such as serum creatinine in acute kidney injury, may lack sensitivity and predictive value. Finding new biomarkers to serve as surrogate endpoints is therefore an important priority in kidney disease research and may help to accelerate nephrology clinical trials. In this paper, I first review key concepts related to the selection of clinical trial endpoints and discuss statistical and regulatory considerations related to the evaluation of biomarkers as surrogate endpoints. This is followed by a discussion of the challenges and opportunities in developing novel biomarkers and surrogate endpoints in three major areas of nephrology research: acute kidney injury, chronic kidney disease, and autosomal dominant polycystic kidney disease. PMID:25980469

Is prostate-specific antigen a valid surrogate end point for survival in hormonally treated patients with metastatic prostate cancer? Joint research of the European Organisation for Research and Treatment of Cancer, the Limburgs Universitair Centrum, and AstraZeneca Pharmaceuticals.

PubMed

Collette, Laurence; Burzykowski, Tomasz; Carroll, Kevin J; Newling, Don; Morris, Tom; Schröder, Fritz H

2005-09-01

The long duration of phase III clinical trials of overall survival (OS) slows down the treatment-development process. It could be shortened by using surrogate end points. Prostate-specific antigen (PSA) is the most studied biomarker in prostate cancer (PCa). This study attempts to validate PSA end points as surrogates for OS in advanced PCa. Individual data from 2,161 advanced PCa patients treated in studies comparing bicalutamide to castration were used in a meta-analytic approach to surrogate end-point validation. PSA response, PSA normalization, time to PSA progression, and longitudinal PSA measurements were considered. The known association between PSA and OS at the individual patient level was confirmed. The association between the effect of intervention on any PSA end point and on OS was generally low (determination coefficient, < 0.69). It is a common misconception that high correlation between biomarkers and true end point justify the use of the former as surrogates. To statistically validate surrogate end points, a high correlation between the treatment effects on the surrogate and true end point needs to be established across groups of patients treated with two alternative interventions. The levels of association observed in this study indicate that the effect of hormonal treatment on OS cannot be predicted with a high degree of precision from observed treatment effects on PSA end points, and thus statistical validity is unproven. In practice, non-null treatment effects on OS can be predicted only from precisely estimated large effects on time to PSA progression (TTPP; hazard ratio, < 0.50).

Use of outcome measures in pulmonary hypertension clinical trials.

PubMed

Parikh, Kishan S; Rajagopal, Sudarshan; Arges, Kristine; Ahmad, Tariq; Sivak, Joseph; Kaul, Prashant; Shah, Svati H; Tapson, Victor; Velazquez, Eric J; Douglas, Pamela S; Samad, Zainab

2015-09-01

To evaluate the use of surrogate measures in pulmonary hypertension (PH) clinical trials and how it relates to clinical practice. Studies of pulmonary arterial hypertension (PAH) employ a variety of surrogate measures in addition to clinical events because of a small patient population, participant burden, and costs. The use of these measures in PH drug trials is poorly defined. We searched PubMed/MEDLINE/Embase for randomized or prospective cohort PAH clinical treatment trials from 1985 to 2013. Extracted data included intervention, trial duration, study design, patient characteristics, and primary and secondary outcome measures. To compare with clinical practice, we assessed the use of surrogate measures in a clinical sample of patients on PH medications at Duke University Medical Center between 2003 and 2014. Between 1985 and 2013, 126 PAH trials were identified and analyzed. Surrogate measures served as primary endpoints in 119 trials (94.0%). Inclusion of invasive hemodynamics decreased over time (78.6%, 75.0%, 52.2%; P for trend = .02), while functional testing (7.1%, 60.0%, 81.5%; P for trend < .0001) and functional status or quality of life (0%, 47.6%, 62.8%; P for trend < .0001) increased in PAH trials over the same time periods. Echocardiography data were reported as a primary or secondary outcome in 32 trials (25.4%) with increased use from 1985-1994 to 1995-2004 (7.1% vs 35.0%, P = .04), but the trend did not continue to 2005-2013 (25.0%). In comparison, among 450 patients on PAH therapies at our institution between 2003 and 2013, clinical assessments regularly incorporated serial echocardiography and 6-minute walk distance tests (92% and 95% of patients, respectively) and repeat measurement of invasive hemodynamics (46% of patients). The majority of PAH trials have utilized surrogate measures as primary endpoints. The use of these surrogate endpoints has evolved significantly over time with increasing use of patient-centered endpoints and decreasing or stable use of imaging and invasive measures. In contrast, imaging and invasive measures are commonly used in contemporary clinical practice. Further research is needed to validate and standardize currently used measures. Copyright © 2015 Elsevier Inc. All rights reserved.

A new proportion measure of the treatment effect captured by candidate surrogate endpoints.

PubMed

Kobayashi, Fumiaki; Kuroki, Manabu

2014-08-30

The use of surrogate endpoints is expected to play an important role in the development of new drugs, as they can be used to reduce the sample size and/or duration of randomized clinical trials. Biostatistical researchers and practitioners have proposed various surrogacy measures; however, (i) most of these surrogacy measures often fall outside the range [0,1] without any assumptions, (ii) these surrogacy measures do not provide a cut-off value for judging a surrogacy level of candidate surrogate endpoints, and (iii) most surrogacy measures are highly variable; thus, the confidence intervals are often unacceptably wide. In order to solve problems (i) and (ii), we propose a new surrogacy measure, a proportion of the treatment effect captured by candidate surrogate endpoints (PCS), on the basis of the decomposition of the treatment effect into parts captured and non-captured by the candidate surrogate endpoints. In order to solve problem (iii), we propose an estimation method based on the half-range mode method with the bootstrap distribution of the estimated surrogacy measures. Finally, through numerical experiments and two empirical examples, we show that the PCS with the proposed estimation method overcomes these difficulties. The results of this paper contribute to the reliable evaluation of how much of the treatment effect is captured by candidate surrogate endpoints. Copyright © 2014 John Wiley & Sons, Ltd.

Biomarkers and surrogate endpoints in clinical trials.

PubMed

Fleming, Thomas R; Powers, John H

2012-11-10

One of the most important considerations in designing clinical trials is the choice of outcome measures. These outcome measures could be clinically meaningful endpoints that are direct measures of how patients feel, function, and survive. Alternatively, indirect measures, such as biomarkers that include physical signs of disease, laboratory measures, and radiological tests, often are considered as replacement endpoints or 'surrogates' for clinically meaningful endpoints. We discuss the definitions of clinically meaningful endpoints and surrogate endpoints, and provide examples from recent clinical trials. We provide insight into why indirect measures such as biomarkers may fail to provide reliable evidence about the benefit-to-risk profile of interventions. We also discuss the nature of evidence that is important in assessing whether treatment effects on a biomarker reliably predict effects on a clinically meaningful endpoint, and provide insights into why this reliability is specific to the context of use of the biomarker. Copyright © 2012 John Wiley & Sons, Ltd.

Surrogate endpoints for cancer screening trials: general principles and an illustration using the UK Flexible Sigmoidoscopy Screening Trial.

PubMed

Cuzick, Jack; Cafferty, Fay H; Edwards, Robert; Møller, Henrik; Duffy, Stephen W

2007-01-01

Cancer screening is aimed primarily at reducing deaths. Thus, site-specific cancer mortality is the appropriate endpoint for evaluating screening interventions. However, it is also the most demanding endpoint, requiring follow-up and a large numbers of patients order to have adequate power. Therefore, it is highly desirable to have surrogate endpoints that can reliably predict mortality reductions many years earlier. We here review a range of surrogate markers in terms of their potential advantages and pitfalls, and argue that a measure which weights incident cancers according to their predicted mortality has many advantages over other measures and should be used more routinely. Application to the UK Flexible Sigmoidoscopy Screening Trial data suggests that predicted colorectal cancer mortality, based on stage-specific incidence, is a more powerful endpoint than actual mortality and could advance the analysis time by about three years. Total colorectal cancer incidence as a surrogate endpoint provides little advance in the analysis time over actual mortality. The approach requires reliable prognostic data, (e.g. stage), for both the study cohort and a representative sample of the whole population. The routine collection of such data should be a priority for cancer registries. Surrogate endpoints should not replace a long-term analysis based directly on mortality, but can provide reliable early indicators which can be useful both for monitoring ongoing screening programmes and for making policy decisions.

Comparing and combining biomarkers as principle surrogates for time-to-event clinical endpoints.

PubMed

Gabriel, Erin E; Sachs, Michael C; Gilbert, Peter B

2015-02-10

Principal surrogate endpoints are useful as targets for phase I and II trials. In many recent trials, multiple post-randomization biomarkers are measured. However, few statistical methods exist for comparison of or combination of biomarkers as principal surrogates, and none of these methods to our knowledge utilize time-to-event clinical endpoint information. We propose a Weibull model extension of the semi-parametric estimated maximum likelihood method that allows for the inclusion of multiple biomarkers in the same risk model as multivariate candidate principal surrogates. We propose several methods for comparing candidate principal surrogates and evaluating multivariate principal surrogates. These include the time-dependent and surrogate-dependent true and false positive fraction, the time-dependent and the integrated standardized total gain, and the cumulative distribution function of the risk difference. We illustrate the operating characteristics of our proposed methods in simulations and outline how these statistics can be used to evaluate and compare candidate principal surrogates. We use these methods to investigate candidate surrogates in the Diabetes Control and Complications Trial. Copyright © 2014 John Wiley & Sons, Ltd.

76 FR 1620 - Trials to Verify and Describe Clinical Benefit of Midodrine Hydrochloride; Establishment of...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-11

... a surrogate endpoint that is reasonably likely to predict clinical benefit or based on a clinical endpoint other than survival or irreversible morbidity. Approval of PROAMATINE was based on trials... surrogate endpoints are ``subject to the requirement that the applicant study the drug further to verify and...

Variable reliability of surrogate measures of insulin sensitivity after Roux-en-Y gastric bypass.

PubMed

Bojsen-Møller, Kirstine N; Dirksen, Carsten; Svane, Maria S; Jørgensen, Nils B; Holst, Jens J; Richter, Erik A; Madsbad, Sten

2017-05-01

Roux-en-Y gastric bypass (RYGB) induces weight loss and improves insulin sensitivity when evaluated by the hyperinsulinemic-euglycemic clamp (HEC). Surrogate indices of insulin sensitivity calculated from insulin and glucose concentrations at fasting or after an oral glucose tolerance test (OGTT) are frequently used, but have not been validated after RYGB. Our aim was to evaluate whether surrogate indices reliably estimate changes in insulin sensitivity after RYGB. Four fasting surrogates (inverse-HOMA-IR, HOMA2-%S, QUICKI, revised-QUICKI) and three OGTT-derived surrogates (Matsuda, Gutt, OGIS) were compared with HEC-estimated peripheral insulin sensitivity ( R d or R d /I, depending on how the index was originally validated) and the tracer-determined hepatic insulin sensitivity index (HISI) in patients with preoperative type 2 diabetes ( n = 10) and normal glucose tolerance ( n = 10) 1 wk, 3 mo, and 1 yr postoperatively. Post-RYGB changes in inverse-HOMA-IR and HOMA2-%S did not correlate with changes in R d at any visit, but were comparable to changes in HISI at 1 wk. Changes in QUICKI and revised-QUICKI correlated with R d /I after surgery. Changes in the Matsuda and Gutt indices did not correlate with changes in R d /I and R d , respectively, whereas OGIS changes correlated with R d changes at 1 yr post-RYGB. In conclusion, surrogate measures of insulin sensitivity may not reflect results obtained with gold standard methodology after RYGB, underscoring the importance of critical reflection when surrogate endpoints are used. Fasting surrogate indices may be particularly affected by post-RYGB changes in insulin clearance, whereas the validity of OGTT-derived surrogates may be compromised by surgical rearrangements of the gut. Copyright © 2017 the American Physiological Society.

Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer: a re-analysis of meta-analyses of individual patients' data.

PubMed

Mauguen, Audrey; Pignon, Jean-Pierre; Burdett, Sarah; Domerg, Caroline; Fisher, David; Paulus, Rebecca; Mandrekar, Samithra J; Belani, Chandra P; Shepherd, Frances A; Eisen, Tim; Pang, Herbert; Collette, Laurence; Sause, William T; Dahlberg, Suzanne E; Crawford, Jeffrey; O'Brien, Mary; Schild, Steven E; Parmar, Mahesh; Tierney, Jayne F; Le Pechoux, Cécile; Michiels, Stefan

2013-06-01

The gold standard endpoint in clinical trials of chemotherapy and radiotherapy for lung cancer is overall survival. Although reliable and simple to measure, this endpoint takes years to observe. Surrogate endpoints that would enable earlier assessments of treatment effects would be useful. We assessed the correlations between potential surrogate endpoints and overall survival at individual and trial levels. We analysed individual patients' data from 15,071 patients involved in 60 randomised clinical trials that were assessed in six meta-analyses. Two meta-analyses were of adjuvant chemotherapy in non-small-cell lung cancer, three were of sequential or concurrent chemotherapy, and one was of modified radiotherapy in locally advanced lung cancer. We investigated disease-free survival (DFS) or progression-free survival (PFS), defined as the time from randomisation to local or distant relapse or death, and locoregional control, defined as the time to the first local event, as potential surrogate endpoints. At the individual level we calculated the squared correlations between distributions of these three endpoints and overall survival, and at the trial level we calculated the squared correlation between treatment effects for endpoints. In trials of adjuvant chemotherapy, correlations between DFS and overall survival were very good at the individual level (ρ(2)=0.83, 95% CI 0.83-0.83 in trials without radiotherapy, and 0.87, 0.87-0.87 in trials with radiotherapy) and excellent at trial level (R(2)=0.92, 95% CI 0.88-0.95 in trials without radiotherapy and 0.99, 0.98-1.00 in trials with radiotherapy). In studies of locally advanced disease, correlations between PFS and overall survival were very good at the individual level (ρ(2) range 0.77-0.85, dependent on the regimen being assessed) and trial level (R(2) range 0.89-0.97). In studies with data on locoregional control, individual-level correlations were good (ρ(2)=0.71, 95% CI 0.71-0.71 for concurrent chemotherapy and ρ(2)=0.61, 0.61-0.61 for modified vs standard radiotherapy) and trial-level correlations very good (R(2)=0.85, 95% CI 0.77-0.92 for concurrent chemotherapy and R(2)=0.95, 0.91-0.98 for modified vs standard radiotherapy). We found a high level of evidence that DFS is a valid surrogate endpoint for overall survival in studies of adjuvant chemotherapy involving patients with non-small-cell lung cancers, and PFS in those of chemotherapy and radiotherapy for patients with locally advanced lung cancers. Extrapolation to targeted agents, however, is not automatically warranted. Programme Hospitalier de Recherche Clinique, Ligue Nationale Contre le Cancer, British Medical Research Council, Sanofi-Aventis. Copyright © 2013 Elsevier Ltd. All rights reserved.

Predicting Treatment Effect from Surrogate Endpoints and Historical Trials | Division of Cancer Prevention

Cancer.gov

By Stuart G. Baker, 2017 Introduction This software fits a zero-intercept random effects linear model to data on surrogate and true endpoints in previous trials. Requirement:  Mathematica Version 11 or later. |

Relevance of Changes in Serum Creatinine During a Heart Failure Trial of Decongestive Strategies: Insights From the DOSE Trial

PubMed Central

BRISCO, MEREDITH A.; ZILE, MICHAEL R.; HANBERG, JENNIFER S.; WILSON, F. PERRY; PARIKH, CHIRAG R.; COCA, STEVEN G.; TANG, W.H. WILSON; TESTANI, JEFFREY M.

2017-01-01

Background Worsening renal function (WRF) is a common endpoint in decompensated heart failure clinical trials because of associations between WRF and adverse outcomes. However, WRF has not universally been identified as a poor prognostic sign, challenging the validity of WRF as a surrogate endpoint. Our aim was to describe the associations between changes in creatinine and adverse outcomes in a clinical trial of decongestive therapies. Methods and Results We investigated the association between changes in creatinine and the composite endpoint of death, rehospitalization or emergency room visit within 60 days in 301 patients in the Diuretic Optimization Strategies Evaluation (DOSE) trial. WRF was defined as an increase in creatinine >0.3 mg/dL and improvement in renal function (IRF) as a decrease >0.3 mg/dL. When examining linear changes in creatinine from baseline to 72 hours (the coprimary endpoint of DOSE), increasing creatinine was associated with lower risk for the composite outcome (HR = 0.81 per 0.3 mg/dL increase, 95% CI 0.67–0.98, P = .026). Compared with patients with stable renal function (n = 219), WRF (n = 54) was not associated with the composite endpoint (HR = 1.17, 95% CI = 0.77–1.78, P = .47). However, compared with stable renal function, there was a strong relationship between IRF (n = 28) and the composite endpoint (HR = 2.52, 95% CI = 1.57–4.03, P <.001). Conclusion The coprimary endpoint of the DOSE trial, a linear increase in creatinine, was paradoxically associated with improved outcomes. This was driven by absence of risk attributable to WRF and a strong risk associated with IRF. These results argue against using changes in serum creatinine as a surrogate endpoint in trials of decongestive strategies. PMID:27374839

Evaluating surrogate endpoints, prognostic markers, and predictive markers: Some simple themes.

PubMed

Baker, Stuart G; Kramer, Barnett S

2015-08-01

A surrogate endpoint is an endpoint observed earlier than the true endpoint (a health outcome) that is used to draw conclusions about the effect of treatment on the unobserved true endpoint. A prognostic marker is a marker for predicting the risk of an event given a control treatment; it informs treatment decisions when there is information on anticipated benefits and harms of a new treatment applied to persons at high risk. A predictive marker is a marker for predicting the effect of treatment on outcome in a subgroup of patients or study participants; it provides more rigorous information for treatment selection than a prognostic marker when it is based on estimated treatment effects in a randomized trial. We organized our discussion around a different theme for each topic. "Fundamentally an extrapolation" refers to the non-statistical considerations and assumptions needed when using surrogate endpoints to evaluate a new treatment. "Decision analysis to the rescue" refers to use the use of decision analysis to evaluate an additional prognostic marker because it is not possible to choose between purely statistical measures of marker performance. "The appeal of simplicity" refers to a straightforward and efficient use of a single randomized trial to evaluate overall treatment effect and treatment effect within subgroups using predictive markers. The simple themes provide a general guideline for evaluation of surrogate endpoints, prognostic markers, and predictive markers. © The Author(s) 2014.

Surrogate and clinical endpoints for studies in peripheral artery occlusive disease: Are statistics the brakes?

PubMed

Waliszewski, Matthias W; Redlich, Ulf; Breul, Victor; Tautenhahn, Jörg

2017-04-30

The aim of this review is to present the available clinical and surrogate endpoints that may be used in future studies performed in patients with peripheral artery occlusive disease (PAOD). Importantly, we describe statistical limitations of the most commonly used endpoints and offer some guidance with respect to study design for a given sample size. The proposed endpoints may be used in studies using surgical or interventional revascularization and/or drug treatments. Considering recently published study endpoints and designs, the usefulness of these endpoints for reimbursement is evaluated. Based on these potential study endpoints and patient sample size estimates with different non-inferiority or tests for difference hypotheses, a rating relative to their corresponding reimbursement values is attempted. As regards the benefit for the patients and for the payers, walking distance and the ankle brachial index (ABI) are the most feasible endpoints in a relatively small study samples given that other non-vascular impact factors can be controlled. Angiographic endpoints such as minimal lumen diameter (MLD) do not seem useful from a reimbursement standpoint despite their intuitiveness. Other surrogate endpoints, such as transcutaneous oxygen tension measurements, have yet to be established as useful endpoints in reasonably sized studies with patients with critical limb ischemia (CLI). From a reimbursement standpoint, WD and ABI are effective endpoints for a moderate study sample size given that non-vascular confounding factors can be controlled.

The potential investment impact of improved access to accelerated approval on the development of treatments for low prevalence rare diseases

PubMed Central

2011-01-01

Background Over 95% of rare diseases lack treatments despite many successful treatment studies in animal models. To improve access to treatments, the Accelerated Approval (AA) regulations were implemented allowing the use of surrogate endpoints to achieve drug approval and accelerate development of life-saving therapies. Many rare diseases have not utilized AA due to the difficulty in gaining acceptance of novel surrogate endpoints in untreated rare diseases. Methods To assess the potential impact of improved AA accessibility, we devised clinical development programs using proposed clinical or surrogate endpoints for fifteen rare disease treatments. Results We demonstrate that better AA access could reduce development costs by approximately 60%, increase investment value, and foster development of three times as many rare disease drugs for the same investment. Conclusion Our research brings attention to the need for well-defined and practical qualification criteria for the use of surrogate endpoints to allow more access to the AA approval pathway in clinical trials for rare diseases. PMID:21733145

Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer: a re-analysis of meta-analyses of individual patients' data

PubMed Central

Mauguen, Audrey; Pignon, Jean-Pierre; Burdett, Sarah; Domerg, Caroline; Fisher, David; Paulus, Rebecca; Mandrekar, Samithra J; Belani, Chandra P; Shepherd, Frances A; Eisen, Tim; Pang, Herbert; Collette, Laurence; Sause, William T; Dahlberg, Suzanne E; Crawford, Jeffrey; O'Brien, Mary; Schild, Steven E; Parmar, Mahesh; Tierney, Jayne F; Pechoux, Cécile Le; Michiels, Stefan

2013-01-01

Summary Background The gold standard endpoint in clinical trials of chemotherapy and radiotherapy for lung cancer is overall survival. Although reliable and simple to measure, this endpoint takes years to observe. Surrogate endpoints that would enable earlier assessments of treatment effects would be useful. We assessed the correlations between potential surrogate endpoints and overall survival at individual and trial levels. Methods We analysed individual patients' data from 15 071 patients involved in 60 randomised clinical trials that were assessed in six meta-analyses. Two meta-analyses were of adjuvant chemotherapy in non-small-cell lung cancer, three were of sequential or concurrent chemotherapy, and one was of modified radiotherapy in locally advanced lung cancer. We investigated disease-free survival (DFS) or progression-free survival (PFS), defined as the time from randomisation to local or distant relapse or death, and locoregional control, defined as the time to the first local event, as potential surrogate endpoints. At the individual level we calculated the squared correlations between distributions of these three endpoints and overall survival, and at the trial level we calculated the squared correlation between treatment effects for endpoints. Findings In trials of adjuvant chemotherapy, correlations between DFS and overall survival were very good at the individual level (ρ2=0·83, 95% CI 0·83–0·83 in trials without radiotherapy, and 0·87, 0·87–0·87 in trials with radiotherapy) and excellent at trial level (R2=0·92, 95% CI 0·88–0·95 in trials without radiotherapy and 0·99, 0·98–1·00 in trials with radiotherapy). In studies of locally advanced disease, correlations between PFS and overall survival were very good at the individual level (ρ2 range 0·77–0·85, dependent on the regimen being assessed) and trial level (R2 range 0·89–0·97). In studies with data on locoregional control, individual-level correlations were good (ρ2=0·71, 95% CI 0·71–0·71 for concurrent chemotherapy and ρ2=0·61, 0·61–0·61 for modified vs standard radiotherapy) and trial-level correlations very good (R2=0·85, 95% CI 0·77–0·92 for concurrent chemotherapy and R2=0·95, 0·91–0·98 for modified vs standard radiotherapy). Interpretation We found a high level of evidence that DFS is a valid surrogate endpoint for overall survival in studies of adjuvant chemotherapy involving patients with non-small-cell lung cancers, and PFS in those of chemotherapy and radiotherapy for patients with locally advanced lung cancers. Extrapolation to targeted agents, however, is not automatically warranted. Funding Programme Hospitalier de Recherche Clinique, Ligue Nationale Contre le Cancer, British Medical Research Council, Sanofi-Aventis. PMID:23680111

Selecting surrogate endpoints for estimating pesticide effects on avian reproductive success

EPA Science Inventory

A Markov chain nest productivity model (MCnest) has been developed for projecting the effects of a specific pesticide-use scenario on the annual reproductive success of avian species of concern. A critical element in MCnest is the use of surrogate endpoints, defined as measured ...

Imputation of a true endpoint from a surrogate: application to a cluster randomized controlled trial with partial information on the true endpoint.

PubMed

Nixon, Richard M; Duffy, Stephen W; Fender, Guy R K

2003-09-24

The Anglia Menorrhagia Education Study (AMES) is a randomized controlled trial testing the effectiveness of an education package applied to general practices. Binary data are available from two sources; general practitioner reported referrals to hospital, and referrals to hospital determined by independent audit of the general practices. The former may be regarded as a surrogate for the latter, which is regarded as the true endpoint. Data are only available for the true end point on a sub set of the practices, but there are surrogate data for almost all of the audited practices and for most of the remaining practices. The aim of this paper was to estimate the treatment effect using data from every practice in the study. Where the true endpoint was not available, it was estimated by three approaches, a regression method, multiple imputation and a full likelihood model. Including the surrogate data in the analysis yielded an estimate of the treatment effect which was more precise than an estimate gained from using the true end point data alone. The full likelihood method provides a new imputation tool at the disposal of trials with surrogate data.

Validation by simulation of a clinical trial model using the standardized mean and variance criteria.

PubMed

Abbas, Ismail; Rovira, Joan; Casanovas, Josep

2006-12-01

To develop and validate a model of a clinical trial that evaluates the changes in cholesterol level as a surrogate marker for lipodystrophy in HIV subjects under alternative antiretroviral regimes, i.e., treatment with Protease Inhibitors vs. a combination of nevirapine and other antiretroviral drugs. Five simulation models were developed based on different assumptions, on treatment variability and pattern of cholesterol reduction over time. The last recorded cholesterol level, the difference from the baseline, the average difference from the baseline and level evolution, are the considered endpoints. Specific validation criteria based on a 10% minus or plus standardized distance in means and variances were used to compare the real and the simulated data. The validity criterion was met by all models for considered endpoints. However, only two models met the validity criterion when all endpoints were considered. The model based on the assumption that within-subjects variability of cholesterol levels changes over time is the one that minimizes the validity criterion, standardized distance equal to or less than 1% minus or plus. Simulation is a useful technique for calibration, estimation, and evaluation of models, which allows us to relax the often overly restrictive assumptions regarding parameters required by analytical approaches. The validity criterion can also be used to select the preferred model for design optimization, until additional data are obtained allowing an external validation of the model.

Comparing biomarkers as principal surrogate endpoints.

PubMed

Huang, Ying; Gilbert, Peter B

2011-12-01

Recently a new definition of surrogate endpoint, the "principal surrogate," was proposed based on causal associations between treatment effects on the biomarker and on the clinical endpoint. Despite its appealing interpretation, limited research has been conducted to evaluate principal surrogates, and existing methods focus on risk models that consider a single biomarker. How to compare principal surrogate value of biomarkers or general risk models that consider multiple biomarkers remains an open research question. We propose to characterize a marker or risk model's principal surrogate value based on the distribution of risk difference between interventions. In addition, we propose a novel summary measure (the standardized total gain) that can be used to compare markers and to assess the incremental value of a new marker. We develop a semiparametric estimated-likelihood method to estimate the joint surrogate value of multiple biomarkers. This method accommodates two-phase sampling of biomarkers and is more widely applicable than existing nonparametric methods by incorporating continuous baseline covariates to predict the biomarker(s), and is more robust than existing parametric methods by leaving the error distribution of markers unspecified. The methodology is illustrated using a simulated example set and a real data set in the context of HIV vaccine trials. © 2011, The International Biometric Society.

[Structural endpoints for glaucoma studies].

PubMed

Popa-Cherechenau, A; Schmidl, D; Garhöfer, G; Schmetterer, L

2018-03-06

Structural endpoints have been discussed as surrogate endpoints for the approval of neuroprotective drugs in glaucoma. Is the evidence strong enough to establish structural endpoints as surrogate endpoints? Review of current understanding between structure and function in glaucoma. The introduction of optical coherence tomography has revolutionized imaging in glaucoma patients. Clinically either the nerve fiber layer thickness can be measured along a circle centered in the optic nerve head or the ganglion cell layer thickness can be assessed in the macular region, the latter being quantified in combination with other inner retinal layers. On a microscopic level there is a strong correlation between structural and functional loss but this relation can only partially be described with currently available clinical methods. This is particularly true for longitudinal course of the disease in glaucoma patients. Novel imaging techniques that are not yet used clinically may have the potential to increase our understanding between structure and function in glaucoma but further research in this field is required. The current evidence does not allow the establishment of structural endpoints as surrogate endpoints for phase 3 studies in glaucoma. Neuroprotective drugs have to be approved on the basis of visual field data because this is the patient-relevant endpoint. Structural endpoints can, however, play an important role in phase 2 and proof of concept studies.

Observations on Three Endpoint Properties and Their Relationship to Regulatory Outcomes of European Oncology Marketing Applications

PubMed Central

Stolk, Pieter; McAuslane, James Neil; Schellens, Jan; Breckenridge, Alasdair M.; Leufkens, Hubert

2015-01-01

Background. Guidance and exploratory evidence indicate that the type of endpoints and the magnitude of their outcome can define a therapy’s clinical activity; however, little empirical evidence relates specific endpoint properties with regulatory outcomes. Materials and Methods. We explored the relationship of 3 endpoint properties to regulatory outcomes by assessing 50 oncology marketing authorization applications (MAAs; reviewed from 2009 to 2013). Results. Overall, 16 (32%) had a negative outcome. The most commonly used hard endpoints were overall survival (OS) and the duration of response or stable disease. OS was a component of 91% approved and 63% failed MAAs. The most commonly used surrogate endpoints were progression-free survival (PFS), response rate, and health-related quality of life assessments. There was no difference (p = .3801) between the approved and failed MAA cohorts in the proportion of hard endpoints used. A mean of slightly more than four surrogate endpoints were used per approved MAA compared with slightly more than two for failed MAAs. Longer OS and PFS duration outcomes were generally associated with approvals, often when not statistically significant. The approved cohort was associated with a preponderance of statistically significant (p < .05) improvements in primary endpoints (p < .0001 difference between the approved and failed groups). Conclusion. Three key endpoint properties (type of endpoint [hard/surrogate], magnitude of an endpoint outcome, and its statistical significance) are consistent with the European Medicines Agency guidance and, notwithstanding the contribution of unique disease-specific circumstances, are associated with a predictable positive outcome for oncology MAAs. Implications for Practice: Regulatory decisions made by the European Medicines Agency determine which new medicines will be available to European prescribers and for which therapeutic indications. Regulatory success or failure can be influenced by many factors. This study assessed three key properties of endpoints used in preauthorization trials (type of endpoint [hard/surrogate], magnitude of endpoint outcome, and its statistical significance) and whether they are associated with a positive regulatory outcome. Clinicians can use these properties, which are described in the publicly available European public assessment reports, to help guide their understanding of the clinical effect of new oncologic therapies. PMID:25948678

Observations on Three Endpoint Properties and Their Relationship to Regulatory Outcomes of European Oncology Marketing Applications.

PubMed

Liberti, Lawrence; Stolk, Pieter; McAuslane, James Neil; Schellens, Jan; Breckenridge, Alasdair M; Leufkens, Hubert

2015-06-01

Guidance and exploratory evidence indicate that the type of endpoints and the magnitude of their outcome can define a therapy's clinical activity; however, little empirical evidence relates specific endpoint properties with regulatory outcomes. We explored the relationship of 3 endpoint properties to regulatory outcomes by assessing 50 oncology marketing authorization applications (MAAs; reviewed from 2009 to 2013). Overall, 16 (32%) had a negative outcome. The most commonly used hard endpoints were overall survival (OS) and the duration of response or stable disease. OS was a component of 91% approved and 63% failed MAAs. The most commonly used surrogate endpoints were progression-free survival (PFS), response rate, and health-related quality of life assessments. There was no difference (p = .3801) between the approved and failed MAA cohorts in the proportion of hard endpoints used. A mean of slightly more than four surrogate endpoints were used per approved MAA compared with slightly more than two for failed MAAs. Longer OS and PFS duration outcomes were generally associated with approvals, often when not statistically significant. The approved cohort was associated with a preponderance of statistically significant (p < .05) improvements in primary endpoints (p < .0001 difference between the approved and failed groups). Three key endpoint properties (type of endpoint [hard/surrogate], magnitude of an endpoint outcome, and its statistical significance) are consistent with the European Medicines Agency guidance and, notwithstanding the contribution of unique disease-specific circumstances, are associated with a predictable positive outcome for oncology MAAs. Regulatory decisions made by the European Medicines Agency determine which new medicines will be available to European prescribers and for which therapeutic indications. Regulatory success or failure can be influenced by many factors. This study assessed three key properties of endpoints used in preauthorization trials (type of endpoint [hard/surrogate], magnitude of endpoint outcome, and its statistical significance) and whether they are associated with a positive regulatory outcome. Clinicians can use these properties, which are described in the publicly available European public assessment reports, to help guide their understanding of the clinical effect of new oncologic therapies. ©AlphaMed Press.

Evaluating surrogate endpoints, prognostic markers, and predictive markers — some simple themes

PubMed Central

Baker, Stuart G.; Kramer, Barnett S.

2014-01-01

Background A surrogate endpoint is an endpoint observed earlier than the true endpoint (a health outcome) that is used to draw conclusions about the effect of treatment on the unobserved true endpoint. A prognostic marker is a marker for predicting the risk of an event given a control treatment; it informs treatment decisions when there is information on anticipated benefits and harms of a new treatment applied to persons at high risk. A predictive marker is a marker for predicting the effect of treatment on outcome in a subgroup of patients or study participants; it provides more rigorous information for treatment selection than a prognostic marker when it is based on estimated treatment effects in a randomized trial. Methods We organized our discussion around a different theme for each topic. Results “Fundamentally an extrapolation” refers to the non-statistical considerations and assumptions needed when using surrogate endpoints to evaluate a new treatment. “Decision analysis to the rescue” refers to use the use of decision analysis to evaluate an additional prognostic marker because it is not possible to choose between purely statistical measures of marker performance. “The appeal of simplicity” refers to a straightforward and efficient use of a single randomized trial to evaluate overall treatment effect and treatment effect within subgroups using predictive markers. Conclusion The simple themes provide a general guideline for evaluation of surrogate endpoints, prognostic markers, and predictive markers. PMID:25385934

An information-theoretic approach to surrogate-marker evaluation with failure time endpoints.

PubMed

Pryseley, Assam; Tilahun, Abel; Alonso, Ariel; Molenberghs, Geert

2011-04-01

Over the last decades, the evaluation of potential surrogate endpoints in clinical trials has steadily been growing in importance, not only thanks to the availability of ever more potential markers and surrogate endpoints, also because more methodological development has become available. While early work has been devoted, to a large extent, to Gaussian, binary, and longitudinal endpoints, the case of time-to-event endpoints is in need of careful scrutiny as well, owing to the strong presence of such endpoints in oncology and beyond. While work had been done in the past, it was often cumbersome to use such tools in practice, because of the need for fitting copula or frailty models that were further embedded in a hierarchical or two-stage modeling approach. In this paper, we present a methodologically elegant and easy-to-use approach based on information theory. We resolve essential issues, including the quantification of "surrogacy" based on such an approach. Our results are put to the test in a simulation study and are applied to data from clinical trials in oncology. The methodology has been implemented in R.

Assessment of Correlation Between Early and Late Efficacy Endpoints to Identify Potential Surrogacy Relationships in Non-Hodgkin Lymphoma: a Literature-Based Meta-analysis of 108 Phase II and Phase III Studies.

PubMed

Zhu, Rui; Lu, Dan; Chu, Yu-Waye; Chai, Akiko; Green, Michelle; Zhang, Nancy; Jin, Jin Yan

2017-05-01

Correlations between early and late efficacy endpoints were assessed to identify potential surrogate endpoints for overall survival (OS) or progression-free survival (PFS) with clinical trial-level data in three non-Hodgkin lymphoma (NHL) subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). One hundred and eight phase II-III trials (129 trial arms) in DLBCL, FL, and MCL were identified and included in the database. Correlations between efficacy endpoints were analyzed using weighted linear regression and Pearson's coefficient of determination (R 2 ). In newly diagnosed DLBCL, 6-month PFS was strongly correlated with 2-year OS (R 2  = 0.81, 95% confidence interval [CI] 0.51-0.96). Six-month PFS was strongly correlated with 3-year PFS (R 2  = 0.89, 95% CI 0.62-0.96) in FL and was moderately correlated with 2-year OS (R 2  = 0.69, 95% CI 0.40-0.91) in MCL trials. Linear regression determined that a 10% increase in 6-month PFS would yield a 13% ± 1.2% increase in 2-year OS in DLBCL, a 23% ± 1.1% increase in 3-year PFS in FL, or a 6.7% ± 1.0% increase in 2-year OS in MCL. Both 6-month PFS and complete response (CR) rate were moderately correlated with median PFS in FL trials with R 2  = 0.66 (95% CI 0.52-0.98) and R 2  = 0.69 (95% CI 0.22-0.89), respectively. Six-month PFS is a potential surrogate endpoint for 2-year OS in newly diagnosed DLBCL and MCL and for 3-year PFS in FL. Both 6-month PFS and CR rate are potential surrogate endpoints for median PFS in FL patients. Confirmation and validation of these correlations may facilitate early interpretation of NHL trials.

Early Fungicidal Activity as a Candidate Surrogate Endpoint for All-Cause Mortality in Cryptococcal Meningitis: A Systematic Review of the Evidence.

PubMed

Montezuma-Rusca, Jairo M; Powers, John H; Follmann, Dean; Wang, Jing; Sullivan, Brigit; Williamson, Peter R

2016-01-01

Cryptococcal meningitis (CM) is a leading cause of HIV-associated mortality. In clinical trials evaluating treatments for CM, biomarkers of early fungicidal activity (EFA) in cerebrospinal fluid (CSF) have been proposed as candidate surrogate endpoints for all- cause mortality (ACM). However, there has been no systematic evaluation of the group-level or trial-level evidence for EFA as a candidate surrogate endpoint for ACM. We conducted a systematic review of randomized trials in treatment of CM to evaluate available evidence for EFA measured as culture negativity at 2 weeks/10 weeks and slope of EFA as candidate surrogate endpoints for ACM. We performed sensitivity analysis on superiority trials and high quality trials as determined by Cochrane measures of trial bias. Twenty-seven trials including 2854 patients met inclusion criteria. Mean ACM was 15.8% at 2 weeks and 27.0% at 10 weeks with no overall significant difference between test and control groups. There was a statistically significant group-level correlation between average EFA and ACM at 10 weeks but not at 2 weeks. There was also no statistically significant group-level correlation between CFU culture negativity at 2weeks/10weeks or average EFA slope at 10 weeks. A statistically significant trial-level correlation was identified between EFA slope and ACM at 2 weeks, but is likely misleading, as there was no treatment effect on ACM. Mortality remains high in short time periods in CM clinical trials. Using published data and Institute of Medicine criteria, evidence for use of EFA as a surrogate endpoint for ACM is insufficient and could provide misleading results from clinical trials. ACM should be used as a primary endpoint evaluating treatments for cryptococcal meningitis.

Relevance of Changes in Serum Creatinine During a Heart Failure Trial of Decongestive Strategies: Insights From the DOSE Trial.

PubMed

Brisco, Meredith A; Zile, Michael R; Hanberg, Jennifer S; Wilson, F Perry; Parikh, Chirag R; Coca, Steven G; Tang, W H Wilson; Testani, Jeffrey M

2016-10-01

Worsening renal function (WRF) is a common endpoint in decompensated heart failure clinical trials because of associations between WRF and adverse outcomes. However, WRF has not universally been identified as a poor prognostic sign, challenging the validity of WRF as a surrogate endpoint. Our aim was to describe the associations between changes in creatinine and adverse outcomes in a clinical trial of decongestive therapies. We investigated the association between changes in creatinine and the composite endpoint of death, rehospitalization or emergency room visit within 60 days in 301 patients in the Diuretic Optimization Strategies Evaluation (DOSE) trial. WRF was defined as an increase in creatinine >0.3 mg/dL and improvement in renal function (IRF) as a decrease >0.3 mg/dL. When examining linear changes in creatinine from baseline to 72 hours (the coprimary endpoint of DOSE), increasing creatinine was associated with lower risk for the composite outcome (HR = 0.81 per 0.3 mg/dL increase, 95% CI 0.67-0.98, P = .026). Compared with patients with stable renal function (n = 219), WRF (n = 54) was not associated with the composite endpoint (HR = 1.17, 95% CI = 0.77-1.78, P = .47). However, compared with stable renal function, there was a strong relationship between IRF (n = 28) and the composite endpoint (HR = 2.52, 95% CI = 1.57-4.03, P < .001). The coprimary endpoint of the DOSE trial, a linear increase in creatinine, was paradoxically associated with improved outcomes. This was driven by absence of risk attributable to WRF and a strong risk associated with IRF. These results argue against using changes in serum creatinine as a surrogate endpoint in trials of decongestive strategies. Copyright © 2016 Elsevier Inc. All rights reserved.

The intermediate endpoint effect in logistic and probit regression

PubMed Central

MacKinnon, DP; Lockwood, CM; Brown, CH; Wang, W; Hoffman, JM

2010-01-01

Background An intermediate endpoint is hypothesized to be in the middle of the causal sequence relating an independent variable to a dependent variable. The intermediate variable is also called a surrogate or mediating variable and the corresponding effect is called the mediated, surrogate endpoint, or intermediate endpoint effect. Clinical studies are often designed to change an intermediate or surrogate endpoint and through this intermediate change influence the ultimate endpoint. In many intermediate endpoint clinical studies the dependent variable is binary, and logistic or probit regression is used. Purpose The purpose of this study is to describe a limitation of a widely used approach to assessing intermediate endpoint effects and to propose an alternative method, based on products of coefficients, that yields more accurate results. Methods The intermediate endpoint model for a binary outcome is described for a true binary outcome and for a dichotomization of a latent continuous outcome. Plots of true values and a simulation study are used to evaluate the different methods. Results Distorted estimates of the intermediate endpoint effect and incorrect conclusions can result from the application of widely used methods to assess the intermediate endpoint effect. The same problem occurs for the proportion of an effect explained by an intermediate endpoint, which has been suggested as a useful measure for identifying intermediate endpoints. A solution to this problem is given based on the relationship between latent variable modeling and logistic or probit regression. Limitations More complicated intermediate variable models are not addressed in the study, although the methods described in the article can be extended to these more complicated models. Conclusions Researchers are encouraged to use an intermediate endpoint method based on the product of regression coefficients. A common method based on difference in coefficient methods can lead to distorted conclusions regarding the intermediate effect. PMID:17942466

Challenges in translating endpoints from trials to observational cohort studies in oncology

PubMed Central

Ording, Anne Gulbech; Cronin-Fenton, Deirdre; Ehrenstein, Vera; Lash, Timothy L; Acquavella, John; Rørth, Mikael; Sørensen, Henrik Toft

2016-01-01

Clinical trials are considered the gold standard for examining drug efficacy and for approval of new drugs. Medical databases and population surveillance registries are valuable resources for post-approval observational research, which are increasingly used in studies of benefits and risk of new cancer drugs. Here, we address the challenges in translating endpoints from oncology trials to observational studies. Registry-based cohort studies can investigate real-world safety issues – including previously unrecognized concerns – by examining rare endpoints or multiple endpoints at once. In contrast to clinical trials, observational cohort studies typically do not exclude real-world patients from clinical practice, such as old and frail patients with comorbidity. The observational cohort study complements the clinical trial by examining the effectiveness of interventions applied in clinical practice and by providing evidence on long-term clinical outcomes, which are often not feasible to study in a clinical trial. Various endpoints can be included in clinical trials, such as hard endpoints, soft endpoints, surrogate endpoints, and patient-reported endpoints. Each endpoint has it strengths and limitations for use in research studies. Endpoints used in oncology trials are often not applicable in observational cohort studies which are limited by the setting of standard clinical practice and by non-standardized endpoint determination. Observational studies can be more helpful moving research forward if they restrict focus to appropriate and valid endpoints. PMID:27354827

Biomarkers and Surrogate Endpoints In Clinical Trials

PubMed Central

Fleming, Thomas R.; Powers, John H

2012-01-01

One of the most important considerations in designing clinical trials is the choice of outcome measures. These outcome measures could be clinically meaningful endpoints that are direct measures of how patients feel, function and survive. Alternatively, indirect measures, such as biomarkers that include physical signs of disease, laboratory measures and radiological tests, often are considered as replacement endpoints or “surrogates” for clinically meaningful endpoints. We discuss the definitions of clinically meaningful endpoints and surrogate endpoints, and provide examples from recent clinical trials. We provide insight into why indirect measures such as biomarkers may fail to provide reliable evidence about the benefit-to-risk profile of interventions. We also discuss the nature of evidence that is important in assessing whether treatment effects on a biomarker reliably predict effects on a clinically meaningful endpoint, and provide insights into why this reliability is specific to the context of use of the biomarker. . PMID:22711298

Evaluating time to cancer recurrence as a surrogate marker for survival from an information theory perspective.

PubMed

Alonso, Ariel; Molenberghs, Geert

2008-10-01

The last two decades have seen a lot of development in the area of surrogate marker validation. One of these approaches places the evaluation in a meta-analytic framework, leading to definitions in terms of trial- and individual-level association. A drawback of this methodology is that different settings have led to different measures at the individual level. Using information theory, Alonso et al. proposed a unified framework, leading to a new definition of surrogacy, which offers interpretational advantages and is applicable in a wide range of situations. In this work, we illustrate how this information-theoretic approach can be used to evaluate surrogacy when both endpoints are of a time-to-event type. Two meta-analyses, in early and advanced colon cancer, respectively, are then used to evaluate the performance of time to cancer recurrence as a surrogate for overall survival.

Persistent high-risk human papillomavirus (HPV) infections as surrogate endpoints of progressive cervical disease. Potential new endpoint for efficacy studies with new-generation (non-HPV 16/18) prophylactic HPV vaccines.

PubMed

Syrjänen, K

2011-01-01

Recent data indicate that persistent HR-HPV infections represent a significantly increased risk of developing incident high-grade CIN and cervical cancer. Accordingly, 6-month (6M+) or 12-month (12M+) type-specific persistence of HR-HPV have been proposed as powerful surrogates of progressive disease. Because of substantial practical impact in future HPV vaccine trials using non-HPV 16/18 vaccines, studies on HR-HPV persistence as a surrogate endpoint of progressive CIN have been subject to a comprehensive meta-analyses recently. The present communication was solicited to bring this important and timely topic to the awareness of the readers, in a format consisting of a review of the recent literature, supplemented with the author's own experience from different studies. Based on a large number of relevant studies, there remains little doubt that persistence of HR-HPV for 6+ or 12+ months is associated with a significantly increased risk of developing incident high-grade CIN. However, some data also disclosed several important issues that need to be carefully considered and/or adequately resolved before adopting 6M+ or 12M+ HR-HPV persistence as a surrogate of progressive disease. These include i) definitions of HPV persistence, ii) HPV detection techniques and iii) testing intervals and iv) length of follow-up, as well as v) diagnosis of the surrogate endpoints, and vi) other study characteristics, including vii) the type of reference category used in calculating the risk estimates. All these issues are critically discussed in the present communication. Of major impact seems to be the reference category used to calculate these risk estimates, as evident from the NIS-LAMS cohort. Taken together, it is suggested that in all future studies using the 6M+ or 12M+ HR-HPV persistence as a surrogate endpoint of progressive disease, a "gold standard" should be used in calculating the risk estimates. In addition to deciding, 1) whether to use 6M+ or 12M+ persistence criteria, and 2) cytological, histological or combined surrogate endpoints (SIL, CIN1, CIN2, CIN/SIL), one should 3) use exclusively the HPV negative reference group in calculating the risk estimates for viral persistence endpoints. This is supported by the data from the recent meta-analysis as well as from the author's combined NIS-LAMS cohort, both implicating that the most consistent association to progressive disease is obtained when women with persistent HR-HPV are compared with HPV-negative women. It is the conviction of this author that the two other reference categories (HPV transient and HPV mixed outcome) are far too heterogeneous and subject to potential misclassifications to give consistent and reproducible risk estimates for HR-HPV persistence as a surrogate endpoint of progressive CIN.

Surrogate Endpoints and Risk Adaptive Strategies in Previously Untreated Follicular Lymphoma.

PubMed

Narkhede, Mayur S; Cheson, Bruce D

2018-05-05

Follicular lymphoma is the second most common subtype of non-Hodgkin lymphoma with an estimated 3.18 cases per 100,000 people. Despite the prolongation of survival with chemoimmunotherapy, variability in response to initial treatment and outcome still exists. Whereas prolonging overall survival is important, it is generally an unreasonable primary endpoint in the front-line setting. The long follow-up needed and the influence of subsequent therapies creates a potential bias. Thus, clinical trials require approximately 5 to 8 years from activation to completion and analysis of outcomes. This duration results in enormous cost and a delay in developing newer therapies. Thus, there is a need to identify markers or surrogate endpoints that can be used in clinical trials to expedite the development of new treatments. This review will discuss various clinical, radiologic, and laboratory measures used to assess outcomes and overall survival in patients with untreated follicular lymphoma, and gauge their utility in clinical trials as surrogate endpoints. Copyright © 2018 Elsevier Inc. All rights reserved.

Correlating Surrogate Endpoints with Overall Survival at the Individual Patient Level in BRAFV600E-Mutated Metastatic Melanoma Patients Treated with Vemurafenib.

PubMed

Zabor, Emily C; Heller, Glenn; Schwartz, Lawrence H; Chapman, Paul B

2016-03-15

Surrogate endpoints are needed that correlate with overall survival (OS). We analyzed individual patient tumor data from a phase III trial of vemurafenib versus dacarbazine (BRIM3) to identify criteria for tumor measures that correlated with OS. Correlates were validated using a separate data set from a phase II trial of vemurafenib (BRIM2). Deidentified tumor measurements and OS data from BRIM3 and from BRIM2 were analyzed. Target tumor measurement data and nontarget tumor data were available from pretreatment, weeks 6,12, and every 9 weeks thereafter. In the BRIM3 data set, associations of OS with both early tumor response (first 12 weeks) and time to progression (TTP) were assessed. Different definitions of response and progression were explored. Findings were validated using the BRIM2 data set. Thresholds of early response were explored ranging from any degree of tumor shrinkage to 100% tumor shrinkage. Correlation was weak at all thresholds tested. TTP, however, was more strongly correlated with OS. The strongest correlation was seen when progression was defined as ≥50% increase in the sum of tumor diameters or appearance of new tumors. This was confirmed by similar analyses in the BRIM2 cohort. TTP defined as ≥50% increase in the sum of tumor diameters or appearance of new tumors was more strongly associated with OS than early tumor shrinkage in melanoma patients treated with RAF inhibitor. In future trials, consideration should be given to replacing response rate with TTP or PFS as preferable clinical endpoints in early-phase studies. ©2015 American Association for Cancer Research.

Improvement in surrogate endpoints by a multidisciplinary team in a mobile clinic serving a low-income, immigrant minority population in South Florida.

PubMed

Singh-Franco, Devada; Perez, Alexandra; Wolowich, William R

2013-02-01

To determine effect on surrogate endpoints for cardiovascular disease (CVD), we performed a retrospective chart review of 114 patients seen by a multidisciplinary team that provided primary care services in a mobile clinic over 12 months. Eligible patients had outcomes available for at least six months. Mixed effect modeling examined variation in surrogate markers for CVD: blood pressure (BP), heart rate, and body mass index. Repeated measures ANOVA compared lipids, hemoglobin A1c, and medication use from baseline and throughout study. Most patients were female (75%), Haitian (76%), and low-income ($747/month) with average age 63 years. Common diagnoses were hypertension (82%) and hyperlipidemia (63%). Significant reduction in systolic BP, total- and LDL-cholesterol, and hemoglobin A1c were found (p<.05). Use of ACE-inhibitors, beta-blockers, diuretics, aspirin, metformin, and statins increased significantly (p<.05). Mobile clinic with a multidisciplinary team improved surrogate endpoints over 12 months in underserved, low-income, mostly foreign-born, Haitian population in U.S.

Impact of copula directional specification on multi-trial evaluation of surrogate endpoints

PubMed Central

Renfro, Lindsay A.; Shang, Hongwei; Sargent, Daniel J.

2014-01-01

Evaluation of surrogate endpoints using patient-level data from multiple trials is the gold standard, where multi-trial copula models are used to quantify both patient-level and trial-level surrogacy. While limited consideration has been given in the literature to copula choice (e.g., Clayton), no prior consideration has been given to direction of implementation (via survival versus distribution functions). We demonstrate that evenwith the “correct” copula family, directional misspecification leads to biased estimates of patient-level and trial-level surrogacy. We illustrate with a simulation study and a re-analysis of disease-free survival as a surrogate for overall survival in early stage colon cancer. PMID:24905465

Prognostic factors versus markers of response to treatment versus surrogate endpoints: Three different concepts.

PubMed

Sormani, Maria Pia

2017-03-01

Multiple sclerosis is a highly heterogeneous disease; the quantitative assessment of disease progression is problematic for many reasons, including the lack of objective methods to measure disability and the long follow-up times needed to detect relevant and stable changes. For these reasons, the importance of prognostic markers, markers of response to treatments and of surrogate endpoints, is crucial in multiple sclerosis research. Aim of this report is to clarify some basic definitions and methodological issues about baseline factors to be considered prognostic markers or markers of response to treatment; to define the dynamic role that variables must have to be considered surrogate markers in relation to specific treatments.

The promise of dynamic contrast-enhanced imaging in radiation therapy.

PubMed

Cao, Yue

2011-04-01

Dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and computed tomography (CT) scanning are emerging as valuable tools to quantitatively map the spatial distribution of vascular parameters, such as perfusion, vascular permeability, blood volume, and mean transit time in tumors and normal organs. DCE MRI/CT have shown prognostic and predictive value for response of certain cancers to chemotherapy and radiation therapy. DCE MRI/CT offer the promise of early assessment of tumor response to radiation therapy, opening a window for adaptively optimizing radiation therapy based upon functional alterations that occur earlier than morphologic changes. DCE MRI/CT has also shown the potential of mapping dose responses in normal organs and tissue for evaluation of individual sensitivity to radiation, providing additional opportunities to minimize risks of radiation injury. The evidence for potentially applying DCE MRI and CT for selection and delineation of radiation boost targets is growing. The clinical use of DCE MRI and CT scanning as a biomarker or even a surrogate endpoint for radiation therapy assessment of tumor and normal organs must consider technical validation issues, including standardization, reproducibility, accuracy and robustness, and clinical validation of the sensitivity and specificity for each specific problem of interest. Although holding great promise, to date, DCE MRI and CT scanning have not been qualified as a surrogate endpoint for radiation therapy assessment or for treatment modification in any prospective phase III clinical trial for any tumor site. Copyright © 2011 Elsevier Inc. All rights reserved.

Early analysis of surrogate endpoints for metastatic melanoma in immune checkpoint inhibitor trials.

PubMed

Petrelli, Fausto; Coinu, Andrea; Cabiddu, Mary; Borgonovo, Karen; Ghilardi, Mara; Lonati, Veronica; Barni, Sandro

2016-06-01

Recent major phase III trials led to the approval of immune checkpoint inhibitors (ipilimumab, pembrolizumab, and nivolumab) in metastatic malignant melanoma (MM). We aim to assess whether median progression-free survival, and 1 and 2-year overall survival (OS) rates are reliable surrogate endpoints for median OS through a meta-analysis of published trials involving immunotherapy. A systematic literature search in PubMed, EMBASE, Web of Science, and SCOPUS of published phase II to III trials with immunotherapy as the treatment for MM was conducted. Adjusted weighted linear regression was used to calculate Pearson correlations (R) between surrogates and median OS, and between treatment effects on surrogates and median OS. A total of 13 studies involving 3373 patients with MM were identified. The correlation of progression-free survival with OS was not significant (R = 0.45, P = .11). Conversely, the correlation between 1-year OS and median OS was very strong (R = 0.93, 95% confidence interval [CI] 0.84-0.96, P < .00001), as was the correlation between 2-year OS and OS (R = 0.79, 95% CI 0.51-0.91, P = .0001). The correlation between the treatment effects on 1-year OS and OS was also significant (R = -0.86, 95% CI -0.3 to 0.97, P = .01). Similar results were obtained for 2-year OS. According to the available study data, 1-year OS rate could be regarded as a potential surrogate for median OS in novel immunotherapy trials of metastatic MM. Waiting for ongoing studies (e.g., pembrolizumab), we suggest that this intermediate endpoint could be considered as a potential primary endpoint in future clinical trials.

Comprehensive Review on the Surrogate Endpoints of Efficacy Proposed or Hypothesized in the Scientific Community Today.

PubMed

von Minckwitz, Gunter; Fontanella, Caterina

2015-05-01

An intermediate endpoint is a surrogate marker of treatment efficacy assessed earlier than the true outcome of interest. A suitable intermediate endpoint in neoadjuvant trials of specific breast cancer subtypes is pathological complete response (pCR) rate, defined as no invasive (+/-noninvasive) residual cancer in breast and nodes at surgery. On the basis of available evidence, Food and Drug Administration the US allowed to use of pCR as a surrogate endpoint for accelerated approval process. However, surrogacy to long-term outcome remains an unresolved issue. Literature data provide indications that triple-negative, HER2-positive, and high-grade hormone receptor-positive breast cancer subtypes achieved the highest pCR rate; the prognostic impact of pCR on survival is established only for these aggressive subtypes. In the German experience, early response after two to four cycles of neoadjuvant treatment strongly correlated with both pCR rate and long-term outcome. Therefore, early response may be considered a predictive marker for pCR and used for driving clinical trial design. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Molecular epidemiology: new rules for new tools?

PubMed

Merlo, Domenico Franco; Sormani, Maria Pia; Bruzzi, Paolo

2006-08-30

Molecular epidemiology combines biological markers and epidemiological observations in the study of the environmental and genetic determinants of cancer and other diseases. The potential advantages associated with biomarkers are manifold and include: (a) increased sensitivity and specificity to carcinogenic exposures; (b) more precise evaluation of the interplay between genetic and environmental determinants of cancer; (c) earlier detection of carcinogenic effects of exposure; (d) characterization of disease subtypes-etiologies patterns; (e) evaluation of primary prevention measures. These, in turn, may translate into better tools for etiologic research, individual risk assessment, and, ultimately, primary and secondary prevention. An area that has not received sufficient attention concerns the validation of these biomarkers as surrogate endpoints for cancer risk. Validation of a candidate biomarker's surrogacy is the demonstration that it possesses the properties required for its use as a substitute for a true endpoint. The principles underlying the validation process underwent remarkable developments and discussion in therapeutic research. However, the challenges posed by the application of these principles to epidemiological research, where the basic tool for this validation (i.e., the randomized study) is seldom possible, have not been thoroughly explored. The validation process of surrogacy must be applied rigorously to intermediate biomarkers of cancer risk before using them as risk predictors at the individual as well as at the population level.

Sperm count as a surrogate endpoint for male fertility control.

PubMed

Benda, Norbert; Gerlinger, Christoph

2007-11-30

When assessing the effectiveness of a hormonal method of fertility control in men, the classical approach used for the assessment of hormonal contraceptives in women, by estimating the pregnancy rate or using a life-table analysis for the time to pregnancy, is difficult to apply in a clinical development program. The main reasons are the dissociation of the treated unit, i.e. the man, and the observed unit, i.e. his female partner, the high variability in the frequency of male intercourse, the logistical cost and ethical concerns related to the monitoring of the trial. A reasonable surrogate endpoint of the definite endpoint time to pregnancy is sperm count. In addition to the avoidance of the mentioned problems, trials that compare different treatments are possible with reasonable sample sizes, and study duration can be shorter. However, current products do not suppress sperm production to 100 per cent in all men and the sperm count is only observed with measurement error. Complete azoospermia might not be necessary in order to achieve an acceptable failure rate compared with other forms of male fertility control. Therefore, the use of sperm count as a surrogate endpoint must rely on the results of a previous trial in which both the definitive- and surrogate-endpoint results were assessed. The paper discusses different estimation functions of the mean pregnancy rate (corresponding to the cumulative hazard) that are based on the results of sperm count trial and a previous trial in which both sperm count and time to pregnancy were assessed, as well as the underlying assumptions. Sample size estimations are given for pregnancy rate estimation with a given precision.

Surrogate and clinical endpoints in interventional cardiology: are statistics the brakes?

PubMed

Waliszewski, Matthias; Rittger, Harald

2016-10-01

Randomized controlled trials are the gold standard for demonstrating safety and efficacy of coronary devices with or without accompanying drug treatments in interventional cardiology. With the advent of last-generation drug-eluting stents having enhanced technical attributes and long-term clinical benefits, the proof of incremental angiographic or long-term clinical efficacy becomes more challenging. The purpose of this review is to provide an overview of the most common and alternative study endpoints in interventional cardiology and their potential reimbursement value. Moreover, we intend to describe the statistical limitations in order to demonstrate differences between potential treatment groups. Furthermore, careful endpoint recommendations for a given patient number are offered for future study designs. The number of patients per treatment group was estimated for various study designs such as noninferiority test hypotheses with hard clinical endpoints and various surrogate endpoints. To test for differences in various surrogate endpoint scenarios, the corresponding patient group sizes were explored. To evaluate these endpoints in terms of their reimbursement impact, preferred endpoints for technical appraisals in interventional cardiology at the National Institute of Health and Care Excellence (NICE) were used. Even with the most stringent experimental control to reduce bias-introducing factors, studies with hard primary clinical endpoints such as the occurrence of major adverse cardiac events (MACE) or target-lesion revascularization (TLR) rates remain the gold standard, with numbers reaching into the 300-700 patient range per group. Study designs using loss in fractional-flow reserve (FFR) or stent-strut-coverage rates can be statistically formulated; however, the clinical ramifications for the patient remain to be discussed. Nonrandomized study designs with intrapatient angiographic controls in nontarget vessels may merit further thoughts and explorations. From a reimbursement impact, the primary endpoints MACE and TLR are the best choices for a moderately sized study population of 500 patients per group. Angiographic endpoints, in particular minimal lumen diameter (MLD), are not useful in this context. The emerging endpoints such as loss in FFR or stent coverage require smaller patient populations. However, their impact on reimbursement-related decisions is limited. © The Author(s), 2016.

Surrogate and clinical endpoints in interventional cardiology: are statistics the brakes?

PubMed Central

Waliszewski, Matthias; Rittger, Harald

2016-01-01

Background: Randomized controlled trials are the gold standard for demonstrating safety and efficacy of coronary devices with or without accompanying drug treatments in interventional cardiology. With the advent of last-generation drug-eluting stents having enhanced technical attributes and long-term clinical benefits, the proof of incremental angiographic or long-term clinical efficacy becomes more challenging. The purpose of this review is to provide an overview of the most common and alternative study endpoints in interventional cardiology and their potential reimbursement value. Moreover, we intend to describe the statistical limitations in order to demonstrate differences between potential treatment groups. Furthermore, careful endpoint recommendations for a given patient number are offered for future study designs. Methods: The number of patients per treatment group was estimated for various study designs such as noninferiority test hypotheses with hard clinical endpoints and various surrogate endpoints. To test for differences in various surrogate endpoint scenarios, the corresponding patient group sizes were explored. To evaluate these endpoints in terms of their reimbursement impact, preferred endpoints for technical appraisals in interventional cardiology at the National Institute of Health and Care Excellence (NICE) were used. Results: Even with the most stringent experimental control to reduce bias-introducing factors, studies with hard primary clinical endpoints such as the occurrence of major adverse cardiac events (MACE) or target-lesion revascularization (TLR) rates remain the gold standard, with numbers reaching into the 300–700 patient range per group. Study designs using loss in fractional-flow reserve (FFR) or stent-strut-coverage rates can be statistically formulated; however, the clinical ramifications for the patient remain to be discussed. Nonrandomized study designs with intrapatient angiographic controls in nontarget vessels may merit further thoughts and explorations. Conclusions: From a reimbursement impact, the primary endpoints MACE and TLR are the best choices for a moderately sized study population of 500 patients per group. Angiographic endpoints, in particular minimal lumen diameter (MLD), are not useful in this context. The emerging endpoints such as loss in FFR or stent coverage require smaller patient populations. However, their impact on reimbursement-related decisions is limited. PMID:27378486

An evaluation of motor evoked potential surrogate endpoints during intracranial vascular procedures.

PubMed

Holdefer, R N; MacDonald, D B; Guo, L; Skinner, S A

2016-02-01

MEPs are used as surrogate endpoints to predict the effectiveness of interventions, made in response to MEP deterioration, in avoiding new postoperative deficits. MEP performance in capturing intervention effects on these outcomes was investigated. A meta-analysis of studies using MEPs during intracranial vascular surgeries between 2003 and 2014 was performed. MEP diagnostic performance and relative risk of new postoperative deficits for reversible compared with irreversible MEP changes were determined. Intervention efficacy in reversing MEP deterioration and postoperative outcomes was compared across studies. MEP diagnostic performance compared favorably with that of other tests used in medicine, with all likelihood ratios >10. The summary relative risk comparing reversible and irreversible changes was 0.40, indicating a 60% decrease in new deficits for reversible MEP changes. The proportion of MEP deteriorations which recovered was negatively correlated with the proportion of new postoperative deficits (r=-0.81, p<.005). The effectiveness of interventions in recovering an MEP decline was predictive of preserved neurologic status. MEPs are provisionally qualified as surrogate endpoints given potentially major harms to the patient if they are not used, compared to the minimal harms and costs associated with their use. The performance of MEPs as substitute, or surrogate, endpoints during intracranial vascular surgeries for new deficits in motor strength in the immediate postoperative period was directly assessed for ten recent studies. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Pulmonary function tests as outcomes for systemic sclerosis interstitial lung disease.

PubMed

Caron, Melissa; Hoa, Sabrina; Hudson, Marie; Schwartzman, Kevin; Steele, Russell

2018-06-30

Interstitial lung disease (ILD) is the leading cause of morbidity and mortality in systemic sclerosis (SSc). We performed a systematic review to characterise the use and validation of pulmonary function tests (PFTs) as surrogate markers for systemic sclerosis-associated interstitial lung disease (SSc-ILD) progression.Five electronic databases were searched to identify all relevant studies. Included studies either used at least one PFT measure as a longitudinal outcome for SSc-ILD progression ( i.e. outcome studies) and/or reported at least one classical measure of validity for the PFTs in SSc-ILD ( i.e. validation studies).This systematic review included 169 outcome studies and 50 validation studies. Diffusing capacity of the lung for carbon monoxide ( D LCO ) was cumulatively the most commonly used outcome until 2010 when it was surpassed by forced vital capacity (FVC). FVC (% predicted) was the primary endpoint in 70.4% of studies, compared to 11.3% for % predicted D LCO Only five studies specifically aimed to validate the PFTs: two concluded that D LCO was the best measure of SSc-ILD extent, while the others did not favour any PFT. These studies also showed respectable validity measures for total lung capacity (TLC).Despite the current preference for FVC, available evidence suggests that D LCO and TLC should not yet be discounted as potential surrogate markers for SSc-ILD progression. Copyright ©ERS 2018.

Correlates of protection for rotavirus vaccines: Possible alternative trial endpoints, opportunities, and challenges.

PubMed

Angel, Juana; Steele, A Duncan; Franco, Manuel A

2014-01-01

Rotavirus (RV) is a major vaccine-preventable killer of young children worldwide. Two RV vaccines are globally commercially available and other vaccines are in different stages of development. Due to the absence of a suitable correlate of protection (CoP), all RV vaccine efficacy trials have had clinical endpoints. These trials represent an important challenge since RV vaccines have to be introduced in many different settings, placebo-controlled studies are unethical due to the availability of licensed vaccines, and comparator assessments for new vaccines with clinical endpoints are very large, complex, and expensive to conduct. A CoP as a surrogate endpoint would allow predictions of vaccine efficacy for new RV vaccines and enable a regulatory pathway, contributing to the more rapid development of new RV vaccines. The goal of this review is to summarize experiences from RV natural infection and vaccine studies to evaluate potential CoP for use as surrogate endpoints for assessment of new RV vaccines, and to explore challenges and opportunities in the field.

Outcome switching in randomized controlled oncology trials reporting on surrogate endpoints: a cross-sectional analysis.

PubMed

Falk Delgado, Alberto; Falk Delgado, Anna

2017-08-23

Inconsistent reporting of clinical trials is well-known in the literature. Despite this, factors associated with poor practice such as outcome switching in clinical trials are poorly understood. We performed a cross-sectional analysis to evaluate the prevalence of, and the factors associated with outcome switching. PubMed and Embase were searched for pharmaceutical randomized controlled trials (RCTs) in oncology reporting on a surrogate primary outcome published in 2015. Outcome switching was present in 18% (39/216). First-author male sex was significantly more likely associated with outcome switching compared to female sex with an OR of 3.05 (95% CI 1.07-8.64, p = 0.04) after multivariable adjustment. For-profit funded RCTs were less likely associated with outcome switching compared to non-profit funded research with an OR of 0.22 (95% CI 0.07-0.74, p = 0.01). First author male sex was more likely associated with outcome switching compared to female sex in drug oncology RCTs reporting on a primary surrogate endpoint. For-profit funded research was less likely associated with outcome switching compared to research funded by non-profit organizations. Furthermore, 18 percent of drug oncology trials reporting on a surrogate endpoint could have a higher risk of false positive results due to primary outcome switching.

The art and science of choosing efficacy endpoints for rare disease clinical trials.

PubMed

Cox, Gerald F

2018-04-01

An important challenge in rare disease clinical trials is to demonstrate a clinically meaningful and statistically significant response to treatment. Selecting the most appropriate and sensitive efficacy endpoints for a treatment trial is part art and part science. The types of endpoints should align with the stage of development (e.g., proof of concept vs. confirmation of clinical efficacy). The patient characteristics and disease stage should reflect the treatment goal of improving disease manifestations or preventing disease progression. For rare diseases, regulatory approval requires demonstration of clinical benefit, defined as how a patient, feels, functions, or survives, in at least one adequate and well-controlled pivotal study conducted according to Good Clinical Practice. In some cases, full regulatory approval can occur using a validated surrogate biomarker, while accelerated, or provisional, approval can occur using a biomarker that is likely to predict clinical benefit. Rare disease studies are small by necessity and require the use of endpoints with large effect sizes to demonstrate statistical significance. Understanding the quantitative factors that determine effect size and its impact on powering the study with an adequate sample size is key to the successful choice of endpoints. Interpreting the clinical meaningfulness of an observed change in an efficacy endpoint can be justified by statistical methods, regulatory precedence, and clinical context. Heterogeneous diseases that affect multiple organ systems may be better accommodated by endpoints that assess mean change across multiple endpoints within the same patient rather than mean change in an individual endpoint across all patients. © 2018 Wiley Periodicals, Inc.

Individual and Composite Study Endpoints: Separating the Wheat from the Chaff

PubMed Central

Goldberg, Robert; Gore, Joel M.; Barton, Bruce; Gurwitz, Jerry

2014-01-01

We provide an overview of the individual and combined clinical endpoints and patient reported outcomes typically used in clinical trials and prospective epidemiological investigations. We discuss the strengths and limitations associated with the utilization of aggregated study endpoints and surrogate measures of important clinical endpoints and patient-centered outcomes. We hope that the points raised in this overview will lead to the collection of clinically rich, relevant, measurable, and cost-efficient study outcomes. PMID:24486289

Surrogate and Intermediate Endpoints in Randomized Trials: What's the Goal?

PubMed

Korn, Edward L; Freidlin, Boris

2018-05-15

Establishing trial-level surrogacy of an intermediate endpoint for predicting survival benefit in future trials is extremely challenging because of the extrapolations required, but there are other useful drug development and patient management applications of intermediate endpoints. Clin Cancer Res; 24(10); 2239-40. ©2018 AACR See related article by Mushti et al., p. 2268 . ©2018 American Association for Cancer Research.

Predicting analysis time in events-driven clinical trials using accumulating time-to-event surrogate information.

PubMed

Wang, Jianming; Ke, Chunlei; Yu, Zhinuan; Fu, Lei; Dornseif, Bruce

2016-05-01

For clinical trials with time-to-event endpoints, predicting the accrual of the events of interest with precision is critical in determining the timing of interim and final analyses. For example, overall survival (OS) is often chosen as the primary efficacy endpoint in oncology studies, with planned interim and final analyses at a pre-specified number of deaths. Often, correlated surrogate information, such as time-to-progression (TTP) and progression-free survival, are also collected as secondary efficacy endpoints. It would be appealing to borrow strength from the surrogate information to improve the precision of the analysis time prediction. Currently available methods in the literature for predicting analysis timings do not consider utilizing the surrogate information. In this article, using OS and TTP as an example, a general parametric model for OS and TTP is proposed, with the assumption that disease progression could change the course of the overall survival. Progression-free survival, related both to OS and TTP, will be handled separately, as it can be derived from OS and TTP. The authors seek to develop a prediction procedure using a Bayesian method and provide detailed implementation strategies under certain assumptions. Simulations are performed to evaluate the performance of the proposed method. An application to a real study is also provided. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Progression-free survival in advanced ovarian cancer: a Canadian review and expert panel perspective

PubMed Central

Oza, A.M.; Castonguay, V.; Tsoref, D.; Diaz–Padilla, I.; Karakasis, K.; Mackay, H.; Welch, S.; Weberpals, J.; Hoskins, P.; Plante, M.; Provencher, D.; Tonkin, K.; Covens, A.; Ghatage, P.; Gregoire, J.; Hirte, H.; Miller, D.; Rosen, B.; Maroun, J.; Buyse, M.; Coens, C.; Brady, M.F.; Stuart, G.C.E.

2011-01-01

Ovarian cancer is leading cause of gynecologic cancer mortality in Canada. To date, overall survival (os) has been the most-used endpoint in oncology trials because of its relevance and objectivity. However, as a result of various factors, including the pattern of sequential salvage therapies, measurement of os and collection of os data are becoming particularly challenging. Phase ii and iii trials have therefore adopted progression-free survival (pfs) as a more convenient surrogate endpoint; however, the clinical significance of pfs remains unclear. This position paper presents discussion topics and findings from a pan-Canadian meeting of experts that set out to evaluate the relevance of pfs as a valid endpoint in ovarian cancer;reach a Canadian consensus on the relevance of pfs in ovarian cancer; andtry to address how pfs translates into clinical benefit in ovarian cancer. Overall, the findings and the group consensus posit that future studies should ensure that trials are designed to evaluate pfs, os, and other clinically relevant endpoints such as disease-related symptoms or quality of life;incorporate interim futility analyses intended to stop accrual early when the experimental regimen is not active;stop trials early to declare superiority only when compelling evidence suggests that a new treatment provides benefit for a pre-specified, clinically relevant endpoint such as os or symptom relief; anddiscourage early release of secondary endpoint results when such a release might increase the frequency of crossover to the experimental intervention. PMID:21969808

The Use of Surrogate and Patient-Relevant Endpoints in Outcomes-Based Market Access Agreements : Current Debate.

PubMed

Toumi, Mondher; Jarosławski, Szymon; Sawada, Toyohiro; Kornfeld, Åsa

2017-02-01

The high cost of novel treatments is the major driver of negative or restricted reimbursement decisions by healthcare payers in many countries. Costly drugs can be subject to Market Access Agreements (MAAs), which are financial (Commercial Agreements [CAs]) or outcomes-based (Payment for Performance Agreements [P4Ps] or Coverage with Evidence Development agreements [CEDs]). Outcomes in outcomes-based MAAs are assessed through changes in surrogate endpoints (SEPs) or patient-relevant endpoints (PEPs). In May 2015, we reviewed published and grey literature on MAAs between manufacturers and large, institutionalised payers from all geographical areas, and classified the schemes into CAs, P4Ps and CEDs, as well as by therapeutic area and country. Outcomes-based MAAs were further categorized by the endpoint used. Overall, we identified 143 MAAs, 56 (39.2 %) of which were pure CAs, 53 (37.1 %) were CEDs, and 34 (23.8 %) were P4Ps. Among the CEDs, 49 were PEP CEDs and four were SEP CEDs; of the 34 P4Ps, 29 were SEP P4Ps for 30 drugs, and five were PEP P4Ps for at least six drugs; and among 87 outcomes-based MAAs (CEDs + P4Ps), PEP CEDs were the most common (56.3 %), followed by SEP P4Ps (34.1 %). The high proportion of SEPs used in P4Ps contrasts with the high proportion of PEPs used in CEDs. CEDs employ PEPs and it appears that they are used to reduce uncertainty about a drug's clinical outcomes and/or real-life use, and thus allow payers to align a product's value with price. We argue that P4Ps do not reduce uncertainty about real-life effectiveness and can only constitute an outcome guarantee for payers if they are based on PEPs or validated SEPs.

Do Surrogate Endpoints Better Correlate with Overall Survival in Studies That Did Not Allow for Crossover or Reported Balanced Postprogression Treatments? An Application in Advanced Non-Small Cell Lung Cancer.

PubMed

Hashim, Mahmoud; Pfeiffer, Boris M; Bartsch, Robert; Postma, Maarten; Heeg, Bart

2018-01-01

In previous studies, correlation between overall survival (OS) and surrogate endpoints like objective response rate (ORR) or progression-free survival (PFS) in advanced non-small cell lung cancer (NSCLC) was poor. This can be biased by crossover and postprogression treatments. To evaluate the relationship between these two surrogate endpoints and OS in advanced NSCLC studies that did not allow for crossover or reported balanced post-progression treatments. A systematic review in patients with advanced NSCLC receiving second- and further-line therapy was performed. The relationship between the absolute difference in ORR or median PFS (mPFS) and the absolute difference in median OS (mOS) was assessed using the correlation coefficient (R) and weighted regression models. The analysis was repeated in predefined data cuts based on crossover and balance of postprogression treatments. When the upper limit of R's 95% confidence interval (CI) was more than 0.7, the surrogate threshold effect (STE) was estimated. In total, 146 randomized clinical trials (43,061 patients) were included. The mean ORR, mPFS, and mOS were 12.2% ± 11.2%, 3.2 ± 1.3 months, and 9.6 ± 4.1 months, respectively. The correlation coefficients of ORR and mPFS were 0.181 (95% CI 0.016-0.337) and 0.254 (95% CI 0.074-0.418), respectively, with mOS. Nevertheless, in trials that did not allow crossover and reported balanced postprogression treatments, the correlation coefficients of ORR and mPFS were 0.528 (95% CI 0.081-0.798) and 0.778 (95% CI 0.475-0.916), respectively, with mOS. On the basis of STE estimation, in trials showing significant treatment effect size of 41.0% or more ORR or 4.15 or more mPFS months, OS benefit can be expected with sufficient certainty. Crossover and postprogression treatments may bias the relationship between surrogate endpoints and OS. Presented STE calculation can be used to interpret treatment effect on either ORR or PFS when used as primary endpoints. Copyright © 2018 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Biomarkers and Surrogate Endpoints in Uveitis: The Impact of Quantitative Imaging.

PubMed

Denniston, Alastair K; Keane, Pearse A; Srivastava, Sunil K

2017-05-01

Uveitis is a major cause of sight loss across the world. The reliable assessment of intraocular inflammation in uveitis ('disease activity') is essential in order to score disease severity and response to treatment. In this review, we describe how 'quantitative imaging', the approach of using automated analysis and measurement algorithms across both standard and emerging imaging modalities, can develop objective instrument-based measures of disease activity. This is a narrative review based on searches of the current world literature using terms related to quantitative imaging techniques in uveitis, supplemented by clinical trial registry data, and expert knowledge of surrogate endpoints and outcome measures in ophthalmology. Current measures of disease activity are largely based on subjective clinical estimation, and are relatively insensitive, with poor discrimination and reliability. The development of quantitative imaging in uveitis is most established in the use of optical coherence tomographic (OCT) measurement of central macular thickness (CMT) to measure severity of macular edema (ME). The transformative effect of CMT in clinical assessment of patients with ME provides a paradigm for the development and impact of other forms of quantitative imaging. Quantitative imaging approaches are now being developed and validated for other key inflammatory parameters such as anterior chamber cells, vitreous haze, retinovascular leakage, and chorioretinal infiltrates. As new forms of quantitative imaging in uveitis are proposed, the uveitis community will need to evaluate these tools against the current subjective clinical estimates and reach a new consensus for how disease activity in uveitis should be measured. The development, validation, and adoption of sensitive and discriminatory measures of disease activity is an unmet need that has the potential to transform both drug development and routine clinical care for the patient with uveitis.

Correlates of protection for inactivated enterovirus 71 vaccine: the analysis of immunological surrogate endpoints.

PubMed

Zhu, Wenbo; Jin, Pengfei; Li, Jing-Xin; Zhu, Feng-Cai; Liu, Pei

2017-09-01

Inactivated Enterovirus 71 (EV71) vaccines showed significant efficacy against the diseases associated with EV71 and a neutralizing antibody (NTAb) titer of 1:16-1:32 was suggested as the correlates of the vaccine protection. This paper aims to further estimate the immunological surrogate endpoints for the protection of inactivated EV71 vaccines and the effect factors. Pre-vaccination NTAb against EV71 at baseline (day 0), post-vaccination NTAb against EV71 at day 56, and the occurrence of laboratory-confirmed EV71-associated diseases during a 24-months follow-up period were collected from a phase 3 efficacy trial of an inactivated EV71 vaccine. We used the mixed-scaled logit model and the absolute sigmoid function by some extensions in continuous models to estimate the immunological surrogate endpoint for the EV71 vaccine protection, respectively. For children with a negative baseline of EV71 NTAb titers, an antibody level of 26.6 U/ml (1:30) was estimated to provide at least a 50% protection for 12 months, and an antibody level of 36.2 U/ml (1:42) may be needed to achieve a 50% protective level of the population for 24 months. Both the pre-vaccination NTAb level and the vaccine protective period could affect the estimation of the immunological surrogate for EV71 vaccine. A post-vaccination NTAb titer of 1:42 or more may be needed for long-term protection. NCT01508247.

The value of surrogate endpoints for predicting real-world survival across five cancer types.

PubMed

Shafrin, Jason; Brookmeyer, Ron; Peneva, Desi; Park, Jinhee; Zhang, Jie; Figlin, Robert A; Lakdawalla, Darius N

2016-01-01

It is unclear how well different outcome measures in randomized controlled trials (RCTs) perform in predicting real-world cancer survival. We assess the ability of RCT overall survival (OS) and surrogate endpoints - progression-free survival (PFS) and time to progression (TTP) - to predict real-world OS across five cancers. We identified 20 treatments and 31 indications for breast, colorectal, lung, ovarian, and pancreatic cancer that had a phase III RCT reporting median OS and median PFS or TTP. Median real-world OS was determined using a Kaplan-Meier estimator applied to patients in the Surveillance and Epidemiology End Results (SEER)-Medicare database (1991-2010). Performance of RCT OS and PFS/TTP in predicting real-world OS was measured using t-tests, median absolute prediction error, and R(2) from linear regressions. Among 72,600 SEER-Medicare patients similar to RCT participants, median survival was 5.9 months for trial surrogates, 14.1 months for trial OS, and 13.4 months for real-world OS. For this sample, regression models using clinical trial OS and trial surrogates as independent variables predicted real-world OS significantly better than models using surrogates alone (P = 0.026). Among all real-world patients using sample treatments (N = 309,182), however, adding trial OS did not improve predictive power over predictions based on surrogates alone (P = 0.194). Results were qualitatively similar using median absolute prediction error and R(2) metrics. Among the five tumor types investigated, trial OS and surrogates were each independently valuable in predicting real-world OS outcomes for patients similar to trial participants. In broader real-world populations, however, trial OS added little incremental value over surrogates alone.

Validity of fish, birds and mammals as surrogates for amphibians and reptiles in pesticide toxicity assessment.

PubMed

Ortiz-Santaliestra, Manuel E; Maia, Joao P; Egea-Serrano, Andrés; Lopes, Isabel

2018-02-28

Amphibians and reptiles are the two most endangered groups of vertebrates. Environmental pollution by pesticides is recognised as one of the major factors threatening populations of these groups. However, the effects of pesticides on amphibians and reptiles have been studied for few substances, which is partly related to the fact that these animals are not included in the mandatory toxicity testing conducted as part of environmental risk assessments of pesticides. Whether risks of pesticides to amphibians and reptiles are addressed by surrogate taxa used in risk assessment is currently under debate. In order to develop a scientifically sound and robust risk assessment scheme, information needs to be gathered to examine whether fish, birds and mammals are valid surrogates for amphibians and reptiles. We updated a systematic review of scientific literature that was recently published compiling toxicity data on amphibians and reptiles. The outcome of this review was analysed with the purposes to (1) compare endpoints from amphibians and reptiles with the available information from fish, birds and mammals, and (2) develop species sensitivity distributions (SSDs) for those substances tested in at least six amphibian species (no substances were found tested in at least six reptile species) to identify a candidate amphibian model species to be used as surrogate in risk assessment. A positive correlation was found between toxicity recorded on fish and amphibians, the former revealing, in general, to be more sensitive than the latter to waterborne pollutants. In the terrestrial environment, although birds and mammals were more sensitive than amphibians and reptiles to at least 60% of tested substances, just a few weak significant correlations were observed. As a general rule, homoeothermic vertebrates are not good surrogates for reptiles and terrestrial amphibians in pesticide risk assessment. However, some chemical-dependent trends were detected, with pyrethroids and organochlorine insecticides being more toxic to amphibians or reptiles than to birds or mammals. These trends could ultimately help in decisions about protection provided by surrogate taxa for specific groups of substances, and also to determine when risk assessment of pesticides needs to pay special consideration to amphibians and reptiles. The outcome of this review reflects that there is still much information needed to reduce uncertainties and extract relevant conclusions on the overall protection of amphibians and reptiles by surrogate vertebrates.

Evidence for the use of parenteral nutrition in the pediatric intensive care unit.

PubMed

Fivez, Tom; Kerklaan, Dorian; Mesotten, Dieter; Verbruggen, Sascha; Joosten, Koen; Van den Berghe, Greet

2017-02-01

During hospitalization in a pediatric intensive care unit (PICU), critically ill children are fed artificially. Administered via the preferred enteral route, caloric targets are often not reached. Hence, parenteral nutrition is given to this patient population. In this review we analyzed the available evidence from randomized controlled trials (RCTs) that supports the use of parenteral nutrition in children during critical illness. A search strategy in Ovid MEDLINE and Ovid EMBASE was created and trial registries were screened to identify the relevant RCTs. Studies were included if they were randomized controlled trials, involved pediatric patients admitted to PICU, and compared different dosing/compositions of parenteral nutrition. Descriptive studies and reviews were excluded. Of the 584 articles identified by the search strategy, only 114 articles were retained after title screening. Further abstract and full text screening identified 6 small RCTs that compared two dosing/composition strategies of parenteral nutrition. These trials reported differences in surrogate endpoints without an effect on hard clinical endpoints. The RCTs observed improvements in these surrogate endpoints with the use of more calories or when parenteral glutamine or fish oil was added. The few RCTs suggest that surrogate endpoints can be affected by providing parenteral nutrition to critically ill children, but the studies were not statistically powered to draw meaningful clinical conclusions. Large RCTs with clinically relevant outcome measures are urgently needed to support the current nutritional guidelines that advise the use of parenteral nutrition in the PICU. Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Validating potential toxicity assays to assess petroleum hydrocarbon toxicity in polar soil.

PubMed

Harvey, Alexis Nadine; Snape, Ian; Siciliano, Steven Douglas

2012-02-01

Potential microbial activities are commonly used to assess soil toxicity of petroleum hydrocarbons (PHC) and are assumed to be a surrogate for microbial activity within the soil ecosystem. However, this assumption needs to be evaluated for frozen soil, in which microbial activity is limited by liquid water (θ(liquid)). Influence of θ(liquid) on in situ toxicity was evaluated and compared to the toxicity endpoints of potential microbial activities using soil from an aged diesel fuel spill at Casey Station, East Antarctica. To determine in situ toxicity, gross mineralization and nitrification rates were determined by the stable isotope dilution technique. Petroleum hydrocarbon-contaminated soil (0-8,000 mg kg(-1)), packed at bulk densities of 1.4, 1.7, and 2.0 g cm(-3) to manipulate liquid water content, was incubated at -5°C for one, two, and three months. Although θ(liquid) did not have a significant effect on gross mineralization or nitrification, gross nitrification was sensitive to PHC contamination, with toxicity decreasing over time. In contrast, gross mineralization was not sensitive to PHC contamination. Toxic response of gross nitrification was comparable to potential nitrification activity (PNA) with similar EC25 (effective concentration causing a 25% effect in the test population) values determined by both measurement endpoints (400 mg kg(-1) for gross nitrification compared to 200 mg kg(-1) for PNA), indicating that potential microbial activity assays are good surrogates for in situ toxicity of PHC contamination in polar regions. Copyright © 2011 SETAC.

Pediatric Crohn Disease Clinical Outcome Assessments and Biomarkers: Current State and Path Forward for Global Collaboration.

PubMed

Sun, Haihao; Vesely, Richard; Lee, Kerry Jo; Klein, Agnes; Ikima, Mutsuhiro; Mulberg, Andrew E

2017-03-01

There is a pressing need for drug development in pediatric Crohn disease (CD). Our aim was to provide strategic approaches toward harmonization of current thinking about clinical outcome assessments (COAs) and biomarkers to facilitate drug development in pediatric CD. Scientists from the United States Food and Drug Administration, European Medicines Agency, Health Canada, and the Pharmaceuticals and Medical Devices Agency of Japan had monthly teleconferences from January 2014 through May 2015. A literature review was conducted to assess the measurement properties of all existing COA tools and to evaluate the current landscape of biomarkers used in pediatric CD. Based on the findings of literature review, we reached the consensus on the strategic approaches for evaluating outcomes in pediatric CD trials. The pediatric Crohn's Disease Activity Index, Crohn's Disease Activity Index, and Harvey-Bradshaw's index were used in pediatric CD clinical studies. But they lack adequate measurement properties (validity, reliability, and ability to detect change of the treatment) that are required to support approval of products intended to treat pediatric CD. Biomarkers (ie, fecal lactoferrin, osteoprotegerin, and calprotectin) have shown some promise for their potential as noninvasive surrogate endpoints in CD. Lack of well-defined and reliable COAs presents a hurdle for global drug development in pediatric CD. It is essential to develop well-defined and reliable COAs that can measure meaningful clinical benefit for patients in terms of how they feel, function, and survive. Development of noninvasive biomarkers as reliable surrogate endpoints needs to be further explored.

Surrogacy Assessment Using Principal Stratification and a Gaussian Copula Model

PubMed Central

Taylor, J.M.G.; Elliott, M.R.

2014-01-01

In clinical trials, a surrogate outcome (S) can be measured before the outcome of interest (T) and may provide early information regarding the treatment (Z) effect on T. Many methods of surrogacy validation rely on models for the conditional distribution of T given Z and S. However, S is a post-randomization variable, and unobserved, simultaneous predictors of S and T may exist, resulting in a non-causal interpretation. Frangakis and Rubin1 developed the concept of principal surrogacy, stratifying on the joint distribution of the surrogate marker under treatment and control to assess the association between the causal effects of treatment on the marker and the causal effects of treatment on the clinical outcome. Working within the principal surrogacy framework, we address the scenario of an ordinal categorical variable as a surrogate for a censored failure time true endpoint. A Gaussian copula model is used to model the joint distribution of the potential outcomes of T, given the potential outcomes of S. Because the proposed model cannot be fully identified from the data, we use a Bayesian estimation approach with prior distributions consistent with reasonable assumptions in the surrogacy assessment setting. The method is applied to data from a colorectal cancer clinical trial, previously analyzed by Burzykowski et al..2 PMID:24947559

Surrogacy assessment using principal stratification and a Gaussian copula model.

PubMed

Conlon, Asc; Taylor, Jmg; Elliott, M R

2017-02-01

In clinical trials, a surrogate outcome ( S) can be measured before the outcome of interest ( T) and may provide early information regarding the treatment ( Z) effect on T. Many methods of surrogacy validation rely on models for the conditional distribution of T given Z and S. However, S is a post-randomization variable, and unobserved, simultaneous predictors of S and T may exist, resulting in a non-causal interpretation. Frangakis and Rubin developed the concept of principal surrogacy, stratifying on the joint distribution of the surrogate marker under treatment and control to assess the association between the causal effects of treatment on the marker and the causal effects of treatment on the clinical outcome. Working within the principal surrogacy framework, we address the scenario of an ordinal categorical variable as a surrogate for a censored failure time true endpoint. A Gaussian copula model is used to model the joint distribution of the potential outcomes of T, given the potential outcomes of S. Because the proposed model cannot be fully identified from the data, we use a Bayesian estimation approach with prior distributions consistent with reasonable assumptions in the surrogacy assessment setting. The method is applied to data from a colorectal cancer clinical trial, previously analyzed by Burzykowski et al.

Alternative methods to evaluate trial level surrogacy.

PubMed

Abrahantes, Josè Cortiñas; Shkedy, Ziv; Molenberghs, Geert

2008-01-01

The evaluation and validation of surrogate endpoints have been extensively studied in the last decade. Prentice [1] and Freedman, Graubard and Schatzkin [2] laid the foundations for the evaluation of surrogate endpoints in randomized clinical trials. Later, Buyse et al. [5] proposed a meta-analytic methodology, producing different methods for different settings, which was further studied by Alonso and Molenberghs [9], in their unifying approach based on information theory. In this article, we focus our attention on the trial-level surrogacy and propose alternative procedures to evaluate such surrogacy measure, which do not pre-specify the type of association. A promising correction based on cross-validation is investigated. As well as the construction of confidence intervals for this measure. In order to avoid making assumption about the type of relationship between the treatment effects and its distribution, a collection of alternative methods, based on regression trees, bagging, random forests, and support vector machines, combined with bootstrap-based confidence interval and, should one wish, in conjunction with a cross-validation based correction, will be proposed and applied. We apply the various strategies to data from three clinical studies: in opthalmology, in advanced colorectal cancer, and in schizophrenia. The results obtained for the three case studies are compared; they indicate that using random forest or bagging models produces larger estimated values for the surrogacy measure, which are in general stabler and the confidence interval narrower than linear regression and support vector regression. For the advanced colorectal cancer studies, we even found the trial-level surrogacy is considerably different from what has been reported. In general the alternative methods are more computationally demanding, and specially the calculation of the confidence intervals, require more computational time that the delta-method counterpart. First, more flexible modeling techniques can be used, allowing for other type of association. Second, when no cross-validation-based correction is applied, overly optimistic trial-level surrogacy estimates will be found, thus cross-validation is highly recommendable. Third, the use of the delta method to calculate confidence intervals is not recommendable since it makes assumptions valid only in very large samples. It may also produce range-violating limits. We therefore recommend alternatives: bootstrap methods in general. Also, the information-theoretic approach produces comparable results with the bagging and random forest approaches, when cross-validation correction is applied. It is also important to observe that, even for the case in which the linear model might be a good option too, bagging methods perform well too, and their confidence intervals were more narrow.

Prediction of survival benefits from progression-free survival benefits in advanced non-small-cell lung cancer: evidence from a meta-analysis of 2334 patients from 5 randomised trials

PubMed Central

Laporte, Silvy; Squifflet, Pierre; Baroux, Noémie; Fossella, Frank; Georgoulias, Vassilis; Pujol, Jean-Louis; Douillard, Jean-Yves; Kudoh, Shinzohy; Pignon, Jean-Pierre; Quinaux, Emmanuel; Buyse, Marc

2013-01-01

Objectives To investigate whether progression-free survival (PFS) can be considered a surrogate endpoint for overall survival (OS) in advanced non-small-cell lung cancer (NSCLC). Design Meta-analysis of individual patient data from randomised trials. Setting Five randomised controlled trials comparing docetaxel-based chemotherapy with vinorelbine-based chemotherapy for the first-line treatment of NSCLC. Participants 2331 patients with advanced NSCLC. Primary and secondary outcome measures Surrogacy of PFS for OS was assessed through the association between these endpoints and between the treatment effects on these endpoints. The surrogate threshold effect was the minimum treatment effect on PFS required to predict a non-zero treatment effect on OS. Results The median follow-up of patients still alive was 23.4 months. Median OS was 10 months and median PFS was 5.5 months. The treatment effects on PFS and OS were correlated, whether using centres (R²=0.62, 95% CI 0.52 to 0.72) or prognostic strata (R²=0.72, 95% CI 0.60 to 0.84) as units of analysis. The surrogate threshold effect was a PFS hazard ratio (HR) of 0.49 using centres or 0.53 using prognostic strata. Conclusions These analyses provide only modest support for considering PFS as an acceptable surrogate for OS in patients with advanced NSCLC. Only treatments that have a major impact on PFS (risk reduction of at least 50%) would be expected to also have a significant effect on OS. Whether these results also apply to targeted therapies is an open question that requires independent evaluation. PMID:23485717

Importance of glomerular filtration rate change as surrogate endpoint for the future incidence of end-stage renal disease in general Japanese population: community-based cohort study.

PubMed

Kanda, Eiichiro; Usui, Tomoko; Kashihara, Naoki; Iseki, Chiho; Iseki, Kunitoshi; Nangaku, Masaomi

2018-04-01

Because of the necessity for extended period and large costs until the event occurs, surrogate endpoints are indispensable for implementation of clinical studies to improve chronic kidney disease (CKD) patients' prognosis. Subjects with serum creatinine level for a baseline period over 1-3 years were enrolled (n = 69,238) in this community-based prospective cohort study in Okinawa, Japan, and followed up for 15 years. The endpoint was end-stage renal disease (ESRD). The percent of estimated glomerular filtration rate (%eGFR) change was calculated on the basis of the baseline period. Subjects had a mean ± SD age, 55.59 ± 14.69 years; eGFR, 80.15 ± 21.15 ml/min/1.73 m 2 . Among the subjects recruited, 15.81% had a low eGFR (<60 ml/min/1.73 m 2 ) and 36.1/100,000 person years developed ESRD. Cox proportional hazards models adjusted for baseline characteristics showed that the risk of ESRD tended to be high with high rates of decrease in %eGFR changes over 2 or 3 years in the high- and low-eGFR groups. The specificities and positive predictive values for ESRD based on a cutoff value of %eGFR change of less than -30% over 2 or 3 years were high in the high- and low-eGFR groups. %eGFR change tends to be associated with the risk of ESRD. %eGFR change of less than -30% over 2 or 3 years can be a candidate surrogate endpoint for ESRD in the general Japanese population.

Surrogacy of progression-free survival (PFS) for overall survival (OS) in esophageal cancer trials with preoperative therapy: Literature-based meta-analysis.

PubMed

Kataoka, K; Nakamura, K; Mizusawa, J; Kato, K; Eba, J; Katayama, H; Shibata, T; Fukuda, H

2017-10-01

There have been no reports evaluating progression-free survival (PFS) as a surrogate endpoint in resectable esophageal cancer. This study was conducted to evaluate the trial level correlations between PFS and overall survival (OS) in resectable esophageal cancer with preoperative therapy and to explore the potential benefit of PFS as a surrogate endpoint for OS. A systematic literature search of randomized trials with preoperative chemotherapy or preoperative chemoradiotherapy for esophageal cancer reported from January 1990 to September 2014 was conducted using PubMed and the Cochrane Library. Weighted linear regression using sample size of each trial as a weight was used to estimate coefficient of determination (R 2 ) within PFS and OS. The primary analysis included trials in which the HR for both PFS and OS was reported. The sensitivity analysis included trials in which either HR or median survival time of PFS and OS was reported. In the sensitivity analysis, HR was estimated from the median survival time of PFS and OS, assuming exponential distribution. Of 614 articles, 10 trials were selected for the primary analysis and 15 for the sensitivity analysis. The primary analysis did not show a correlation between treatment effects on PFS and OS (R 2 0.283, 95% CI [0.00-0.90]). The sensitivity analysis did not show an association between PFS and OS (R 2 0.084, 95% CI [0.00-0.70]). Although the number of randomized controlled trials evaluating preoperative therapy for esophageal cancer is limited at the moment, PFS is not suitable for primary endpoint as a surrogate endpoint for OS. Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Growth Hormone Research Society perspective on biomarkers of GH action in children and adults.

PubMed

Johannsson, Gudmundur; Bidlingmaier, Martin; Biller, Beverly M K; Boguszewski, Margaret; Casanueva, Felipe F; Chanson, Philippe; Clayton, Peter E; Choong, Catherine S; Clemmons, David; Dattani, Mehul; Frystyk, Jan; Ho, Ken; Hoffman, Andrew R; Horikawa, Reiko; Juul, Anders; Kopchick, John J; Luo, Xiaoping; Neggers, Sebastian; Netchine, Irene; Olsson, Daniel S; Radovick, Sally; Rosenfeld, Ron; Ross, Richard J; Schilbach, Katharina; Solberg, Paulo; Strasburger, Christian; Trainer, Peter; Yuen, Kevin C J; Wickstrom, Kerstin; Jorgensen, Jens O L

2018-03-01

The Growth Hormone Research Society (GRS) convened a Workshop in 2017 to evaluate clinical endpoints, surrogate endpoints and biomarkers during GH treatment of children and adults and in patients with acromegaly. GRS invited 34 international experts including clinicians, basic scientists, a regulatory scientist and physicians from the pharmaceutical industry. Current literature was reviewed and expert opinion was utilized to establish the state of the art and identify current gaps and unmet needs. Following plenary presentations, breakout groups discussed questions framed by the planning committee. The attendees re-convened after each breakout session to share the group reports. A writing team compiled the breakout session reports into a document that was subsequently discussed and revised by participants. This was edited further and circulated for final review after the meeting. Participants from pharmaceutical companies were not part of the writing process. The clinical endpoint in paediatric GH treatment is adult height with height velocity as a surrogate endpoint. Increased life expectancy is the ideal but unfeasible clinical endpoint of GH treatment in adult GH-deficient patients (GHDA) and in patients with acromegaly. The pragmatic clinical endpoints in GHDA include normalization of body composition and quality of life, whereas symptom relief and reversal of comorbidities are used in acromegaly. Serum IGF-I is widely used as a biomarker, even though it correlates weakly with clinical endpoints in GH treatment, whereas in acromegaly, normalization of IGF-I may be related to improvement in mortality. There is an unmet need for novel biomarkers that capture the pleiotropic actions of GH in relation to GH treatment and in patients with acromegaly. © 2018 Growth Hormone Research Society.

Granins as disease-biomarkers: translational potential for psychiatric and neurological disorders.

PubMed

Bartolomucci, A; Pasinetti, G M; Salton, S R J

2010-09-29

The identification of biomarkers represents a fundamental medical advance that can lead to an improved understanding of disease pathogenesis, and holds the potential to define surrogate diagnostic and prognostic endpoints. Because of the inherent difficulties in assessing brain function in patients and objectively identifying neurological and cognitive/emotional symptoms, future application of biomarkers to neurological and psychiatric disorders is extremely desirable. This article discusses the biomarker potential of the granin family, a group of acidic proteins present in the secretory granules of a wide variety of endocrine, neuronal and neuroendocrine cells: chromogranin A (CgA), CgB, Secretogranin II (SgII), SgIII, HISL-19 antigen, 7B2, NESP55, VGF and ProSAAS. Their relative abundance, functional significance, and secretion into the cerebrospinal fluid (CSF), saliva, and the general circulation have made granins tractable targets as biomarkers for many diseases of neuronal and endocrine origin, recently impacting diagnosis of a number of neurological and psychiatric disorders including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, frontotemporal dementia, and schizophrenia. Although research has not yet validated the clinical utility of granins as surrogate endpoints for the progression or treatment of neurological or psychiatric disease, a growing body of experimental evidence indicates that the use of granins as biomarkers might be of great potential clinical interest. Advances that further elucidate the mechanism(s) of action of granins, coupled with improvements in biomarker technology and direct clinical application, should increase the translational effectiveness of this family of proteins in disease diagnosis and drug discovery. Copyright 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Using Standardized Interpretation of Chest Radiographs to Identify Adults with Bacterial Pneumonia--Guatemala, 2007-2012.

PubMed

Wortham, Jonathan M; Gray, Jennifer; Verani, Jennifer; Contreras, Carmen Lucia; Bernart, Chris; Moscoso, Fabiola; Moir, Juan Carlos; Reyes Marroquin, Emma Lissette; Castellan, Rigoberto; Arvelo, Wences; Lindblade, Kim; McCracken, John P

2015-01-01

Bacterial pneumonia is a leading cause of illness and death worldwide, but quantifying its burden is difficult due to insensitive diagnostics. Although World Health Organization (WHO) protocol standardizes pediatric chest radiograph (CXR) interpretation for epidemiologic studies of bacterial pneumonia, its validity in adults is unknown. Patients (age ≥ 15 years) admitted with respiratory infections to two Guatemalan hospitals between November 2007 and March 2012 had urine and nasopharyngeal/oropharyngeal (NP/OP) swabs collected; blood cultures and CXR were also performed at physician clinical discretion. 'Any bacterial infection' was defined as a positive urine pneumococcal antigen test, isolation of a bacterial pneumonia pathogen from blood culture, or detection of an atypical bacterial pathogen by polymerase chain reaction (PCR) of nasopharyngeal/oropharyngeal (NP/OP) specimens. 'Viral infection' was defined as detection of viral pathogens by PCR of NP/OP specimens. CXRs were interpreted according to the WHO protocol as having 'endpoint consolidation', 'other infiltrate', or 'normal' findings. We examined associations between bacterial and viral infections and endpoint consolidation. Urine antigen and/or blood culture results were available for 721 patients with CXR interpretations; of these, 385 (53%) had endpoint consolidation and 253 (35%) had other infiltrate. Any bacterial infection was detected in 119 (17%) patients, including 106 (89%) pneumococcal infections. Any bacterial infection (Diagnostic Odds Ratio [DOR] = 2.9; 95% confidence Interval (CI): 1.3-7.9) and pneumococcal infection (DOR = 3.4; 95% CI: 1.5-10.0) were associated with 'endpoint consolidation', but not 'other infiltrate' (DOR = 1.7; 95% CI: 0.7-4.9, and 1.7; 95% CI: 0.7-4.9 respectively). Viral infection was not significantly associated with 'endpoint consolidation', 'other infiltrate,' or 'normal' findings. 'Endpoint consolidation' was associated with 'any bacterial infection,' specifically pneumococcal infection. Therefore, endpoint consolidation may be a useful surrogate for studies measuring the impact of interventions, such as conjugate vaccines, against bacterial pneumonia.

Is serial determination of inspiratory muscle strength a useful prognostic marker in chronic heart failure?

PubMed

Frankenstein, Lutz; Meyer, Franz Joachim; Sigg, Caroline; Nelles, Manfred; Schellberg, Dieter; Remppis, Andrew; Katus, Hugo A; Zugck, Christian

2008-04-01

Little data exists on the prognostic role of inspiratory muscle strength (PImax) in chronic heart failure (CHF). Training studies, however, frequently use it as a therapeutic target and surrogate marker for prognosis. The prognostic value of changes of PImax that allow this extrapolation is unknown. Patients with stable CHF were prospectively included and 1-year and all-time event rates recorded for endpoint analysis. In 158 patients (85% men; New York Heart Association functional class: 2.4+/-0.6), PImax was measured along with clinical evaluations at two visits, the initial visit and the second visit, 6.4+/-1.4 months apart. The mean follow-up was 59+/-34 months. Overall, 59 patients (37%) reached the primary endpoint of death or hospitalization (endpoint positive), and overall mortality rate (secondary endpoint) was 26% (42 patients). PImax did not differ between endpoint-negative and endpoint-positive patients, both at the initial and at the second visit (8.3+/-5.6 vs. 7.3+/-3.4 kPa and 8.8+/-6.0 vs. 7.9+/-3.6 kPa, respectively; P=NS), and both groups showed increased PImax (0.6+/-2.6 vs. 0.6+/-2.8 kPa; P=NS). Cox analyses found neither the absolute nor the relative change of PImax to be significant predictors for the primary and secondary endpoints (P=NS for both), both for the 1-year and for the all-time event rates. Endpoint rates did not differ between patients showing increasing or decreasing PImax (P=NS; relative risk (RR): 0.77; 95% confidence interval: 0.47-1.27). Trials focusing on inspiratory muscle function should use the actual levels of PImax as a surrogate marker to represent prognostic information, rather than relative or absolute changes. This is the first study to investigate the prognostic information of the changes of PImax over time, regarding both short-term and long-term morbidity and mortality in patients with stable CHF.

Selection of Surrogate Bacteria for Use in Food Safety Challenge Studies: A Review.

PubMed

Hu, Mengyi; Gurtler, Joshua B

2017-09-01

Nonpathogenic surrogate bacteria are prevalently used in a variety of food challenge studies in place of foodborne pathogens such as Listeria monocytogenes, Salmonella, Escherichia coli O157:H7, and Clostridium botulinum because of safety and sanitary concerns. Surrogate bacteria should have growth characteristics and/or inactivation kinetics similar to those of target pathogens under given conditions in challenge studies. It is of great importance to carefully select and validate potential surrogate bacteria when verifying microbial inactivation processes. A validated surrogate responds similar to the targeted pathogen when tested for inactivation kinetics, growth parameters, or survivability under given conditions in agreement with appropriate statistical analyses. However, a considerable number of food studies involving putative surrogate bacteria lack convincing validation sources or adequate validation processes. Most of the validation information for surrogates in these studies is anecdotal and has been collected from previous publications but may not be sufficient for given conditions in the study at hand. This review is limited to an overview of select studies and discussion of the general criteria and approaches for selecting potential surrogate bacteria under given conditions. The review also includes a list of documented bacterial pathogen surrogates and their corresponding food products and treatments to provide guidance for future studies.

A Surrogate Approach to the Experimental Optimization of Multielement Airfoils

NASA Technical Reports Server (NTRS)

Otto, John C.; Landman, Drew; Patera, Anthony T.

1996-01-01

The incorporation of experimental test data into the optimization process is accomplished through the use of Bayesian-validated surrogates. In the surrogate approach, a surrogate for the experiment (e.g., a response surface) serves in the optimization process. The validation step of the framework provides a qualitative assessment of the surrogate quality, and bounds the surrogate-for-experiment error on designs "near" surrogate-predicted optimal designs. The utility of the framework is demonstrated through its application to the experimental selection of the trailing edge ap position to achieve a design lift coefficient for a three-element airfoil.

Experimental Validation and Combustion Modeling of a JP-8 Surrogate in a Single Cylinder Diesel Engine

DTIC Science & Technology

2014-04-15

SINGLE CYLINDER DIESEL ENGINE Amit Shrestha, Umashankar Joshi, Ziliang Zheng, Tamer Badawy, Naeim A. Henein, Wayne State University, Detroit, MI, USA...13-03-2014 4. TITLE AND SUBTITLE EXPERIMENTAL VALIDATION AND COMBUSTION MODELING OF A JP-8 SURROGATE IN A SINGLE CYLINDER DIESEL ENGINE 5a...INTERNATIONAL UNCLASSIFIED • Validate a two-component JP-8 surrogate in a single cylinder diesel engine. Validation parameters include – Ignition delay

Surrogates for numerical simulations; optimization of eddy-promoter heat exchangers

NASA Technical Reports Server (NTRS)

Patera, Anthony T.; Patera, Anthony

1993-01-01

Although the advent of fast and inexpensive parallel computers has rendered numerous previously intractable calculations feasible, many numerical simulations remain too resource-intensive to be directly inserted in engineering optimization efforts. An attractive alternative to direct insertion considers models for computational systems: the expensive simulation is evoked only to construct and validate a simplified, input-output model; this simplified input-output model then serves as a simulation surrogate in subsequent engineering optimization studies. A simple 'Bayesian-validated' statistical framework for the construction, validation, and purposive application of static computer simulation surrogates is presented. As an example, dissipation-transport optimization of laminar-flow eddy-promoter heat exchangers are considered: parallel spectral element Navier-Stokes calculations serve to construct and validate surrogates for the flowrate and Nusselt number; these surrogates then represent the originating Navier-Stokes equations in the ensuing design process.

Marital quality and health: A meta-analytic review

PubMed Central

Robles, Theodore F.; Slatcher, Richard B.; Trombello, Joseph M.; McGinn, Meghan M.

2013-01-01

This meta-analysis reviewed 126 published empirical articles over the past 50 years describing associations between marital relationship quality and physical health in over 72,000 individuals. Health outcomes included clinical endpoints (objective assessments of function, disease severity, and mortality; subjective health assessments) and surrogate endpoints (biological markers that substitute for clinical endpoints, such as blood pressure). Biological mediators included cardiovascular reactivity and hypothalamic-pituitary-adrenal axis activity. Greater marital quality was related to better health, with mean effect sizes from r = .07 to .21, including lower risk of mortality, r = .11, and lower cardiovascular reactivity during marital conflict, r = −.13, but not daily cortisol slopes or cortisol reactivity during conflict. The small effect sizes were similar in magnitude to previously found associations between health behaviors (e.g., diet) and health outcomes. Effect sizes for a small subset of clinical outcomes were susceptible to publication bias. In some studies, effect sizes remained significant after accounting for confounds such as age and socioeconomic status. Studies with a higher proportion of women in the sample demonstrated larger effect sizes, but we found little evidence for gender differences in studies that explicitly tested gender moderation, with the exception of surrogate endpoint studies. Our conclusions are limited by small numbers of studies for specific health outcomes, unexplained heterogeneity, and designs that limit causal inferences. These findings highlight the need to explicitly test affective, health behavior, and biological mechanisms in future research, and focus on moderating factors that may alter the relationship between marital quality and health. PMID:23527470

Evaluating the Effectiveness of Passive Sampling as a Surrogate for Organism Bioaccumulation.

EPA Science Inventory

Measurement of hydrophobic organic contaminants (HOCs) and the subsequent evaluation of their ecological and human health risks are common endpoints in aquatic environmental monitoring. Due to their hydrophobicity, many anthropogenic HOCs will partition from the water into organi...

Evaluating the Effectiveness of Passive Sampling as a Surrogate for Organism Bioaccumulation

EPA Science Inventory

Measurement of hydrophobic organic contaminants (HOCs) and the subsequent evaluation of their ecological and human health risks are common endpoints in aquatic environmental monitoring. Due to their hydrophobicity, many anthropogenic HOCs will partition from the water into organi...

Shape Optimization by Bayesian-Validated Computer-Simulation Surrogates

NASA Technical Reports Server (NTRS)

Patera, Anthony T.

1997-01-01

A nonparametric-validated, surrogate approach to optimization has been applied to the computational optimization of eddy-promoter heat exchangers and to the experimental optimization of a multielement airfoil. In addition to the baseline surrogate framework, a surrogate-Pareto framework has been applied to the two-criteria, eddy-promoter design problem. The Pareto analysis improves the predictability of the surrogate results, preserves generality, and provides a means to rapidly determine design trade-offs. Significant contributions have been made in the geometric description used for the eddy-promoter inclusions as well as to the surrogate framework itself. A level-set based, geometric description has been developed to define the shape of the eddy-promoter inclusions. The level-set technique allows for topology changes (from single-body,eddy-promoter configurations to two-body configurations) without requiring any additional logic. The continuity of the output responses for input variations that cross the boundary between topologies has been demonstrated. Input-output continuity is required for the straightforward application of surrogate techniques in which simplified, interpolative models are fitted through a construction set of data. The surrogate framework developed previously has been extended in a number of ways. First, the formulation for a general, two-output, two-performance metric problem is presented. Surrogates are constructed and validated for the outputs. The performance metrics can be functions of both outputs, as well as explicitly of the inputs, and serve to characterize the design preferences. By segregating the outputs and the performance metrics, an additional level of flexibility is provided to the designer. The validated outputs can be used in future design studies and the error estimates provided by the output validation step still apply, and require no additional appeals to the expensive analysis. Second, a candidate-based a posteriori error analysis capability has been developed which provides probabilistic error estimates on the true performance for a design randomly selected near the surrogate-predicted optimal design.

Progression-free survival as surrogate and as true end point: insights from the breast and colorectal cancer literature.

PubMed

Saad, E D; Katz, A; Hoff, P M; Buyse, M

2010-01-01

Significant achievements in the systemic treatment of both advanced breast cancer and advanced colorectal cancer over the past 10 years have led to a growing number of drugs, combinations, and sequences to be tested. The choice of surrogate and true end points has become a critical issue and one that is currently the subject of much debate. Many recent randomized trials in solid tumor oncology have used progression-free survival (PFS) as the primary end point. PFS is an attractive end point because it is available earlier than overall survival (OS) and is not influenced by second-line treatments. PFS is now undergoing validation as a surrogate end point in various disease settings. The question of whether PFS can be considered an acceptable surrogate end point depends not only on formal validation studies but also on a standardized definition and unbiased ascertainment of disease progression in clinical trials. In advanced breast cancer, formal validation of PFS as a surrogate for OS has so far been unsuccessful. In advanced colorectal cancer, in contrast, current evidence indicates that PFS is a valid surrogate for OS after first-line treatment with chemotherapy. The other question is whether PFS sufficiently reflects clinical benefit to be considered a true end point in and of itself.

The association of funding source on effect size in randomized controlled trials: 2013-2015 - a cross-sectional survey and meta-analysis.

PubMed

Falk Delgado, Alberto; Falk Delgado, Anna

2017-03-14

Trials financed by for-profit organizations have been associated with favorable outcomes of new treatments, although the effect size of funding source impact on outcome is unknown. The aim of this study was to estimate the effect size for a favorable outcome in randomized controlled trials (RCTs), stratified by funding source, that have been published in general medical journals. Parallel-group RCTs published in The Lancet, New England Journal of Medicine, and JAMA between 2013 and 2015 were identified. RCTs with binary primary endpoints were included. The primary outcome was the OR of patients' having a favorable outcome in the intervention group compared with the control group. The OR of a favorable outcome in each trial was calculated by the number of positive events that occurred in the intervention and control groups. A meta-analytic technique with random effects model was used to calculate summary OR. Data were stratified by funding source as for-profit, mixed, and nonprofit. Prespecified sensitivity, subgroup, and metaregression analyses were performed. Five hundred nine trials were included. The OR for a favorable outcome in for-profit-funded RCTs was 1.92 (95% CI 1.72-2.14), which was higher than mixed source-funded RCTs (OR 1.34, 95% CI 1.25-1.43) and nonprofit-funded RCTs (OR 1.32, 95% CI 1.26-1.39). The OR for a favorable outcome was higher for both clinical and surrogate endpoints in for-profit-funded trials than in RCTs with other funding sources. Excluding drug trials lowered the OR for a favorable outcome in for-profit-funded RCTs. The OR for a favorable surrogate outcome in drug trials was higher in for-profit-funded trials than in nonprofit-funded trials. For-profit-funded RCTs have a higher OR for a favorable outcome than nonprofit- and mixed source-funded RCTs. This difference is associated mainly with the use of surrogate endpoints in for-profit-financed drug trials.

Evaluation of early efficacy endpoints for proof-of-concept trials.

PubMed

Chen, Cong; Sun, Linda; Li, Chih-Lin

2013-03-11

A Phase II proof-of-concept (POC) trial usually uses an early efficacy endpoint other than a clinical endpoint as the primary endpoint. Because of the advancement in bioscience and technology, which has yielded a number of new surrogate biomarkers, drug developers often have more candidate endpoints to choose from than they can handle. As a result, selection of endpoint and its effect size as well as choice of type I/II error rates are often at the center of heated debates in design of POC trials. While optimization of the trade-off between benefit and cost is the implicit objective in such a decision-making process, it is seldom explicitly accounted for in practice. In this research note, motivated by real examples from the oncology field, we provide practical measures for evaluation of early efficacy endpoints (E4) for POC trials. We further provide optimal design strategies for POC trials that include optimal Go-No Go decision criteria for initiation of Phase III and optimal resource allocation strategies for conducting multiple POC trials in a portfolio under fixed resources. Although oncology is used for illustration purpose, the same idea developed in this research note also applies to similar situations in other therapeutic areas or in early-stage drug development in that a Go-No Go decision has to rely on limited data from an early efficacy endpoint and cost-effectiveness is the main concern.

78 FR 76443 - Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-17

... Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 22, Rm. 5411, Silver... surrogate endpoints and study design issues for the in vivo testing of health care antiseptics (Ref. 3... addressed when designing a clinical outcome study of the effectiveness of antiseptic washes in the consumer...

Predicting skin sensitization potential and inter-laboratory reproducibility of a human Cell Line Activation Test (h-CLAT) in the European Cosmetics Association (COLIPA) ring trials.

PubMed

Sakaguchi, Hitoshi; Ryan, Cindy; Ovigne, Jean-Marc; Schroeder, Klaus R; Ashikaga, Takao

2010-09-01

Regulatory policies in Europe prohibited the testing of cosmetic ingredients in animals for a number of toxicological endpoints. Currently no validated non-animal test methods exist for skin sensitization. Evaluation of changes in cell surface marker expression in dendritic cell (DC)-surrogate cell lines represents one non-animal approach. The human Cell Line Activation Test (h-CLAT) examines the level of CD86 and CD54 expression on the surface of THP-1 cells, a human monocytic leukemia cell line, following 24h of chemical exposure. To examine protocol transferability, between-lab reproducibility, and predictive capacity, the h-CLAT has been evaluated by five independent laboratories in several ring trials (RTs) coordinated by the European Cosmetics Association (COLIPA). The results of the first and second RTs demonstrated that the protocol was transferable and basically had good between-lab reproducibility and predictivity, but there were some false negative data. To improve performance, protocol and prediction model were modified. Using the modified prediction model in the first and second RT, accuracy was improved. However, about 15% of the outcomes were not correctly identified, which exposes some of the limitations of the assay. For the chemicals evaluated, the limitation may due to chemical being a weak allergen or having low solubility (ex. alpha-hexylcinnamaldehyde). The third RT evaluated the modified prediction model and satisfactory results were obtained. From the RT data, the feasibility of utilizing cell lines as surrogate DC in development of in vitro skin sensitization methods shows promise. The data also support initiating formal pre-validation of the h-CLAT in order to fully understand the capabilities and limitations of the assay. Copyright 2010 Elsevier Ltd. All rights reserved.

Clinical evidence for orphan medicinal products-a cause for concern?

PubMed

Picavet, Eline; Cassiman, David; Hollak, Carla E; Maertens, Johan A; Simoens, Steven

2013-10-16

The difficulties associated with organising clinical studies for orphan medicinal products (OMPs) are plentiful. Recent debate on the long-term effectiveness of some OMPs, led us to question whether the initial standards for clinical evidence for OMPs, set by the European Medicines Agency (EMA) at the time of marketing authorization, are too low. Therefore, the aim of this study was to quantitatively evaluate the characteristics and quality of clinical evidence that is presented for OMPs to obtain marketing authorization in Europe, using the new and validated COMPASS tool. We quantitatively assessed the characteristics and quality of clinical evidence of the pivotal studies of 64 OMPs as described in the European Public Assessment Report and/or the Scientific Discussion document prepared by the Committee for Human Medicinal Products of the EMA. The 64 OMPs were altogether authorized for 78 orphan indications, for which 117 studies were identified as 'pivotal' or 'main' studies. In approximately two thirds of the studies, the allocation was randomized (64.8%) and a control arm was used (68.5%). Half of the studies applied some type of blinding. Only a minority (26.9%) of the studies included a Quality-of-Life (QoL) related endpoint, of which a third claim an improvement in QoL. Upon analyzing the quality of reporting, we found that some aspects (i.e. the endpoints, the sampling criteria, and the interventions) are well described, whereas other items (i.e. a description of the patients and of potential biases) are not reported for all studies. In conclusion, the pivotal studies that are the basis for marketing authorization of OMPs are a cause for concern, as they exhibit methodological flaws i.e. the lack of QoL-related endpoints as outcome, lack of blinding in the study design and the use of surrogate endpoints. Additionally, there are shortcomings in the reporting of those studies that complicate the interpretation. A more demanding regulatory process for OMPs is needed to guide evidence-based clinical decision-making.

Useful pharmacodynamic endpoints in children: selection, measurement, and next steps

PubMed Central

Kelly, Lauren E; Sinha, Yashwant; Barker, Charlotte I S; Standing, Joseph F; Offringa, Martin

2018-01-01

Pharmacodynamic (PD) endpoints are essential for establishing the benefit-to-risk ratio for therapeutic interventions in children and neonates. This article discusses the selection of an appropriate measure of response, the PD endpoint, which is a critical methodological step in designing pediatric efficacy and safety studies. We provide an overview of existing guidance on the choice of PD endpoints in pediatric clinical research. We identified several considerations relevant to the selection and measurement of PD endpoints in pediatric clinical trials, including the use of biomarkers, modeling, compliance, scoring systems, and validated measurement tools. To be useful, PD endpoints in children need to be clinically relevant, responsive to both treatment and/or disease progression, reproducible, and reliable. In most pediatric disease areas, this requires significant validation efforts. We propose a minimal set of criteria for useful PD endpoint selection and measurement. We conclude that, given the current heterogeneity of pediatric PD endpoint definitions and measurements, both across and within defined disease areas, there is an acute need for internationally agreed, validated, and condition-specific pediatric PD endpoints that consider the needs of all stakeholders, including healthcare providers, policy makers, patients, and families. PMID:29667952

Surrogate matrix and surrogate analyte approaches for definitive quantitation of endogenous biomolecules.

PubMed

Jones, Barry R; Schultz, Gary A; Eckstein, James A; Ackermann, Bradley L

2012-10-01

Quantitation of biomarkers by LC-MS/MS is complicated by the presence of endogenous analytes. This challenge is most commonly overcome by calibration using an authentic standard spiked into a surrogate matrix devoid of the target analyte. A second approach involves use of a stable-isotope-labeled standard as a surrogate analyte to allow calibration in the actual biological matrix. For both methods, parallelism between calibration standards and the target analyte in biological matrix must be demonstrated in order to ensure accurate quantitation. In this communication, the surrogate matrix and surrogate analyte approaches are compared for the analysis of five amino acids in human plasma: alanine, valine, methionine, leucine and isoleucine. In addition, methodology based on standard addition is introduced, which enables a robust examination of parallelism in both surrogate analyte and surrogate matrix methods prior to formal validation. Results from additional assays are presented to introduce the standard-addition methodology and to highlight the strengths and weaknesses of each approach. For the analysis of amino acids in human plasma, comparable precision and accuracy were obtained by the surrogate matrix and surrogate analyte methods. Both assays were well within tolerances prescribed by regulatory guidance for validation of xenobiotic assays. When stable-isotope-labeled standards are readily available, the surrogate analyte approach allows for facile method development. By comparison, the surrogate matrix method requires greater up-front method development; however, this deficit is offset by the long-term advantage of simplified sample analysis.

Surrogate end points in clinical research: hazardous to your health.

PubMed

Grimes, David A; Schulz, Kenneth F

2005-05-01

Surrogate end points in clinical research pose real danger. A surrogate end point is an outcome measure, commonly a laboratory test, that substitutes for a clinical event of true importance. Resistance to activated protein C, for example, has been used as a surrogate for venous thrombosis in women using oral contraceptives. Other examples of inappropriate surrogate end points in contraception include the postcoital test instead of pregnancy to evaluate new spermicides, breakage and slippage instead of pregnancy to evaluate condoms, and bone mineral density instead of fracture to assess the safety of depo-medroxyprogesterone acetate. None of these markers captures the effect of the treatment on the true outcome. A valid surrogate end point must both correlate with and accurately predict the outcome of interest. Although many surrogate markers correlate with an outcome, few have been shown to capture the effect of a treatment (for example, oral contraceptives) on the outcome (venous thrombosis). As a result, thousands of useless and misleading reports on surrogate end points litter the medical literature. New drugs have been shown to benefit a surrogate marker, but, paradoxically, triple the risk of death. Thousands of patients have died needlessly because of reliance on invalid surrogate markers. Researchers should avoid surrogate end points unless they have been validated; that requires at least one well done trial using both the surrogate and true outcome. The clinical maxim that "a difference to be a difference must make a difference" applies to research as well. Clinical research should focus on outcomes that matter.

Non-invasive assessment of liver fibrosis

PubMed Central

Papastergiou, Vasilios; Tsochatzis, Emmanuel; Burroughs, Andrew K.

2012-01-01

The presence and degree of hepatic fibrosis is crucial in order to make therapeutic decisions and predict clinical outcomes. Currently, the place of liver biopsy as the standard of reference for assessing liver fibrosis has been challenged by the increasing awareness of a number of drawbacks related to its use (invasiveness, sampling error, inter-/intraobserver variability). In parallel with this, noninvasive assessment of liver fibrosis has experienced explosive growth in recent years and a wide spectrum of noninvasive methods ranging from serum assays to imaging techniques have been developed. Some are validated methods, such as the Fibrotest/ Fibrosure and transient elastography in Europe, and are gaining a growing role in routine clinical practice, especially in chronic hepatitis C. Large-scale validation is awaited in the setting of other chronic liver diseases. However, noninvasive tests used to detect significant fibrosis and cirrhosis, the two major clinical endpoints, are not yet at a level of performance suitable for routine diagnostic tests, and there is still no perfect surrogate or method able to completely replace an optimal liver biopsy. This article aims to review current noninvasive tests for the assessment of liver fibrosis and the perspectives for their rational use in clinical practice. PMID:24714123

Temperature sensitivity of phospho-Ser{sup 473}-PKB/AKT

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

Oehler-Jaenne, Christoph; Bueren, Andre O. von; Vuong, Van

2008-10-24

The phospho-PKB/Akt status is often used as surrogate marker to measure activation of the PI3K/Akt/mTOR signal transduction pathway. Though, inconsistencies of the p-Ser{sup 473}-PKB/Akt status have raised doubts in the validity of p-Ser{sup 473}-PKB/Akt phosphorylation as endpoint. Here, we determined that p-Ser{sup 473}-PKB/Akt but not p-Thr{sup 308}-PKB/Akt phosphorylation is highly temperature sensitive. p-Ser{sup 473}-PKB/Akt phosphorylation was rapidly reduced to levels below 50% on exposure to 20-25 deg. C in murine and human cell lines including cells expressing constitutively active PI3K or lacking PTEN. Down-regulation of p-Ser{sup 473}-PKB/Akt was reversible and re-exposure to physiological temperature resulted in increased p-Ser{sup 473}-PKB/Akt phosphorylationmore » levels. Phosphatase activity at low temperature was sustained at 75% baseline level and phosphatase inhibition prevented p-Ser{sup 473}-PKB/Akt dephosphorylation induced by the low temperature shift. Interestingly temperature-dependent deregulation of the p-Ser{sup 473}-PKB/Akt status was also observed in response to irradiation. Thus our data demonstrate that minimal additional stress factors deregulate the PI3K/Akt-survival pathway and the p-Ser{sup 473}-PKB/Akt status as experimental endpoint.« less

Isotope Inversion Experiment evaluating the suitability of calibration in surrogate matrix for quantification via LC-MS/MS-Exemplary application for a steroid multi-method.

PubMed

Suhr, Anna Catharina; Vogeser, Michael; Grimm, Stefanie H

2016-05-30

For quotable quantitative analysis of endogenous analytes in complex biological samples by isotope dilution LC-MS/MS, the creation of appropriate calibrators is a challenge, since analyte-free authentic material is in general not available. Thus, surrogate matrices are often used to prepare calibrators and controls. However, currently employed validation protocols do not include specific experiments to verify the suitability of a surrogate matrix calibration for quantification of authentic matrix samples. The aim of the study was the development of a novel validation experiment to test whether surrogate matrix based calibrators enable correct quantification of authentic matrix samples. The key element of the novel validation experiment is the inversion of nonlabelled analytes and their stable isotope labelled (SIL) counterparts in respect to their functions, i.e. SIL compound is the analyte and nonlabelled substance is employed as internal standard. As a consequence, both surrogate and authentic matrix are analyte-free regarding SIL analytes, which allows a comparison of both matrices. We called this approach Isotope Inversion Experiment. As figure of merit we defined the accuracy of inverse quality controls in authentic matrix quantified by means of a surrogate matrix calibration curve. As a proof-of-concept application a LC-MS/MS assay addressing six corticosteroids (cortisol, cortisone, corticosterone, 11-deoxycortisol, 11-deoxycorticosterone, and 17-OH-progesterone) was chosen. The integration of the Isotope Inversion Experiment in the validation protocol for the steroid assay was successfully realized. The accuracy results of the inverse quality controls were all in all very satisfying. As a consequence the suitability of a surrogate matrix calibration for quantification of the targeted steroids in human serum as authentic matrix could be successfully demonstrated. The Isotope Inversion Experiment fills a gap in the validation process for LC-MS/MS assays quantifying endogenous analytes. We consider it a valuable and convenient tool to evaluate the correct quantification of authentic matrix samples based on a calibration curve in surrogate matrix. Copyright © 2016 Elsevier B.V. All rights reserved.

Validation of the Family Inpatient Communication Survey.

PubMed

Torke, Alexia M; Monahan, Patrick; Callahan, Christopher M; Helft, Paul R; Sachs, Greg A; Wocial, Lucia D; Slaven, James E; Montz, Kianna; Inger, Lev; Burke, Emily S

2017-01-01

Although many family members who make surrogate decisions report problems with communication, there is no validated instrument to accurately measure surrogate/clinician communication for older adults in the acute hospital setting. The objective of this study was to validate a survey of surrogate-rated communication quality in the hospital that would be useful to clinicians, researchers, and health systems. After expert review and cognitive interviewing (n = 10 surrogates), we enrolled 350 surrogates (250 development sample and 100 validation sample) of hospitalized adults aged 65 years and older from three hospitals in one metropolitan area. The communication survey and a measure of decision quality were administered within hospital days 3 and 10. Mental health and satisfaction measures were administered six to eight weeks later. Factor analysis showed support for both one-factor (Total Communication) and two-factor models (Information and Emotional Support). Item reduction led to a final 30-item scale. For the validation sample, internal reliability (Cronbach's alpha) was 0.96 (total), 0.94 (Information), and 0.90 (Emotional Support). Confirmatory factor analysis fit statistics were adequate (one-factor model, comparative fit index = 0.981, root mean square error of approximation = 0.62, weighted root mean square residual = 1.011; two-factor model comparative fit index = 0.984, root mean square error of approximation = 0.055, weighted root mean square residual = 0.930). Total score and subscales showed significant associations with the Decision Conflict Scale (Pearson correlation -0.43, P < 0.001 for total score). Emotional Support was associated with improved mental health outcomes at six to eight weeks, such as anxiety (-0.19 P < 0.001), and Information was associated with satisfaction with the hospital stay (0.49, P < 0.001). The survey shows high reliability and validity in measuring communication experiences for hospital surrogates. The scale has promise for measurement of communication quality and is predictive of important outcomes, such as surrogate satisfaction and well-being. Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Used fuel rail shock and vibration testing options analysis

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

Ross, Steven B.; Best, Ralph E.; Klymyshyn, Nicholas A.

2014-09-25

The objective of the rail shock and vibration tests is to complete the framework needed to quantify loads of fuel assembly components that are necessary to guide materials research and establish a technical basis for review organizations such as the U.S. Nuclear Regulatory Commission (NRC). A significant body of experimental and numerical modeling data exists to quantify loads and failure limits applicable to normal conditions of transport (NCT) rail transport, but the data are based on assumptions that can only be verified through experimental testing. The test options presented in this report represent possible paths for acquiring the data thatmore » are needed to confirm the assumptions of previous work, validate modeling methods that will be needed for evaluating transported fuel on a case-by-case basis, and inform material test campaigns on the anticipated range of fuel loading. The ultimate goal of this testing is to close all of the existing knowledge gaps related to the loading of used fuel under NCT conditions and inform the experiments and analysis program on specific endpoints for their research. The options include tests that would use an actual railcar, surrogate assemblies, and real or simulated rail transportation casks. The railcar carrying the cradle, cask, and surrogate fuel assembly payload would be moved in a train operating over rail track modified or selected to impart shock and vibration forces that occur during normal rail transportation. Computer modeling would be used to help design surrogates that may be needed for a rail cask, a cask’s internal basket, and a transport cradle. The objective of the design of surrogate components would be to provide a test platform that effectively simulates responses to rail shock and vibration loads that would be exhibited by state-of-the-art rail cask, basket, and/or cradle structures. The computer models would also be used to help determine the placement of instrumentation (accelerometers and strain gauges) on the surrogate fuel assemblies, cask and cradle structures, and the railcar so that forces and deflections that would result in the greatest potential for damage to high burnup and long-cooled UNF can be determined. For purposes of this report we consider testing on controlled track when we have control of the track and speed to facilitate modeling.« less

Surrogate Endpoints in Second-Line Trials of Targeted Agents in Metastatic Colorectal Cancer: A Literature-Based Systematic Review and Meta-Analysis.

PubMed

Cremolini, Chiara; Antoniotti, Carlotta; Pietrantonio, Filippo; Berenato, Rosa; Tampellini, Marco; Baratelli, Chiara; Salvatore, Lisa; Marmorino, Federica; Borelli, Beatrice; Nichetti, Federico; Bironzo, Paolo; Sonetto, Cristina; Bartolomeo, Maria Di; Braud, Filippo de; Loupakis, Fotios; Falcone, Alfredo; Di Maio, M

2017-07-01

The purpose of this study was to evaluate progression-free survival (PFS) and objective response rate (ORR) as surrogate endpoints of overall survival (OS) in modern clinical trials investigating the efficacy of targeted agents in the second-line treatment of metastatic colorectal cancer (mCRC). A systematic search of literature pertaining to randomized phase II and III trials evaluating targeted agents as second-line treatments for mCRC was performed. The strength of the correlation between both PFS and ORR and OS was assessed based on the Pearson's correlation coefficient (R) and the coefficient of determination (R 2 ). Twenty trials, including a total of 7,571 patients, met the search criteria. The median duration of post-progression survival (PPS) was 7.6 months. The median differences between experimental and control arms were 0.65 months (range, -2.4 to 3.4) for the median PFS and 0.7 months (range, -5.8 to 3.9) for the median OS. PFS and ORR showed moderate (R=0.734, R 2 =0.539, p < 0.001) and poor correlation (R=0.169, R 2 =0.029, p=0.476) with OS, respectively. No differences between anti-angiogenic agents and other drugs were evident. Targeted agents investigated in the second-line treatment of mCRC provided minimal PFS gains translating into modest OS improvements. Considering both the moderate correlation between PFS and OS and the short duration of PPS, the OS should remain the preferred primary endpoint for randomized clinical trials in the second-line treatment of mCRC.

Discrepancy between recurrence-free survival and overall survival in patients with resectable colorectal liver metastases: a potential surrogate endpoint for time to surgical failure.

PubMed

Oba, Masaru; Hasegawa, Kiyoshi; Matsuyama, Yutaka; Shindoh, Junichi; Mise, Yoshihiro; Aoki, Taku; Sakamoto, Yoshihiro; Sugawara, Yasuhiko; Makuuchi, Masatoshi; Kokudo, Norihiro

2014-06-01

Recurrence-free survival (RFS) may not be a surrogate for overall survival (OS) in patients with resectable colorectal liver metastases (CLM). We investigated whether a new composite tool-time to surgical failure (TSF)-is a suitable endpoint. The medical records of consecutive patients who underwent curative resection for CLM at our center over a 17-year period were reviewed. Patients with liver-limited tumors (n = 371) who had not received previous treatment for metastasis were eligible for analysis. TSF was defined as the time until unresectable relapse or death. The correlations between TSF and OS, and between RFS and OS, were assessed for all the eligible patients. The median OS, TSF, and RFS were 5.7, 2.7, and 0.7 years, respectively, and the 5-year OS, TSF, and RFS rates were 52.6, 39.8, and 23.7 %, respectively, for all patients. The rates of first, second, and third relapse were 75.5, 77.6, and 70.8 %, respectively, and repeat resections were performed in 54.3 % (first relapses), 40.7 % (second relapses), and 47.1 % (third relapses) of patients. The concordance proportions of TSF and RFS for OS events were 0.83 and 0.65, respectively. The correlation between TSF and OS was stronger than that between RFS and OS in terms of the predicted probabilities. The correlation between TSF and OS was stronger than that between RFS and OS after curative hepatic resection. TSF could be a suitable endpoint for CLM overall management.

The potential of tumor-derived exosomes for noninvasive cancer monitoring

PubMed Central

Whiteside, Theresa L.

2016-01-01

Tumor-derived exosomes (TEXs) are emerging as a new type of cancer biomarker. TEXs are membrane-bound, virus-size vesicles of endocytic origin present in all body fluids of cancer patients. Based on the expanding albeit incomplete knowledge of their biogenesis, secretion by tumor cells and cancer cell-specific molecular and genetic contents, TEXs are viewed as promising, clinically-relevant surrogates of cancer progression and response to therapy. Preliminary proteomic, genetic and functional profiling of tumor cell-derived or cancer plasma-derived exosomes confirms their unique characteristics. Alterations in protein or nucleic acid profiles of exosomes in plasma of cancer patients responding to therapies appear to correlate with clinical endpoints. However, methods for TEX isolation and separation from the bulk of human plasma-derived exosomes are not yet established and their role as biomarkers remains to be confirmed. Further development and validation of TEXs as noninvasive, liquid equivalents of tumor biopsies are necessary to move this effort forward. PMID:26289602

Analyzing Thorough QT Study 1 & 2 in the Telemetric and Holter ECG Warehouse (THEW) using Hannover ECG System HES : A validation study.

PubMed

Khawaja, A; Petrovic, R; Safer, A; Baas, T; Dössel, O; Fischer, R

2010-01-01

Following the ICH E14 clinical evaluation guideline [1], the measurement of QT/QTc interval prolongation has become the standard surrogate biomarker for cardiac drug safety assessment and the faith of a drug development. In Thorough QT (TQT) study, a so-called positive control is employed to assess the ability of this study to detect the endpoint of interest, i.e. the QT prolongation by about five milliseconds. In other words the lower bound of the one-sided 95% confidence interval (CI) must be above 0 [ms]. Fully automated detection of ECG fiducial points and measurement of the corresponding intervals including QT intervals and RR intervals vary between different computerized algorithms. In this work we demonstrate the ability and reliability of Hannover ECG System (HES(®)) to assess drug effects by detecting QT/QTc prolongation effects that meet the threshold of regulatory concern as mentioned by using THEW database studies namely TQT studies one and two.

Relevance of randomised controlled trials in oncology.

PubMed

Tannock, Ian F; Amir, Eitan; Booth, Christopher M; Niraula, Saroj; Ocana, Alberto; Seruga, Bostjan; Templeton, Arnoud J; Vera-Badillo, Francisco

2016-12-01

Well-designed randomised controlled trials (RCTs) can prevent bias in the comparison of treatments and provide a sound basis for changes in clinical practice. However, the design and reporting of many RCTs can render their results of little relevance to clinical practice. In this Personal View, we discuss the limitations of RCT data and suggest some ways to improve the clinical relevance of RCTs in the everyday management of patients with cancer. RCTs should ask questions of clinical rather than commercial interest, avoid non-validated surrogate endpoints in registration trials, and have entry criteria that allow inclusion of all patients who are fit to receive treatment. Furthermore, RCTs should be reported with complete accounting of frequency and management of toxicities, and with strict guidelines to ensure freedom from bias. Premature reporting of results should be avoided. The bar for clinical benefit should be raised for drug registration, which should require publication and review of mature data from RCTs, post-marketing health outcome studies, and value-based pricing. Copyright © 2016 Elsevier Ltd. All rights reserved.

The potential of tumor-derived exosomes for noninvasive cancer monitoring.

PubMed

Whiteside, Theresa L

2015-01-01

Tumor-derived exosomes (TEX) are emerging as a new type of cancer biomarker. TEX are membrane-bound, virus-size vesicles of endocytic origin present in all body fluids of cancer patients. Based on the expanding albeit incomplete knowledge of their biogenesis, secretion by tumor cells and cancer cell-specific molecular and genetic contents, TEX are viewed as promising, clinically-relevant surrogates of cancer progression and response to therapy. Preliminary proteomic, genetic and functional profiling of tumor cell-derived or cancer plasma-derived exosomes confirms their unique characteristics. Alterations in protein or nucleic acid profiles of exosomes in plasma of cancer patients responding to therapies appear to correlate with clinical endpoints. However, methods for TEX isolation and separation from the bulk of human plasma-derived exosomes are not yet established and their role as biomarkers remains to be confirmed. Further development and validation of TEX as noninvasive, liquid equivalents of tumor biopsies are necessary to move this effort forward.

[Pharmacotherapy of obesity].

PubMed

Rotthoff, Thomas; Scherbaum, Werner A

2006-12-01

Long-term success in obesity therapy is difficult to obtain, therefore drug therapy appears to be helpful. Until today, end-point studies for obesity drugs beyond the improvement of individual surrogate parameters are still missing. For all available drugs, medical treatment can be recommended only for a limited period of time due to the data of the studies and under consideration of side effects. Although a weight reduction leads to an improvement of cardiovascular risk factors and hence a reduction of cardiovascular morbidity and mortality should be expected, no study could prove it so far. Despite the positive influence on individual surrogate parameters, the use of the present available therapies appears underwhelming. In this overview the approved substances and perspectives of new therapeutic concepts are represented.

Role of Intensive Glucose Control in Development of Renal Endpoints in Type 2 Diabetes: Systematic Review and Meta-analysis

PubMed Central

Coca, Steven G.; Ismail-Beigi, Faramarz; Haq, Nowreen; Krumholz, Harlan M.; Parikh, Chirag R.

2013-01-01

Background Aggressive glycemic control has been hypothesized to prevent renal disease in type 2 diabetics. A systematic review was conducted to summarize the benefits of intensive versus conventional glucose control on kidney-related outcomes for adults with type 2 diabetes. Methods Three databases were systematically searched (January 1950 to December 2010) with no language restrictions to identify randomized trials that compared surrogate renal endpoints (micro and macroalbuminuria) and clinical renal endpoints (doubling of serum creatinine, End Stage Renal Disease [ESRD] and death from renal disease) in patients with type 2 diabetes receiving intensive glucose control versus receiving conventional glucose control. Results Seven trials involving 28,065 adults who were followed-up for 2 to 15 years. Compared with conventional control, intensive glucose control reduced the risk for microalbuminuria (risk ratio [RR], 0.86 [95% CI, 0.76 to 0.96]) and macroalbuminuria (RR 0.74 [95% CI, 0.65–0.85]), but not doubling of serum creatinine (RR 1.06 [95% CI, 0.92 to 1.22]), ESRD (RR 0.69 [95% CI, 0.46–1.05]), or death from renal disease (RR 0.99 [95% CI 0.55–1.79]). Meta-regression revealed that larger differences in HbA1C between intensive and conventional therapy at the study level were associated with greater benefit for both micro- and macroalbuminuria. The pooled cumulative incidence of doubling of creatinine, ESRD, and death from renal disease was low (< 4%, <1.5%, and <0.5%, respectively) compared with the surrogate renal endpoints of micro- (23%) and macroalbuminuria (5%). Conclusion Intensive glucose control reduces the risk for microalbuminuria and macroalbuminuria but evidence is lacking that intensive glycemic control reduces the risk for significant clinical renal outcomes such as doubling of creatinine, ESRD or death from renal disease during the years of follow-up of the trials. PMID:22636820

Evaluation and comparison of predictive individual-level general surrogates.

PubMed

Gabriel, Erin E; Sachs, Michael C; Halloran, M Elizabeth

2018-07-01

An intermediate response measure that accurately predicts efficacy in a new setting at the individual level could be used both for prediction and personalized medical decisions. In this article, we define a predictive individual-level general surrogate (PIGS), which is an individual-level intermediate response that can be used to accurately predict individual efficacy in a new setting. While methods for evaluating trial-level general surrogates, which are predictors of trial-level efficacy, have been developed previously, few, if any, methods have been developed to evaluate individual-level general surrogates, and no methods have formalized the use of cross-validation to quantify the expected prediction error. Our proposed method uses existing methods of individual-level surrogate evaluation within a given clinical trial setting in combination with cross-validation over a set of clinical trials to evaluate surrogate quality and to estimate the absolute prediction error that is expected in a new trial setting when using a PIGS. Simulations show that our method performs well across a variety of scenarios. We use our method to evaluate and to compare candidate individual-level general surrogates over a set of multi-national trials of a pentavalent rotavirus vaccine.

Complexity of bioindicator selection for ecological, human, and cultural health: Chinook salmon and red knot as case studies

PubMed Central

Burger, Joanna; Gochfeld, Michael; Niles, Lawrence; Powers, Charles; Brown, Kevin; Clarke, James; Dey, Amanda; Kosson, David

2015-01-01

There is considerable interest in developing bioindicators of ecological health that are also useful indicators for human health. Yet, human health assessment usually encompasses physical/chemical exposures and not cultural well-being. In this paper, we propose that bioindicators can be selected for all three purposes. We use Chinook or king salmon (Oncorhynchus tshawytscha) and red knot (Calidris canutus rufa, a sandpiper) as examples of indicators that can be used to assess human, ecological, and cultural health. Even so, selecting endpoints or metrics for each indicator species is complex and is explored in this paper. We suggest that there are several endpoint types to examine for a given species, including physical environment, environmental stressors, habitat, life history, demography, population counts, and cultural/societal aspects. Usually cultural endpoints are economic indicators (e.g., number of days fished, number of hunting licenses), rather than the importance of a fishing culture. Development of cultural/societal endpoints must include the perceptions of local communities, cultural groups, and tribal nations, as well as governmental and regulatory communities (although not usually so defined, the latter have cultures as well). Endpoint selection in this category is difficult because the underlying issues need to be identified and used to develop endpoints that tribes and stakeholders themselves see as reasonable surrogates of the qualities they value. We describe several endpoints for salmon and knots that can be used for ecological, human, and cultural/societal health. PMID:25666646

Complexity of bioindicator selection for ecological, human, and cultural health: Chinook salmon and red knot as case studies

DOE PAGES

Burger, Joanna; Gochfeld, Michael; Niles, Lawrence; ...

2015-02-10

There is considerable interest in developing bioindicators of ecological health that are also useful indicators for human health. Yet, human health assessment usually encompasses physical/chemical exposures and not cultural well-being. In this paper, we propose that bioindicators can be selected for all three purposes. We use Chinook or king salmon (Oncorhynchus tshawytscha) and red knot (Calidris canutus rufa, a sandpiper) as examples of indicators that can be used to assess human, ecological, and cultural health. Even so, selecting endpoints or metrics for each indicator species is complex and is explored in this paper. Here, we suggest that there are severalmore » endpoint types to examine for a given species, including physical environment, environmental stressors, habitat, life history, demography, population counts, and cultural/societal aspects. Usually cultural endpoints are economic indicators (e.g., number of days fished, number of hunting licenses), rather than the importance of a fishing culture. Development of cultural/societal endpoints must include the perceptions of local communities, cultural groups, and tribal nations, as well as governmental and regulatory communities (although not usually so defined, the latter have cultures as well). Endpoint selection in this category is difficult because the underlying issues need to be identified and used to develop endpoints that tribes and stakeholders themselves see as reasonable surrogates of the qualities they value. We describe several endpoints for salmon and knots that can be used for ecological, human, and cultural/societal health.« less

Complexity of bioindicator selection for ecological, human, and cultural health: Chinook salmon and red knot as case studies

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

Burger, Joanna; Gochfeld, Michael; Niles, Lawrence

There is considerable interest in developing bioindicators of ecological health that are also useful indicators for human health. Yet, human health assessment usually encompasses physical/chemical exposures and not cultural well-being. In this paper, we propose that bioindicators can be selected for all three purposes. We use Chinook or king salmon (Oncorhynchus tshawytscha) and red knot (Calidris canutus rufa, a sandpiper) as examples of indicators that can be used to assess human, ecological, and cultural health. Even so, selecting endpoints or metrics for each indicator species is complex and is explored in this paper. Here, we suggest that there are severalmore » endpoint types to examine for a given species, including physical environment, environmental stressors, habitat, life history, demography, population counts, and cultural/societal aspects. Usually cultural endpoints are economic indicators (e.g., number of days fished, number of hunting licenses), rather than the importance of a fishing culture. Development of cultural/societal endpoints must include the perceptions of local communities, cultural groups, and tribal nations, as well as governmental and regulatory communities (although not usually so defined, the latter have cultures as well). Endpoint selection in this category is difficult because the underlying issues need to be identified and used to develop endpoints that tribes and stakeholders themselves see as reasonable surrogates of the qualities they value. We describe several endpoints for salmon and knots that can be used for ecological, human, and cultural/societal health.« less

Treatment Paradigms for Advanced Non‐Small Cell Lung Cancer at Academic Medical Centers: Involvement in Clinical Trial Endpoint Design

PubMed Central

Borghaei, Hossein

2017-01-01

Abstract Based on the positive results of various clinical trials, treatment options for non‐small cell lung cancer (NSCLC) have expanded greatly over the last 25 years. While regulatory approvals of chemotherapeutic agents for NSCLC have largely been based on improvements in overall survival, recent approvals of many targeted agents for NSCLC (afatinib, crizotinib, ceritinib, osimertinib) have been based on surrogate endpoints such as progression‐free survival and objective response. As such, selection of appropriate clinical endpoints for examining the efficacy of investigational agents for NSCLC is of vital importance in clinical trial design. This review provides an overview of clinical trial endpoints previously utilized for approved agents for NSCLC and highlights the key efficacy results for these trials. Trends for more recent approvals in NSCLC, including those for the immunotherapeutic agents nivolumab and pembrolizumab, are also discussed. The results of a correlative analysis of endpoints from 18 clinical trials that supported approvals of investigational agents in clinical trials for NSCLC are also presented. Implications for Practice. While improving survival remains the ultimate goal of oncology clinical trials, overall survival may not always be the most feasible or appropriate endpoint to assess patient response. Recently, several investigational agents, both targeted agents and immunotherapies, have gained U.S. Food and Drug Administration approval in non‐small cell lung cancer based on alternate endpoints such as progression‐free survival or response rate. An understanding of the assessment of response and trial endpoint choice is important for future oncology clinical trial design. PMID:28408617

Quantification of free and total desmosine and isodesmosine in human urine by liquid chromatography tandem mass spectrometry: a comparison of the surrogate-analyte and the surrogate-matrix approach for quantitation.

PubMed

Ongay, Sara; Hendriks, Gert; Hermans, Jos; van den Berge, Maarten; ten Hacken, Nick H T; van de Merbel, Nico C; Bischoff, Rainer

2014-01-24

In spite of the data suggesting the potential of urinary desmosine (DES) and isodesmosine (IDS) as biomarkers for elevated lung elastic fiber turnover, further validation in large-scale studies of COPD populations, as well as the analysis of longitudinal samples is required. Validated analytical methods that allow the accurate and precise quantification of DES and IDS in human urine are mandatory in order to properly evaluate the outcome of such clinical studies. In this work, we present the development and full validation of two methods that allow DES and IDS measurement in human urine, one for the free and one for the total (free+peptide-bound) forms. To this end we compared the two principle approaches that are used for the absolute quantification of endogenous compounds in biological samples, analysis against calibrators containing authentic analyte in surrogate matrix or containing surrogate analyte in authentic matrix. The validated methods were employed for the analysis of a small set of samples including healthy never-smokers, healthy current-smokers and COPD patients. This is the first time that the analysis of urinary free DES, free IDS, total DES, and total IDS has been fully validated and that the surrogate analyte approach has been evaluated for their quantification in biological samples. Results indicate that the presented methods have the necessary quality and level of validation to assess the potential of urinary DES and IDS levels as biomarkers for the progression of COPD and the effect of therapeutic interventions. Copyright © 2014 Elsevier B.V. All rights reserved.

Selection, validation and utility of pathogen surrogate bacteria used in food safety challenge studies: A Review

USDA-ARS?s Scientific Manuscript database

Non-pathogenic surrogate bacteria are prevalently used in a variety of food challenge studies in place of foodborne pathogens such as Listeria monocytogenes, Salmonella, Escherichia coli O157:H7, and Clostridium botulinum, due to safety and sanitary concerns. Surrogate bacteria should demonstrate si...

Robust best linear estimator for Cox regression with instrumental variables in whole cohort and surrogates with additive measurement error in calibration sample

PubMed Central

Wang, Ching-Yun; Song, Xiao

2017-01-01

SUMMARY Biomedical researchers are often interested in estimating the effect of an environmental exposure in relation to a chronic disease endpoint. However, the exposure variable of interest may be measured with errors. In a subset of the whole cohort, a surrogate variable is available for the true unobserved exposure variable. The surrogate variable satisfies an additive measurement error model, but it may not have repeated measurements. The subset in which the surrogate variables are available is called a calibration sample. In addition to the surrogate variables that are available among the subjects in the calibration sample, we consider the situation when there is an instrumental variable available for all study subjects. An instrumental variable is correlated with the unobserved true exposure variable, and hence can be useful in the estimation of the regression coefficients. In this paper, we propose a nonparametric method for Cox regression using the observed data from the whole cohort. The nonparametric estimator is the best linear combination of a nonparametric correction estimator from the calibration sample and the difference of the naive estimators from the calibration sample and the whole cohort. The asymptotic distribution is derived, and the finite sample performance of the proposed estimator is examined via intensive simulation studies. The methods are applied to the Nutritional Biomarkers Study of the Women’s Health Initiative. PMID:27546625

[Clinical end-points and surrogate markers of pulmonary arterial hypertension in the light of evidence-based treatment].

PubMed

Can, Mehmet Mustafa; Kaymaz, Cihangir

2010-08-01

Pulmonary arterial hypertension (PAH) is a rare, fatal and progressive disease. There is an acceleration in the advent of new therapies in parallel to the development of the knowledge about etiogenesis and pathogenesis of PAH. Therefore, to optimize the goals of PAH-specific treatment and to determine the time to shift from monotherapy to combination therapy, simple, objective and reproducible end-points, which may predict the disease severity, progression rate and life expectancy are needed. The adventure of end points in PAH has started with six minute walk distance and functional capacity, and continues with new parameters (biochemical marker, time to clinical worsening, echocardiography and magnetic resonance imaging etc.), which can better reflect the clinical outcome.

THE 6-MINUTE WALK TEST AND OTHER CLINICAL ENDPOINTS IN DUCHENNE MUSCULAR DYSTROPHY: RELIABILITY, CONCURRENT VALIDITY, AND MINIMAL CLINICALLY IMPORTANT DIFFERENCES FROM A MULTICENTER STUDY

PubMed Central

McDonald, Craig M; Henricson, Erik K; Abresch, R Ted; Florence, Julaine; Eagle, Michelle; Gappmaier, Eduard; Glanzman, Allan M; Spiegel, Robert; Barth, Jay; Elfring, Gary; Reha, Allen; Peltz, Stuart W

2013-01-01

Introduction: An international clinical trial enrolled 174 ambulatory males ≥5 years old with nonsense mutation Duchenne muscular dystrophy (nmDMD). Pretreatment data provide insight into reliability, concurrent validity, and minimal clinically important differences (MCIDs) of the 6-minute walk test (6MWT) and other endpoints. Methods: Screening and baseline evaluations included the 6-minute walk distance (6MWD), timed function tests (TFTs), quantitative strength by myometry, the PedsQL, heart rate–determined energy expenditure index, and other exploratory endpoints. Results: The 6MWT proved feasible and reliable in a multicenter context. Concurrent validity with other endpoints was excellent. The MCID for 6MWD was 28.5 and 31.7 meters based on 2 statistical distribution methods. Conclusions: The ratio of MCID to baseline mean is lower for 6MWD than for other endpoints. The 6MWD is an optimal primary endpoint for Duchenne muscular dystrophy (DMD) clinical trials that are focused therapeutically on preservation of ambulation and slowing of disease progression. Muscle Nerve 48: 357–368, 2013 PMID:23674289

Military Suicide Research Consortium

DTIC Science & Technology

2012-10-01

J. E. (2010). Surrogate endpoints in suicide research. Suicide and Life-Threatening Behavior, 40(5), 500- 505 . doi:10.1521/suli.2010.40.5.500...symptoms (Baglioni et al., 2010)—all of which may serve to mediate the relationship between insom- nia symptoms and suicidal ideation and behavior. 3...baseline insom- nia symptom index, MSSI, BHS, PTSD, and MCMI scores. Addi- tional analyses involved a logistic regression examining the relation of

Quality of Documentation as a Surrogate Marker for Awareness and Training Effectiveness of PHTLS-Courses. Part of the Prospective Longitudinal Mixed-Methods EPPTC-Trial.

PubMed

Häske, David; Beckers, Stefan K; Hofmann, Marzellus; Lefering, Rolf; Gliwitzky, Bernhard; Wölfl, Christoph C; Grützner, Paul; Stöckle, Ulrich; Dieroff, Marc; Münzberg, Matthias

2017-01-01

Care for severely injured patients requires multidisciplinary teamwork. A decrease in the number of accident victims ultimately affects the routine and skills. PHTLS ("Pre-Hospital Trauma Life Support") courses are established two-day courses for medical and non-medical rescue service personnel, aimed at improving the pre-hospital care of trauma patients worldwide. The study aims the examination of the quality of documentation before and after PHTLS courses as a surrogate endpoint of training effectiveness and awareness. This was a prospective pre-post intervention trial and was part of the mixed-method longitudinal EPPTC (Effect of Paramedic Training on Pre-Hospital Trauma Care) study, evaluating subjective and objective changes among participants and real patient care, as a result of PHTLS courses. The courses provide an overview of the SAMPLE approach for interrogation of anamnestic information, which is believed to be responsible for patient safety as relevant, among others, "Allergies," "Medication," and "Patient History" (AMP). The focus of the course is not the documentation. In total, 320 protocols were analyzed before and after the training. The PHTLS course led to a significant increase (p < 0.001) in the "AMP" information in the documentation. The subgroups analysis of "allergies" (+47.2%), "drugs" (+38.1%), and "medical history" (+27.8%) before and after the PHTLS course showed a significant increase in the information content. In summary, we showed that PHTLS training improves documentation quality, which we used as a surrogate endpoint for learning effectiveness and awareness. In this regard, we demonstrated that participants use certain parts of training in real life, thereby suggesting that the learning methods of PHTLS training are effective. These results, however, do not indicate whether patient care has changed.

Evidence overview: benefit of cerebral protection devices during carotid artery stenting.

PubMed

Vos, Jan A

2017-04-01

Embolic protection devices (EPDs) are often used during carotid angioplasty and stenting (CAS) to reduce procedural cerebral emboli. This manuscript seeks to present an overview of evidence on EPDs during CAS. There are three categories of EPDs: distal occlusion (DO-EPD), filter (F-EPD) and proximal occlusion (PO-EPD). DO and F-EPDs have the disadvantage that the device has to be advanced through the stenosis, without protection and that the device may damage the distal internal carotid artery (ICA). F-EPDs have the advantage of maintaining antegrade flow throughout the procedure. PO-EPDs occlude the ICA and external carotid artery (ECA) (blocking antegrade flow), but do not require manipulation of the stenosis before protection is established. All devices add to procedural time and costs. Many single-center series and meta-analyses have shown lower incidence of procedural complications and surrogate endpoints when EPDs are used. However, these series are hampered by a serious confounder: protected cases were generally performed later, when institutions had more experience and when newer stents, techniques etc. had become available. Two small randomized trials showed no difference between filter-protected and unprotected procedures in clinical outcome, but found significantly more surrogate endpoints (diffusion-weighted MRI lesions and transcranial Doppler detected micro-emboli) in the protected groups. Comparing between groups of EPDs, some studies slightly favored PO to F-EPDs, while others found no difference. All devices were associated with low numbers of clinical cerebral complications, but frequent surrogate signs of cerebral embolization. In conclusion, all currently available EPDs still result in some degree of cerebral embolization. No solid recommendation for a particular type of EPDs, if any, can be derived from literature.

Surrogate screening models for the low physical activity criterion of frailty.

PubMed

Eckel, Sandrah P; Bandeen-Roche, Karen; Chaves, Paulo H M; Fried, Linda P; Louis, Thomas A

2011-06-01

Low physical activity, one of five criteria in a validated clinical phenotype of frailty, is assessed by a standardized, semiquantitative questionnaire on up to 20 leisure time activities. Because of the time demanded to collect the interview data, it has been challenging to translate to studies other than the Cardiovascular Health Study (CHS), for which it was developed. Considering subsets of activities, we identified and evaluated streamlined surrogate assessment methods and compared them to one implemented in the Women's Health and Aging Study (WHAS). Using data on men and women ages 65 and older from the CHS, we applied logistic regression models to rank activities by "relative influence" in predicting low physical activity.We considered subsets of the most influential activities as inputs to potential surrogate models (logistic regressions). We evaluated predictive accuracy and predictive validity using the area under receiver operating characteristic curves and assessed criterion validity using proportional hazards models relating frailty status (defined using the surrogate) to mortality. Walking for exercise and moderately strenuous household chores were highly influential for both genders. Women required fewer activities than men for accurate classification. The WHAS model (8 CHS activities) was an effective surrogate, but a surrogate using 6 activities (walking, chores, gardening, general exercise, mowing and golfing) was also highly predictive. We recommend a 6 activity questionnaire to assess physical activity for men and women. If efficiency is essential and the study involves only women, fewer activities can be included.

Non-invasive prediction of forthcoming cirrhosis-related complications

PubMed Central

Kang, Wonseok; Kim, Seung Up; Ahn, Sang Hoon

2014-01-01

In patients with chronic liver diseases, identification of significant liver fibrosis and cirrhosis is essential for determining treatment strategies, assessing therapeutic response, and stratifying long-term prognosis. Although liver biopsy remains the reference standard for evaluating the extent of liver fibrosis in patients with chronic liver diseases, several non-invasive methods have been developed as alternatives to liver biopsies. Some of these non-invasive methods have demonstrated clinical accuracy for diagnosing significant fibrosis or cirrhosis in many cross-sectional studies with the histological fibrosis stage as a reference standard. However, non-invasive methods cannot be fully validated through cross-sectional studies since liver biopsy is not a perfect surrogate endpoint marker. Accordingly, recent studies have focused on assessing the performance of non-invasive methods through long-term, longitudinal, follow-up studies with solid clinical endpoints related to advanced stages of liver fibrosis and cirrhosis. As a result, current view is that these alternative methods can independently predict future cirrhosis-related complications, such as hepatic decompensation, liver failure, hepatocellular carcinoma, or liver-related death. The clinical role of non-invasive models seems to be shifting from a simple tool for predicting the extent of fibrosis to a surveillance tool for predicting future liver-related events. In this article, we will summarize recent longitudinal studies of non-invasive methods for predicting forthcoming complications related to liver cirrhosis and discuss the clinical value of currently available non-invasive methods based on evidence from the literature. PMID:24627597

Dose escalation methods in phase I cancer clinical trials.

PubMed

Le Tourneau, Christophe; Lee, J Jack; Siu, Lillian L

2009-05-20

Phase I clinical trials are an essential step in the development of anticancer drugs. The main goal of these studies is to establish the recommended dose and/or schedule of new drugs or drug combinations for phase II trials. The guiding principle for dose escalation in phase I trials is to avoid exposing too many patients to subtherapeutic doses while preserving safety and maintaining rapid accrual. Here we review dose escalation methods for phase I trials, including the rule-based and model-based dose escalation methods that have been developed to evaluate new anticancer agents. Toxicity has traditionally been the primary endpoint for phase I trials involving cytotoxic agents. However, with the emergence of molecularly targeted anticancer agents, potential alternative endpoints to delineate optimal biological activity, such as plasma drug concentration and target inhibition in tumor or surrogate tissues, have been proposed along with new trial designs. We also describe specific methods for drug combinations as well as methods that use a time-to-event endpoint or both toxicity and efficacy as endpoints. Finally, we present the advantages and drawbacks of the various dose escalation methods and discuss specific applications of the methods in developmental oncotherapeutics.

GDF15 is elevated in mice following retinal ganglion cell death and in glaucoma patients

PubMed Central

Ban, Norimitsu; Siegfried, Carla J.; Lin, Jonathan B.; Shui, Ying-Bo; Sein, Julia; Pita-Thomas, Wolfgang; Sene, Abdoulaye; Santeford, Andrea; Gordon, Mae; Lamb, Rachel; Dong, Zhenyu; Kelly, Shannon C.; Cavalli, Valeria; Yoshino, Jun

2017-01-01

Glaucoma is the second leading cause of blindness worldwide. Physicians often use surrogate endpoints to monitor the progression of glaucomatous neurodegeneration. These approaches are limited in their ability to quantify disease severity and progression due to inherent subjectivity, unreliability, and limitations of normative databases. Therefore, there is a critical need to identify specific molecular markers that predict or measure glaucomatous neurodegeneration. Here, we demonstrate that growth differentiation factor 15 (GDF15) is associated with retinal ganglion cell death. Gdf15 expression in the retina is specifically increased after acute injury to retinal ganglion cell axons and in a murine chronic glaucoma model. We also demonstrate that the ganglion cell layer may be one of the sources of secreted GDF15 and that GDF15 diffuses to and can be detected in aqueous humor (AH). In validating these findings in human patients with glaucoma, we find not only that GDF15 is increased in AH of patients with primary open angle glaucoma (POAG), but also that elevated GDF15 levels are significantly associated with worse functional outcomes in glaucoma patients, as measured by visual field testing. Thus, GDF15 maybe a reliable metric of glaucomatous neurodegeneration, although further prospective validation studies will be necessary to determine if GDF15 can be used in clinical practice. PMID:28469085

Comparison between surrogate indexes of insulin sensitivity/resistance and hyperinsulinemic euglycemic clamp estimates in rats

PubMed Central

Muniyappa, Ranganath; Chen, Hui; Muzumdar, Radhika H.; Einstein, Francine H.; Yan, Xu; Yue, Lilly Q.; Barzilai, Nir

2009-01-01

Assessing insulin resistance in rodent models gives insight into mechanisms that cause type 2 diabetes and the metabolic syndrome. The hyperinsulinemic euglycemic glucose clamp, the reference standard for measuring insulin sensitivity in humans and animals, is labor intensive and technically demanding. A number of simple surrogate indexes of insulin sensitivity/resistance have been developed and validated primarily for use in large human studies. These same surrogates are also frequently used in rodent studies. However, in general, these indexes have not been rigorously evaluated in animals. In a recent validation study in mice, we demonstrated that surrogates have a weaker correlation with glucose clamp estimates of insulin sensitivity/resistance than in humans. This may be due to increased technical difficulties in mice and/or intrinsic differences between human and rodent physiology. To help distinguish among these possibilities, in the present study, using data from rats substantially larger than mice, we compared the clamp glucose infusion rate (GIR) with surrogate indexes, including QUICKI, HOMA, 1/HOMA, log (HOMA), and 1/fasting insulin. All surrogates were modestly correlated with GIR (r = 0.34–0.40). Calibration analyses of surrogates adjusted for body weight demonstrated similar predictive accuracy for GIR among all surrogates. We conclude that linear correlations of surrogate indexes with clamp estimates and predictive accuracy of surrogate indexes in rats are similar to those in mice (but not as substantial as in humans). This additional rat study (taken with the previous mouse study) suggests that application of surrogate insulin sensitivity indexes developed for humans may not be appropriate for determining primary outcomes in rodent studies due to intrinsic differences in metabolic physiology. However, use of surrogates may be appropriate in rodents, where feasibility of clamps is an obstacle and measurement of insulin sensitivity is a secondary outcome. PMID:19706785

Robust best linear estimator for Cox regression with instrumental variables in whole cohort and surrogates with additive measurement error in calibration sample.

PubMed

Wang, Ching-Yun; Song, Xiao

2016-11-01

Biomedical researchers are often interested in estimating the effect of an environmental exposure in relation to a chronic disease endpoint. However, the exposure variable of interest may be measured with errors. In a subset of the whole cohort, a surrogate variable is available for the true unobserved exposure variable. The surrogate variable satisfies an additive measurement error model, but it may not have repeated measurements. The subset in which the surrogate variables are available is called a calibration sample. In addition to the surrogate variables that are available among the subjects in the calibration sample, we consider the situation when there is an instrumental variable available for all study subjects. An instrumental variable is correlated with the unobserved true exposure variable, and hence can be useful in the estimation of the regression coefficients. In this paper, we propose a nonparametric method for Cox regression using the observed data from the whole cohort. The nonparametric estimator is the best linear combination of a nonparametric correction estimator from the calibration sample and the difference of the naive estimators from the calibration sample and the whole cohort. The asymptotic distribution is derived, and the finite sample performance of the proposed estimator is examined via intensive simulation studies. The methods are applied to the Nutritional Biomarkers Study of the Women's Health Initiative. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Validating (d,p gamma) as a Surrogate for Neutron Capture

DOE PAGES

Ratkiewicz, A.; Cizewski, J.A.; Pain, S.D.; ...

2015-05-28

The r-process is responsible for creating roughly half of the elements heavier than iron. It has recently become understood that the rates at which neutron capture reactions proceed at late times in the r-process may dramatically affect the final abundance pattern. However, direct measurements of neutron capture reaction rates on exotic nuclei are exceptionally difficult, necessitating the development of indirect approaches such as the surrogate technique. The (d,pγ) reaction at low energies was identified as a promising surrogate for the (n,γ) reaction, as both reactions share many characteristics. We report on a program to validate (d,pγ) as a surrogate formore » (n,γ) using 95Mo as a target. The experimental campaign includes direct measurements of the γ-ray intensities from the decay of excited states populated in the 95Mo(n,γ) and 95Mo(d,pγ) reactions.« less

Computer-Simulation Surrogates for Optimization: Application to Trapezoidal Ducts and Axisymmetric Bodies

NASA Technical Reports Server (NTRS)

Otto, John C.; Paraschivoiu, Marius; Yesilyurt, Serhat; Patera, Anthony T.

1995-01-01

Engineering design and optimization efforts using computational systems rapidly become resource intensive. The goal of the surrogate-based approach is to perform a complete optimization with limited resources. In this paper we present a Bayesian-validated approach that informs the designer as to how well the surrogate performs; in particular, our surrogate framework provides precise (albeit probabilistic) bounds on the errors incurred in the surrogate-for-simulation substitution. The theory and algorithms of our computer{simulation surrogate framework are first described. The utility of the framework is then demonstrated through two illustrative examples: maximization of the flowrate of fully developed ow in trapezoidal ducts; and design of an axisymmetric body that achieves a target Stokes drag.

Issues Surrounding Clinical Trial Endpoints in Solid Malignancies With a Focus on Metastatic Non-Small Cell Lung Cancer

PubMed Central

Garon, Edward B

2013-01-01

Summary Relative to best supportive care alone, cytotoxic chemotherapy has an established role in prolonging overall survival (OS) in patients with or without previous treatment for metastatic non-small cell lung cancer (NSCLC). OS has been the principal endpoint influencing regulatory decisions regarding targeted therapies for metastatic NSCLC, including the vascular endothelial growth factor monoclonal antibody bevacizumab in the frontline setting and the epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib in patients after prior treatment. Progression-free survival (PFS), another common endpoint in oncology clinical trials, has been discussed as a potential surrogate for OS in metastatic NSCLC. A number of phase III clinical trials of investigational targeted agents for treatment of metastatic NSCLC are ongoing, with OS designated as the primary endpoint in some cases and PFS in others. Both endpoints have been developed largely to evaluate outcomes in unselected populations in which a fraction of patients are anticipated to derive significant benefit. New approaches are being considered for the evaluation of targeted agents. Recent high profile trials have been designed to assess PFS using a randomized discontinuation design and disease control rate after 8 weeks of treatment. With a series of recent advances towards increasingly personalized biomarker-directed anticancer therapies, the appropriateness of the traditional regulatory approach has been questioned. PMID:22795702

Bioanalytical method development and validation for the determination of glycine in human cerebrospinal fluid by ion-pair reversed-phase liquid chromatography-tandem mass spectrometry.

PubMed

Jiang, Jian; James, Christopher A; Wong, Philip

2016-09-05

A LC-MS/MS method has been developed and validated for the determination of glycine in human cerebrospinal fluid (CSF). The validated method used artificial cerebrospinal fluid as a surrogate matrix for calibration standards. The calibration curve range for the assay was 100-10,000ng/mL and (13)C2, (15)N-glycine was used as an internal standard (IS). Pre-validation experiments were performed to demonstrate parallelism with surrogate matrix and standard addition methods. The mean endogenous glycine concentration in a pooled human CSF determined on three days by using artificial CSF as a surrogate matrix and the method of standard addition was found to be 748±30.6 and 768±18.1ng/mL, respectively. A percentage difference of -2.6% indicated that artificial CSF could be used as a surrogate calibration matrix for the determination of glycine in human CSF. Quality control (QC) samples, except the lower limit of quantitation (LLOQ) QC and low QC samples, were prepared by spiking glycine into aliquots of pooled human CSF sample. The low QC sample was prepared from a separate pooled human CSF sample containing low endogenous glycine concentrations, while the LLOQ QC sample was prepared in artificial CSF. Standard addition was used extensively to evaluate matrix effects during validation. The validated method was used to determine the endogenous glycine concentrations in human CSF samples. Incurred sample reanalysis demonstrated reproducibility of the method. Copyright © 2016 Elsevier B.V. All rights reserved.

The Mediterranean diet, its components, and cardiovascular disease.

PubMed

Widmer, R Jay; Flammer, Andreas J; Lerman, Lilach O; Lerman, Amir

2015-03-01

One of the best-studied diets for cardiovascular health is the Mediterranean diet. This consists of fish, monounsaturated fats from olive oil, fruits, vegetables, whole grains, legumes/nuts, and moderate alcohol consumption. The Mediterranean diet has been shown to reduce the burden, or even prevent the development, of cardiovascular disease, breast cancer, depression, colorectal cancer, diabetes, obesity, asthma, erectile dysfunction, and cognitive decline. This diet is also known to improve surrogates of cardiovascular disease, such as waist-to-hip ratio, lipids, and markers of inflammation, as well as primary cardiovascular disease outcomes such as death and events in both observational and randomized controlled trial data. These enhancements easily rival those seen with more established tools used to fight cardiovascular disease such as aspirin, beta-blockers, angiotensin-converting enzyme inhibitors, and exercise. However, it is unclear if the Mediterranean diet offers cardiovascular disease benefit from its individual constituents or in aggregate. Furthermore, the potential benefit of the Mediterranean diet or its components is not yet validated by concrete cardiovascular disease endpoints in randomized trials or observational studies. This review will focus on the effects of the whole and parts of the Mediterranean diet with regard to both population-based and experimental data highlighting cardiovascular disease morbidity or mortality and cardiovascular disease surrogates when hard outcomes are not available. Our synthesis will highlight the potential for the Mediterranean diet to act as a key player in cardiovascular disease prevention, and attempt to identify certain aspects of the diet that are particularly beneficial for cardioprotection. Copyright © 2015 Elsevier Inc. All rights reserved.

Review of oncology and hematology drug product approvals at the US Food and Drug Administration between July 2005 and December 2007.

PubMed

Sridhara, Rajeshwari; Johnson, John R; Justice, Robert; Keegan, Patricia; Chakravarty, Aloka; Pazdur, Richard

2010-02-24

The Office of Oncology Drug Products (OODP) in the Center for Drug Evaluation and Research at the US Food and Drug Administration began reviewing marketing applications for oncological and hematologic indications in July 2005. We conducted an overview of products that were reviewed by the OODP for marketing approval and the regulatory actions taken during July 2005 to December 2007. We identified all applications that were reviewed by the OODP from July 1, 2005, through December 31, 2007, and reviewed the actions that OODP took. We also sought the basis for the actions taken, including the clinical trial design, endpoints used, patient accrual in the trial(s) supporting approval, and the type of regulatory approval. During the study period, the OODP reviewed marketing applications for 60 new indications and took regulatory action on 58 indications. Regulatory action was based on a risk-benefit evaluation of the data submitted with each application. Products that demonstrated efficacy and had an acceptable risk-benefit ratio were granted either regular or accelerated marketing approval for use in the specific indication that was studied. Regular approval was based on endpoints that demonstrated that the drug provided clinical benefit as evidenced by a longer or better life or a favorable effect on an established surrogate for a longer or better life. Accelerated approval was based on a less well-established surrogate endpoint that was reasonably likely to predict a longer or better life. Of the 53 new indications that were approved during the study period, 39 received regular approval, nine received accelerated approval, and five were converted from accelerated to regular approval. Five applications were not approved, and two applications were withdrawn before any regulatory action was taken. Eighteen of the 53 indications that were approved were for new molecular entities. During the study period, regulatory action was taken on 58 of the 60 marketing applications. Fifty-three applications were approved. A variety of clinical trial endpoints were used in the approval trials.

Skin penetration surrogate for the evaluation of less lethal kinetic energy munitions.

PubMed

Bir, Cynthia A; Resslar, Marianne; Stewart, Shelby

2012-07-10

Although the benefits of the use of less lethal kinetic energy munitions are numerous, there is a need to evaluate the munitions prior to deployment to ensure their intended effect. The objective of the current research was to validate a surrogate that could be used to predict the risk of penetration of these devices. Existing data from biomechanical testing with post-mortem human specimens (PMHS) served as the foundation for this research. Development of the surrogate involved simulating the various layers of the skin and underlying soft tissues using a combination of materials. A standardized 12-gauge impactor was used to assess each combination. The energy density that resulted in a 50% risk of penetration for the anterior thorax region (23.99 J/cm(2)) from the previous research was matched using a specific combination of layers. Twelve various combinations of materials were tested with the 50% risk of penetration determined. The final validated surrogate consisted of a Laceration Assessment Layer (LAL) of natural chamois and .6 cm of closed-cell foam over a Penetration Assessment Layer (PAL) of 20% ordnance gelatin. This surrogate predicted a 50% risk of penetration at 23.88 J/cm(2). Injury risk curves for the PMHS and surrogate development work are presented. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

From the Cover: Development and Application of a Dual Rat and Human AHR Activation Assay.

PubMed

Brown, Martin R; Garside, Helen; Thompson, Emma; Atwal, Saseela; Bean, Chloe; Goodall, Tony; Sullivan, Michael; Graham, Mark J

2017-12-01

Significant prolonged aryl hydrocarbon receptor (AHR) activation, classically exhibited following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin, can cause a variety of undesirable toxicological effects. Novel pharmaceutical chemistries also have the potential to cause activation of AHR and consequent toxicities in pre-clinical species and man. Previous methods either employed relatively expensive and low-throughput primary hepatocyte dosing with PCR endpoint, or low resolution overexpressing reporter gene assays. We have developed, validated and applied an in vitro microtitre plate imaging-based medium throughput screening assay for the assessment of endogenous species-specific AHR activation potential via detection of induction of the surrogate transcriptional target Cytochrome P450 CYP1A1. Routine testing of pharmaceutical drug development candidate chemistries using this assay can influence the chemical design process and highlight AHR liabilities. This assay should be introduced such that human AHR activation liability is flagged early for confirmatory testing. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Prostate cancer prevention agent development: Criteria and pipeline for candidate chemoprevention agents.

PubMed

Nelson, W G; Wilding, G

2001-04-01

Epidemiologic data suggest that prostate cancer morbidity and mortality ought to be preventable. New insights into the molecular pathogenesis of prostate cancer offer new opportunities for the discovery of prostate cancer chemoprevention drugs and new challenges for their development. Established pathways that lead to US Food and Drug Administration (FDA) approval of drugs for advanced prostate cancer may not be appropriate for the development of drugs for prostate cancer chemoprevention. For example, large randomized clinical trials designed to test the efficacy of new chemoprevention drugs on prostate cancer survival in the general population are likely to be conducted at great expense and take many years, threatening to increase commercial development risks while decreasing exclusive marketing revenues. As a consequence, to accelerate progress in research, new validated surrogate and strategic clinical trial endpoints, and new clinical trial designs featuring more precisely defined high-risk clinical trial cohorts, are needed. In this review, 10 criteria for prostate cancer chemoprevention agent development are offered and the pipeline of new prostate cancer chemoprevention drug candidates is considered.

The MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models

EPA Science Inventory

The second phase of the MicroArray Quality Control (MAQC-II) project evaluated common practices for developing and validating microarray-based models aimed at predicting toxicological and clinical endpoints. Thirty-six teams developed classifiers for 13 endpoints - some easy, som...

A general framework to learn surrogate relevance criterion for atlas based image segmentation

NASA Astrophysics Data System (ADS)

Zhao, Tingting; Ruan, Dan

2016-09-01

Multi-atlas based image segmentation sees great opportunities in the big data era but also faces unprecedented challenges in identifying positive contributors from extensive heterogeneous data. To assess data relevance, image similarity criteria based on various image features widely serve as surrogates for the inaccessible geometric agreement criteria. This paper proposes a general framework to learn image based surrogate relevance criteria to better mimic the behaviors of segmentation based oracle geometric relevance. The validity of its general rationale is verified in the specific context of fusion set selection for image segmentation. More specifically, we first present a unified formulation for surrogate relevance criteria and model the neighborhood relationship among atlases based on the oracle relevance knowledge. Surrogates are then trained to be small for geometrically relevant neighbors and large for irrelevant remotes to the given targets. The proposed surrogate learning framework is verified in corpus callosum segmentation. The learned surrogates demonstrate superiority in inferring the underlying oracle value and selecting relevant fusion set, compared to benchmark surrogates.

Remote preconditioning and major clinical complications following adult cardiovascular surgery: systematic review and meta-analysis.

PubMed

Healy, D A; Khan, W A; Wong, C S; Moloney, M Clarke; Grace, P A; Coffey, J C; Dunne, C; Walsh, S R; Sadat, U; Gaunt, M E; Chen, S; Tehrani, S; Hausenloy, D J; Yellon, D M; Kramer, R S; Zimmerman, R F; Lomivorotov, V V; Shmyrev, V A; Ponomarev, D N; Rahman, I A; Mascaro, J G; Bonser, R S; Jeon, Y; Hong, D M; Wagner, R; Thielmann, M; Heusch, G; Zacharowski, K; Meybohm, P; Bein, B; Tang, T Y

2014-09-01

A number of 'proof-of-concept' trials suggest that remote ischaemic preconditioning (RIPC) reduces surrogate markers of end-organ injury in patients undergoing major cardiovascular surgery. To date, few studies have involved hard clinical outcomes as primary end-points. Randomised clinical trials of RIPC in major adult cardiovascular surgery were identified by a systematic review of electronic abstract databases, conference proceedings and article reference lists. Clinical end-points were extracted from trial reports. In addition, trial principal investigators provided unpublished clinical outcome data. In total, 23 trials of RIPC in 2200 patients undergoing major adult cardiovascular surgery were identified. RIPC did not have a significant effect on clinical end-points (death, peri-operative myocardial infarction (MI), renal failure, stroke, mesenteric ischaemia, hospital or critical care length of stay). Pooled data from pilot trials cannot confirm that RIPC has any significant effect on clinically relevant end-points. Heterogeneity in study inclusion and exclusion criteria and in the type of preconditioning stimulus limits the potential for extrapolation at present. An effort must be made to clarify the optimal preconditioning stimulus. Following this, large-scale trials in a range of patient populations are required to ascertain the role of this simple, cost-effective intervention in routine practice. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

The utility of a composite biological endpoint in HIV/STI prevention trials.

PubMed

Hartwell, Tyler D; Pequegnat, Willo; Moore, Janet L; Parker, Corette B; Strader, Lisa C; Green, Annette M; Quinn, Thomas C; Wasserheit, Judith N; Klausner, Jeffrey D

2013-11-01

A human immunodeficiency virus (HIV) as a biological endpoint in HIV prevention trials may not be feasible, so investigators have used surrogate biological outcomes. In a multisite trial, the epidemiology of STIs may be different across sites and preclude using one STI as the outcome. This study explored using a composite STI outcome to address that problem. The combined biological endpoint was the incidence of any of six new STIs (chlamydia, gonorrhea, trichomonas (women only), syphilis, herpes simplex virus type 2 infection and HIV) during a 24-month follow up period. We investigated how a composite STI outcome would perform compared to single and dual STI outcomes under various conditions. We simulated outcomes for four populations that represented a wide range of sex and age distributions, and STI prevalences. The simulations demonstrated that a combined biologic outcome was superior to single and dual STI outcomes in assessing intervention effects in 82 % of the cases. A composite biological outcome was effective in detecting intervention effects and might allow more investigations to incorporate multiple biological outcomes in the assessment of behavioral intervention trials for HIV prevention.

Development and application of a green fluorescent protein (GFP) expressing E. coli O103 surrogate for tracking contamination through grinding and identifying persistent points of contamination

USDA-ARS?s Scientific Manuscript database

Objective: To 1.) develop and validate an easily trackable E. coli O157:H7/non-O157 STEC surrogate that can be detected to the same level of sensitivity as E. coli O157:H7; and 2.) apply the trackable surrogate to model contamination passage through grinding and identify points where contamination ...

Surrogate end points in women's health research: science, protoscience, and pseudoscience.

PubMed

Grimes, David A; Schulz, Kenneth F; Raymond, Elizabeth G

2010-04-01

A surrogate end point (e.g., a laboratory test or image) serves as a proxy for a clinical end point of importance (e.g., fracture, thrombosis, or death). Adoption and use of surrogate end points lacking validation, especially in cardiovascular medicine, have caused thousands of patients' deaths, a serious violation of the ethical principle of beneficence. Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Evaluating Principal Surrogate Markers in Vaccine Trials in the Presence of Multiphase Sampling

PubMed Central

Huang, Ying

2017-01-01

Summary This paper focuses on the evaluation of vaccine-induced immune responses as principal surrogate markers for predicting a given vaccine’s effect on the clinical endpoint of interest. To address the problem of missing potential outcomes under the principal surrogate framework, we can utilize baseline predictors of the immune biomarker(s) or vaccinate uninfected placebo recipients at the end of the trial and measure their immune biomarkers. Examples of good baseline predictors are baseline immune responses when subjects enrolled in the trial have been previously exposed to the same antigen, as in our motivating application of the Zostavax Efficacy and Safety Trial (ZEST). However, laboratory assays of these baseline predictors are expensive and therefore their subsampling among participants is commonly performed. In this paper we develop a methodology for estimating principal surrogate values in the presence of baseline predictor subsampling. Under a multiphase sampling framework, we propose a semiparametric pseudo-score estimator based on conditional likelihood and also develop several alternative semiparametric pseudo-score or estimated likelihood estimators. We derive corresponding asymptotic theories and analytic variance formulas for these estimators. Through extensive numeric studies, we demonstrate good finite sample performance of these estimators and the efficiency advantage of the proposed pseudo-score estimator in various sampling schemes. We illustrate the application of our proposed estimators using data from an immune biomarker study nested within the ZEST trial. PMID:28653408

Surrogate outcomes: experiences at the Common Drug Review

PubMed Central

2013-01-01

Background Surrogate outcomes are a significant challenge in drug evaluation for health technology assessment (HTA) agencies. The research objectives were to: identify factors associated with surrogate use and acceptability in Canada’s Common Drug Review (CDR) recommendations, and compare the CDR with other HTA or regulatory agencies regarding surrogate concerns. Methods Final recommendations were identified from CDR inception (September 2003) to December 31, 2010. Recommendations were classified by type of outcome (surrogate, final, other) and acceptability of surrogates (determined by the presence/absence of statements of concern regarding surrogates). Descriptive and statistical analyses examined factors related to surrogate use and acceptability. For thirteen surrogate-based submissions, recommendations from international HTA and regulatory agencies were reviewed for statements about surrogate acceptability. Results Of 156 final recommendations, 68 (44%) involved surrogates. The overall ‘do not list’ (DNL) rate was 48%; the DNL rate for surrogates was 41% (p = 0.175). The DNL rate was 64% for non-accepted surrogates (n = 28) versus 25% for accepted surrogates (odds ratio 5.4, p = 0.002). Clinical uncertainty, use of economic evidence over price alone, and a premium price were significantly associated with non-accepted surrogates. Surrogates were used most commonly for HIV, diabetes, rare diseases, cardiovascular disease and cancer. For the subset of drugs studied, other HTA agencies did not express concerns for most recommendations, while regulatory agencies frequently stated surrogate acceptance. Conclusions The majority of surrogates were accepted at the CDR. Non-accepted surrogates were significantly associated with clinical uncertainty and a DNL recommendation. There was inconsistency of surrogate acceptability across several international agencies. Stakeholders should consider collaboratively establishing guidelines on the use, validation, and acceptability of surrogates. PMID:24341379

Health economic evaluation of treatments for Alzheimer's disease: impact of new diagnostic criteria.

PubMed

Wimo, A; Ballard, C; Brayne, C; Gauthier, S; Handels, R; Jones, R W; Jonsson, L; Khachaturian, A S; Kramberger, M

2014-03-01

The socio-economic impact of Alzheimer's disease (AD) and other dementias is enormous, and the potential economic challenges ahead are clear given the projected future numbers of individuals with these conditions. Because of the high prevalence and cost of dementia, it is very important to assess any intervention from a cost-effectiveness viewpoint. The diagnostic criteria for preclinical AD suggested by the National Institute on Aging and Alzheimer's Association workgroups in combination with the goal of effective disease-modifying treatment (DMT) are, however, a challenge for clinical practice and for the design of clinical trials. Key issues for future cost-effectiveness studies include the following: (i) the consequences for patients if diagnosis is shifted from AD-dementia to predementia states, (ii) bridging the gap between clinical trial populations and patients treated in clinical practice, (iii) translation of clinical trial end-points into measures that are meaningful to patients and policymakers/payers and (iv) how to measure long-term effects. To improve cost-effectiveness studies, long-term population-based data on disease progression, costs and outcomes in clinical practice are needed not only in dementia but also in predementia states. Reliable surrogate end-points in clinical trials that are sensitive to detect effects even in predementia states are also essential as well as robust and validated modelling methods from predementia states that also take into account comorbidities and age. Finally, the ethical consequences of early diagnosis should be considered. © 2014 The Association for the Publication of the Journal of Internal Medicine.

Assessing head and neck cancer patient preferences and expectations: A systematic review.

PubMed

Blanchard, Pierre; Volk, Robert J; Ringash, Jolie; Peterson, Susan K; Hutcheson, Katherine A; Frank, Steven J

2016-11-01

To enhance the value of care, interventions should aim at improving endpoints that matter to patients. The preferences of head and neck cancer patients regarding treatment outcomes are therefore a major topic for patient-centered research. A systematic review (PROSPERO number CRD42016035692) was conducted by searching electronic databases (Medline, Embase, Cochrane, CINAHL) for articles evaluating patient or surrogate preferences in head and neck cancer. A qualitative review was performed but no quantitative synthesis. Of 817 references retrieved, 20full-text articles were eventually included in the qualitative analysis Disease sites included mixed head and neck tumor sites, n=9; larynx, n=6; oropharynx/oral cavity, n=5. Overall, patients prioritized survival over functional endpoints. However, preferences and utility scores varied greatly between patients and healthy subjects, and differences were less pronounced with spouses or healthcare providers. Findings from studies of laryngeal preservation are consistent and conclude that a subset of patients would be willing to compromise a certain amount of survival to avoid laryngectomy. On the other hand, studies of patients with oropharyngeal cancer are too heterogeneous to draw conclusions about acceptable functional trade-offs or priorities, and should be the focus of future research. Future research surrounding head and neck cancer patients will most likely be clinically applicable if the questions are focused on well-defined patient groups and treatment options. Gathering reliable and valid quality-of-life data, designing patient preference studies that use reliable and generalizable methods, and using the results to develop decision aids for shared decision-making strategies are recommended going forward. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effects of Exposure Measurement Error in the Analysis of Health Effects from Traffic-Related Air Pollution

EPA Science Inventory

In large epidemiological studies, many researchers use surrogates of air pollution exposure such as geographic information system (GIS)-based characterizations of traffic or simple housing characteristics. It is important to validate these surrogates against measured pollutant co...

External Heat Transfer Coefficient Measurements on a Surrogate Indirect Inertial Confinement Fusion Target

DOE PAGES

Miles, Robin; Havstad, Mark; LeBlanc, Mary; ...

2015-09-15

External heat transfer coefficients were measured around a surrogate Indirect inertial confinement fusion (ICF) based on the Laser Inertial Fusion Energy (LIFE) design target to validate thermal models of the LIFE target during flight through a fusion chamber. Results indicate that heat transfer coefficients for this target 25-50 W/m 2∙K are consistent with theoretically derived heat transfer coefficients and valid for use in calculation of target heating during flight through a fusion chamber.

Study Designs and Statistical Analyses for Biomarker Research

PubMed Central

Gosho, Masahiko; Nagashima, Kengo; Sato, Yasunori

2012-01-01

Biomarkers are becoming increasingly important for streamlining drug discovery and development. In addition, biomarkers are widely expected to be used as a tool for disease diagnosis, personalized medication, and surrogate endpoints in clinical research. In this paper, we highlight several important aspects related to study design and statistical analysis for clinical research incorporating biomarkers. We describe the typical and current study designs for exploring, detecting, and utilizing biomarkers. Furthermore, we introduce statistical issues such as confounding and multiplicity for statistical tests in biomarker research. PMID:23012528

Proof of concept demonstration of optimal composite MRI endpoints for clinical trials.

PubMed

Edland, Steven D; Ard, M Colin; Sridhar, Jaiashre; Cobia, Derin; Martersteck, Adam; Mesulam, M Marsel; Rogalski, Emily J

2016-09-01

Atrophy measures derived from structural MRI are promising outcome measures for early phase clinical trials, especially for rare diseases such as primary progressive aphasia (PPA), where the small available subject pool limits our ability to perform meaningfully powered trials with traditional cognitive and functional outcome measures. We investigated a composite atrophy index in 26 PPA participants with longitudinal MRIs separated by two years. Rogalski et al . [ Neurology 2014;83:1184-1191] previously demonstrated that atrophy of the left perisylvian temporal cortex (PSTC) is a highly sensitive measure of disease progression in this population and a promising endpoint for clinical trials. Using methods described by Ard et al . [ Pharmaceutical Statistics 2015;14:418-426], we constructed a composite atrophy index composed of a weighted sum of volumetric measures of 10 regions of interest within the left perisylvian cortex using weights that maximize signal-to-noise and minimize sample size required of trials using the resulting score. Sample size required to detect a fixed percentage slowing in atrophy in a two-year clinical trial with equal allocation of subjects across arms and 90% power was calculated for the PSTC and optimal composite surrogate biomarker endpoints. The optimal composite endpoint required 38% fewer subjects to detect the same percent slowing in atrophy than required by the left PSTC endpoint. Optimal composites can increase the power of clinical trials and increase the probability that smaller trials are informative, an observation especially relevant for PPA, but also for related neurodegenerative disorders including Alzheimer's disease.

Robust estimation of the proportion of treatment effect explained by surrogate marker information.

PubMed

Parast, Layla; McDermott, Mary M; Tian, Lu

2016-05-10

In randomized treatment studies where the primary outcome requires long follow-up of patients and/or expensive or invasive obtainment procedures, the availability of a surrogate marker that could be used to estimate the treatment effect and could potentially be observed earlier than the primary outcome would allow researchers to make conclusions regarding the treatment effect with less required follow-up time and resources. The Prentice criterion for a valid surrogate marker requires that a test for treatment effect on the surrogate marker also be a valid test for treatment effect on the primary outcome of interest. Based on this criterion, methods have been developed to define and estimate the proportion of treatment effect on the primary outcome that is explained by the treatment effect on the surrogate marker. These methods aim to identify useful statistical surrogates that capture a large proportion of the treatment effect. However, current methods to estimate this proportion usually require restrictive model assumptions that may not hold in practice and thus may lead to biased estimates of this quantity. In this paper, we propose a nonparametric procedure to estimate the proportion of treatment effect on the primary outcome that is explained by the treatment effect on a potential surrogate marker and extend this procedure to a setting with multiple surrogate markers. We compare our approach with previously proposed model-based approaches and propose a variance estimation procedure based on a perturbation-resampling method. Simulation studies demonstrate that the procedure performs well in finite samples and outperforms model-based procedures when the specified models are not correct. We illustrate our proposed procedure using a data set from a randomized study investigating a group-mediated cognitive behavioral intervention for peripheral artery disease participants. Copyright © 2015 John Wiley & Sons, Ltd.

Accurate quantification of PGE2 in the polyposis in rat colon (Pirc) model by surrogate analyte-based UPLC-MS/MS.

PubMed

Yun, Changhong; Dashwood, Wan-Mohaiza; Kwong, Lawrence N; Gao, Song; Yin, Taijun; Ling, Qinglan; Singh, Rashim; Dashwood, Roderick H; Hu, Ming

2018-01-30

An accurate and reliable UPLC-MS/MS method is reported for the quantification of endogenous Prostaglandin E2 (PGE 2 ) in rat colonic mucosa and polyps. This method adopted the "surrogate analyte plus authentic bio-matrix" approach, using two different stable isotopic labeled analogs - PGE 2 -d9 as the surrogate analyte and PGE 2 -d4 as the internal standard. A quantitative standard curve was constructed with the surrogate analyte in colonic mucosa homogenate, and the method was successfully validated with the authentic bio-matrix. Concentrations of endogenous PGE 2 in both normal and inflammatory tissue homogenates were back-calculated based on the regression equation. Because of no endogenous interference on the surrogate analyte determination, the specificity was particularly good. By using authentic bio-matrix for validation, the matrix effect and exaction recovery are identically same for the quantitative standard curve and actual samples - this notably increased the assay accuracy. The method is easy, fast, robust and reliable for colon PGE 2 determination. This "surrogate analyte" approach was applied to measure the Pirc (an Apc-mutant rat kindred that models human FAP) mucosa and polyps PGE 2 , one of the strong biomarkers of colorectal cancer. A similar concept could be applied to endogenous biomarkers in other tissues. Copyright © 2017 Elsevier B.V. All rights reserved.

Magnetic resonance imaging as a surrogate outcome for multiple sclerosis relapses

PubMed Central

Petkau, J; Reingold, SC; Held, U; Cutter, GR; Fleming, TR; Hughes, MD; Miller, DH; McFarland, HF; Wolinsky, JS

2009-01-01

Background Magnetic resonance imaging (MRI) of lesions in the brain may be the best current candidate for a surrogate biological marker of clinical outcomes in relapsing remitting multiple sclerosis (MS), based on its role as an objective indicator of disease pathology. No biological surrogate marker has yet been validated for MS clinical outcomes. Objective The objective of this study was to use a multi-phased study to determine if a valid surrogate relationship could be demonstrated between counts of contrast enhancing lesions (CELs) and occurrence of relapses in MS. Methods We examined correlations for the concurrent and predictive relationship between CELs over 6 months and MS relapses over the same 6 months and an additional 6 months (total: 12 months), using available data on untreated patients from a large clinical trial and natural history database. Results Concurrent and predictive correlations were inadequate to justify continuation of this study to the planned additional phases required to demonstrate a surrogate relationship between CELs and MS relapses. Conclusions Confidence intervals for correlations between CELs and MS relapses exclude the possibility that CELs can be a good surrogate for relapses over the time scales we investigated. Further exploration of surrogacy between MRI measures and MS clinical outcomes may require improved datasets, the development of MRI techniques that couple better to clinical disease, and the ability to test a wide range of imaging- and clinically-based hypotheses for surrogacy. PMID:18535021

External validation of structure-biodegradation relationship (SBR) models for predicting the biodegradability of xenobiotics.

PubMed

Devillers, J; Pandard, P; Richard, B

2013-01-01

Biodegradation is an important mechanism for eliminating xenobiotics by biotransforming them into simple organic and inorganic products. Faced with the ever growing number of chemicals available on the market, structure-biodegradation relationship (SBR) and quantitative structure-biodegradation relationship (QSBR) models are increasingly used as surrogates of the biodegradation tests. Such models have great potential for a quick and cheap estimation of the biodegradation potential of chemicals. The Estimation Programs Interface (EPI) Suite™ includes different models for predicting the potential aerobic biodegradability of organic substances. They are based on different endpoints, methodologies and/or statistical approaches. Among them, Biowin 5 and 6 appeared the most robust, being derived from the largest biodegradation database with results obtained only from the Ministry of International Trade and Industry (MITI) test. The aim of this study was to assess the predictive performances of these two models from a set of 356 chemicals extracted from notification dossiers including compatible biodegradation data. Another set of molecules with no more than four carbon atoms and substituted by various heteroatoms and/or functional groups was also embodied in the validation exercise. Comparisons were made with the predictions obtained with START (Structural Alerts for Reactivity in Toxtree). Biowin 5 and Biowin 6 gave satisfactorily prediction results except for the prediction of readily degradable chemicals. A consensus model built with Biowin 1 allowed the diminution of this tendency.

Development and validation of phytotoxicity tests with emergent and submerged aquatic plants

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

Hughes, J.S.; Powell, R.L.; Nelson, M.K.

1995-12-31

Toxicity testing procedures have recently been developed for assessment of contaminant effects on emergent and submerged aquatic macrophytes commonly found in freshwater wetlands. These tests have potential application in risk assessments for contaminated wetlands as well as for new chemical substances. The objective of this study was to evaluate and modify, if necessary, these methods and to validate them, using two benchmark chemicals, in a contract laboratory setting. Oryza sativa (domestic rice) was used as a surrogate emergent vascular plant, while Ceratophylium demersum (coontail) and Myriophyllum heterophyllum (variable-leaf milfoil) were the representative submerged vascular plants. Subsequent to evaluating culturing techniquesmore » and testing conditions, toxicity tests were conducted using boron and metribuzin. The test procedure for the emergent plants involves a two-week pro-exposure period followed by a two-week aqueous exposure. Five types of sediment, including both natural and artificial sediments, were evaluated for use with rice. Fresh weight and chlorophyll a content were the selected test endpoints. The submerged plants were exposed for two weeks, and the response variables evaluated included length, weight (fresh and dry), and root number. The sensitivity of these tests were comparable to the results obtained for the same two chemicals using the green alga, Selenastrum capricornutum, and the duckweed, Lemna gibba, with the exception that rice was less sensitive to metribuzin than the other species.« less

40 CFR Appendix A to Part 63 - Test Methods

Code of Federal Regulations, 2010 CFR

2010-07-01

... components by a different analyst). 3.3Surrogate Reference Materials. The analyst may use surrogate compounds... the variance of the proposed method is significantly different from that of the validated method by... variables can be determined in eight experiments rather than 128 (W.J. Youden, Statistical Manual of the...

Critical review of norovirus surrogates in food safety research: rationale for considering volunteer studies.

PubMed

Richards, Gary P

2012-03-01

The inability to propagate human norovirus (NoV) or to clearly differentiate infectious from noninfectious virus particles has led to the use of surrogate viruses, like feline calicivirus (FCV) and murine norovirus-1 (MNV), which are propagatable in cell culture. The use of surrogates is predicated on the assumption that they generally mimic the viruses they represent; however, studies are proving this concept invalid. In direct comparisons between FCV and MNV, their susceptibility to temperatures, environmental and food processing conditions, and disinfectants are dramatically different. Differences have also been noted between the inactivation of NoV and its surrogates, thus questioning the validity of surrogates. Considerable research funding is provided globally each year to conduct surrogate studies on NoVs; however, there is little demonstrated benefit derived from these studies in regard to the development of virus inactivation techniques or food processing strategies. Human challenge studies are needed to determine which processing techniques are effective in reducing NoVs in foods. A major obstacle to clinical trials on NoVs is the perception that such trials are too costly and risky, but in reality, there is far more cost and risk in allowing millions of unsuspecting consumers to contract NoV illness each year, when practical interventions are only a few volunteer studies away. A number of clinical trials have been conducted, providing important insights into NoV inactivation. A shift in research priorities from surrogate research to volunteer studies is essential if we are to identify realistic, practical, and scientifically valid processing approaches to improve food safety.

GLNE 003: Preliminary Validation of Biomarkers Predictive of Barrett’s Esophagus Progression to Dysplasia and Adenocarcinoma — EDRN Public Portal

Cancer.gov

   Recognizing that novel potential biomarkers are continually being identified and will need to be validated in a rapid, efficient, and scientifically rigorous manner, the NCI has made an enormous commitment to the development of a network that will facilitate biomarker development and validation in multiple organ sites. As part of the National Cancer Institute-funded Early Detection Research Network (EDRN), the Great Lakes-New England Clinical Epidemiological Center (GLNE CEC) proposes a research program that provides the structure for validating and discovering potential surrogate endpoint biomarkers (“biomarkers”). Although examples of such biomarkers are currently in clinical use (i.e. CEA, CA-125), there are limitations to all of them. Our consortium focuses specifically on gastrointestinal neoplasia.    There are three goals for this phase of the proposed research. 1. Establish the feasibility of measuring the biomarkers in a multi-center clinical trial. 2. Estimate the variance of the biomarkers in cohorts defined by sex, race, age and histologic diagnosis (non-Barrett’s controls, Barrett’s intestinal metaplasia, Barrett’s intestinal dysplasia [low and high-grade] and adenocarcinoma). 3. Determine if the distributions of the biomarkers differ significantly among patients with different histologic diagnoses.    In this protocol, biological samples will consist of serum, plasma, urine, and biopsies from Barrett’s esophagus (metaplasia, low and high-grade dysplasia) patients, from patients with esophageal adenocarcinoma, and from non-Barrett’s controls. Samples will be assayed for villin, p53, Hsp27, cyclooxygenase-2, and Cyclin D1. Samples will also be used for two biomarker discovery projects, one exploring genetic expression using genomic microarrays and a second using two-dimensional gene arrays to discover and characterize amplified proteins associated with esophageal carcinogenesis. Fifty subjects will

A Surrogate Technique for Investigating Deterministic Dynamics in Discrete Human Movement.

PubMed

Taylor, Paul G; Small, Michael; Lee, Kwee-Yum; Landeo, Raul; O'Meara, Damien M; Millett, Emma L

2016-10-01

Entropy is an effective tool for investigation of human movement variability. However, before applying entropy, it can be beneficial to employ analyses to confirm that observed data are not solely the result of stochastic processes. This can be achieved by contrasting observed data with that produced using surrogate methods. Unlike continuous movement, no appropriate method has been applied to discrete human movement. This article proposes a novel surrogate method for discrete movement data, outlining the processes for determining its critical values. The proposed technique reliably generated surrogates for discrete joint angle time series, destroying fine-scale dynamics of the observed signal, while maintaining macro structural characteristics. Comparison of entropy estimates indicated observed signals had greater regularity than surrogates and were not only the result of stochastic but also deterministic processes. The proposed surrogate method is both a valid and reliable technique to investigate determinism in other discrete human movement time series.

Warfarin Pharmacogenetics

PubMed Central

Johnson, Julie A.; Cavallari, Larisa H.

2014-01-01

The cytochrome P450 (CYP) 2C9 and vitamin K epoxide reductase complex 1 (VKORC1) genotypes have been strongly and consistently associated with warfarin dose requirements, and dosing algorithms incorporating genetic and clinical information have been shown to be predictive of stable warfarin dose. However, clinical trials evaluating genotype-guided warfarin dosing produced mixed results, calling into question the utility of this approach. Recent trials used surrogate markers as endpoints rather than clinical endpoints, further complicating translation of the data to clinical practice. The present data do not support genetic testing to guide warfarin dosing, but in the setting where genotype data are available, use of such data in those of European ancestry is reasonable. Outcomes data are expected from an on-going trial, observational studies continue, and more work is needed to define dosing algorithms that incorporate appropriate variants in minority populations; all these will further shape guidelines and recommendations on the clinical utility of genotype-guided warfarin dosing. PMID:25282448

Best (but oft-forgotten) practices: mediation analysis.

PubMed

Fairchild, Amanda J; McDaniel, Heather L

2017-06-01

This contribution in the "Best (but Oft-Forgotten) Practices" series considers mediation analysis. A mediator (sometimes referred to as an intermediate variable, surrogate endpoint, or intermediate endpoint) is a third variable that explains how or why ≥2 other variables relate in a putative causal pathway. The current article discusses mediation analysis with the ultimate intention of helping nutrition researchers to clarify the rationale for examining mediation, avoid common pitfalls when using the model, and conduct well-informed analyses that can contribute to improving causal inference in evaluations of underlying mechanisms of effects on nutrition-related behavioral and health outcomes. We give specific attention to underevaluated limitations inherent in common approaches to mediation. In addition, we discuss how to conduct a power analysis for mediation models and offer an applied example to demonstrate mediation analysis. Finally, we provide an example write-up of mediation analysis results as a model for applied researchers. © 2017 American Society for Nutrition.

Best (but oft-forgotten) practices: mediation analysis12

PubMed Central

McDaniel, Heather L

2017-01-01

This contribution in the “Best (but Oft-Forgotten) Practices” series considers mediation analysis. A mediator (sometimes referred to as an intermediate variable, surrogate endpoint, or intermediate endpoint) is a third variable that explains how or why ≥2 other variables relate in a putative causal pathway. The current article discusses mediation analysis with the ultimate intention of helping nutrition researchers to clarify the rationale for examining mediation, avoid common pitfalls when using the model, and conduct well-informed analyses that can contribute to improving causal inference in evaluations of underlying mechanisms of effects on nutrition-related behavioral and health outcomes. We give specific attention to underevaluated limitations inherent in common approaches to mediation. In addition, we discuss how to conduct a power analysis for mediation models and offer an applied example to demonstrate mediation analysis. Finally, we provide an example write-up of mediation analysis results as a model for applied researchers. PMID:28446497

PET/CT imaging correlates with treatment outcome in patients with multidrug-resistant tuberculosis.

PubMed

Chen, Ray Y; Dodd, Lori E; Lee, Myungsun; Paripati, Praveen; Hammoud, Dima A; Mountz, James M; Jeon, Doosoo; Zia, Nadeem; Zahiri, Homeira; Coleman, M Teresa; Carroll, Matthew W; Lee, Jong Doo; Jeong, Yeon Joo; Herscovitch, Peter; Lahouar, Saher; Tartakovsky, Michael; Rosenthal, Alexander; Somaiyya, Sandeep; Lee, Soyoung; Goldfeder, Lisa C; Cai, Ying; Via, Laura E; Park, Seung-Kyu; Cho, Sang-Nae; Barry, Clifton E

2014-12-03

Definitive clinical trials of new chemotherapies for treating tuberculosis (TB) require following subjects until at least 6 months after treatment discontinuation to assess for durable cure, making these trials expensive and lengthy. Surrogate endpoints relating to treatment failure and relapse are currently limited to sputum microbiology, which has limited sensitivity and specificity. We prospectively assessed radiographic changes using 2-deoxy-2-[(18)F]-fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) at 2 and 6 months (CT only) in a cohort of subjects with multidrug-resistant TB, who were treated with second-line TB therapy for 2 years and then followed for an additional 6 months. CT scans were read semiquantitatively by radiologists and were computationally evaluated using custom software to provide volumetric assessment of TB-associated abnormalities. CT scans at 6 months (but not 2 months) assessed by radiologist readers were predictive of outcomes, and changes in computed abnormal volumes were predictive of drug response at both time points. Quantitative changes in FDG uptake 2 months after starting treatment were associated with long-term outcomes. In this cohort, some radiologic markers were more sensitive than conventional sputum microbiology in distinguishing successful from unsuccessful treatment. These results support the potential of imaging scans as possible surrogate endpoints in clinical trials of new TB drug regimens. Larger cohorts confirming these results are needed. Copyright © 2014, American Association for the Advancement of Science.

The influence of TRP53 in the dose response of radiation-induced apoptosis, DNA repair and genomic stability in murine haematopoietic cells

DOE PAGES

Lemon, Jennifer A.; Taylor, Kristina; Verdecchia, Kyle; ...

2014-01-01

Apoptotic and DNA damage endpoints are frequently used as surrogate markers of cancer risk, and have been well-studied in the Trp53+/- mouse model. We report the effect of differing Trp53 gene status on the dose response of ionizing radiation exposures (0.01-2 Gy), with the unique perspective of determining if effects of gene status remain at extended time points. Here we report no difference in the dose response for radiation-induced DNA double-strand breaks in bone marrow and genomic instability (MN-RET levels) in peripheral blood, between wild-type ( Trp53+/+) and heterozygous ( Trp53+/-) mice. The dose response for Trp53+/+ mice showed highermore » initial levels of radiation-induced lymphocyte apoptosis relative to Trp53+/- between 0 and 1 Gy. Although this trend was observed up to 12 hours post-irradiation, both genotypes ultimately reached the same level of apoptosis at 14 hours, suggesting the importance of late-onset p53-independent apoptotic responses in this mouse model. Expected radiation-induced G1 cell cycle delay was observed in Trp53+/+ but not Trp53+/-. Although p53 has an important role in cancer risk, we have shown its influence on radiation dose response can be temporally variable. This research highlights the importance of caution when using haematopoietic endpoints as surrogates to extrapolate radiation-induced cancer risk estimation.« less

NCI–RTOG Translational Program Strategic Guidelines for the Early-Stage Development of Radiosensitizers

PubMed Central

2013-01-01

The addition of chemotherapeutic agents to ionizing radiation has improved survival in many malignancies. Cure rates may be further improved by adding novel targeted agents to current radiotherapy or radiochemotherapy regimens. Despite promising laboratory data, progress in the clinical development of new drugs with radiation has been limited. To define and address the problems involved, a collaborative effort between individuals within the translational research program of the Radiation Oncology Therapy Group and the National Cancer Institute was established. We discerned challenges to drug development with radiation including: 1) the limited relevance of preclinical work, 2) the pharmaceutical industry’s diminished interest, and 3) the important individual skills and institutional commitments required to ensure a successful program. The differences between early-phase trial designs with and without radiation are noted as substantial. The traditional endpoints for early-phase clinical trials—acute toxicity and maximum-tolerated dose—are of limited value when combining targeted agents with radiation. Furthermore, response rate is not a useful surrogate marker of activity in radiation combination trials.Consequently, a risk-stratified model for drug-dose escalation with radiation is proposed, based upon the known and estimated adverse effects. The guidelines discuss new clinical trial designs, such as the time-to-event continual reassessment method design for phase I trials, randomized phase II “screening” trials, and the use of surrogate endpoints, such as pathological response. It is hoped that by providing a clear pathway, this article will accelerate the rate of drug development with radiation. PMID:23231975

Neutron capture on short-lived nuclei via the surrogate (d,pγ) reaction

NASA Astrophysics Data System (ADS)

Cizewski, Jolie A.; Ratkiewicz, Andrew

2018-05-01

Rapid r-process nucleosynthesis is responsible for the creation of about half of the elements heavier than iron. Neutron capture on shortlived nuclei in cold processes or during freeze out from hot processes can have a significant impact on the final observed r-process abundances. We are validating the (d,pγ) reaction as a surrogate for neutron capture with measurements on 95Mo targets and a focus on discrete transitions. The experimental results have been analyzed within the Hauser-Feshbach approach with non-elastic breakup of the deuteron providing a neutron to be captured. Preliminary results support the (d,pγ) reaction as a valid surrogate for neutron capture. We are poised to measure the (d,pγ) reaction in inverse kinematics with unstable beams following the development of the experimental techniques.

A web-based endpoint adjudication system for interim analyses in clinical trials.

PubMed

Nolen, Tracy L; Dimmick, Bill F; Ostrosky-Zeichner, Luis; Kendrick, Amy S; Sable, Carole; Ngai, Angela; Wallace, Dennis

2009-02-01

A data monitoring committee (DMC) is often employed to assess trial progress and review safety data and efficacy endpoints throughout a trail. Interim analyses performed for the DMC should use data that are as complete and verified as possible. Such analyses are complicated when data verification involves subjective study endpoints or requires clinical expertise to determine each subject's status with respect to the study endpoint. Therefore, procedures are needed to obtain adjudicated data for interim analyses in an efficient manner. In the past, methods for handling such data included using locally reported results as surrogate endpoints, adjusting analysis methods for unadjudicated data, or simply performing the adjudication as rapidly as possible. These methods all have inadequacies that make their sole usage suboptimal. For a study of prophylaxis for invasive candidiasis, adjudication of both study eligibility criteria and clinical endpoints prior to two interim analyses was required. Because the study was expected to enroll at a moderate rate and the sponsor required adjudicated endpoints to be used for interim analyses, an efficient process for adjudication was required. We created a web-based endpoint adjudication system (WebEAS) that allows for expedited review by the endpoint adjudication committee (EAC). This system automatically identifies when a subject's data are complete, creates a subject profile from the study data, and assigns EAC reviewers. The reviewers use the WebEAS to review the subject profile and submit their completed review form. The WebEAS then compares the reviews, assigns an additional review as a tiebreaker if needed, and stores the adjudicated data. The study for which this system was originally built was administratively closed after 10 months with only 38 subjects enrolled. The adjudication process was finalized and the WebEAS system activated prior to study closure. Some website accessibility issues presented initially. However, once these issues were resolved, the reviewers found the system user-friendly and easy to navigate. Web-based data adjudication depends upon expeditious data collection and verification. Further, ability to use web-based technologies, in addition to clinical expertise, must be considered in selecting EAC members. The automated nature of this system makes it a practical mechanism for ensuring timely endpoint adjudication. The authors believe a similar approach could be useful for handling endpoint adjudication for future clinical trials.

SITE-SPECIFIC VALIDATION OF A CHRONIC TOXICITY TEST WITH THE AMPHIPOD HYALELLA AZTECA : AN INTEGRATED STUDY OF HEAVY METAL CONTAMINATED SEDIMENTS IN PEAK CREEK, VIRGINIA

EPA Science Inventory

We will measure the correspondence of endpoints from chronic toxicity tests with the amphipod, Hyalella azteca, to a series of in situ macrobenthic community endpoints, starting with those endpoints most similar to those monitored in the laboratory test, then expanding to include...

Development of the Galaxy Chronic Obstructive Pulmonary Disease (COPD) Model Using Data from ECLIPSE: Internal Validation of a Linked-Equations Cohort Model.

PubMed

Briggs, Andrew H; Baker, Timothy; Risebrough, Nancy A; Chambers, Mike; Gonzalez-McQuire, Sebastian; Ismaila, Afisi S; Exuzides, Alex; Colby, Chris; Tabberer, Maggie; Muellerova, Hana; Locantore, Nicholas; Rutten van Mölken, Maureen P M H; Lomas, David A

2017-05-01

The recent joint International Society for Pharmacoeconomics and Outcomes Research / Society for Medical Decision Making Modeling Good Research Practices Task Force emphasized the importance of conceptualizing and validating models. We report a new model of chronic obstructive pulmonary disease (COPD) (part of the Galaxy project) founded on a conceptual model, implemented using a novel linked-equation approach, and internally validated. An expert panel developed a conceptual model including causal relationships between disease attributes, progression, and final outcomes. Risk equations describing these relationships were estimated using data from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study, with costs estimated from the TOwards a Revolution in COPD Health (TORCH) study. Implementation as a linked-equation model enabled direct estimation of health service costs and quality-adjusted life years (QALYs) for COPD patients over their lifetimes. Internal validation compared 3 years of predicted cohort experience with ECLIPSE results. At 3 years, the Galaxy COPD model predictions of annual exacerbation rate and annual decline in forced expiratory volume in 1 second fell within the ECLIPSE data confidence limits, although 3-year overall survival was outside the observed confidence limits. Projections of the risk equations over time permitted extrapolation to patient lifetimes. Averaging the predicted cost/QALY outcomes for the different patients within the ECLIPSE cohort gives an estimated lifetime cost of £25,214 (undiscounted)/£20,318 (discounted) and lifetime QALYs of 6.45 (undiscounted/5.24 [discounted]) per ECLIPSE patient. A new form of model for COPD was conceptualized, implemented, and internally validated, based on a series of linked equations using epidemiological data (ECLIPSE) and cost data (TORCH). This Galaxy model predicts COPD outcomes from treatment effects on disease attributes such as lung function, exacerbations, symptoms, or exercise capacity; further external validation is required.

Limited predictive ability of surrogate indices of insulin sensitivity/resistance in Asian-Indian men.

PubMed

Muniyappa, Ranganath; Irving, Brian A; Unni, Uma S; Briggs, William M; Nair, K Sreekumaran; Quon, Michael J; Kurpad, Anura V

2010-12-01

Insulin resistance is highly prevalent in Asian Indians and contributes to worldwide public health problems, including diabetes and related disorders. Surrogate measurements of insulin sensitivity/resistance are used frequently to study Asian Indians, but these are not formally validated in this population. In this study, we compared the ability of simple surrogate indices to accurately predict insulin sensitivity as determined by the reference glucose clamp method. In this cross-sectional study of Asian-Indian men (n = 70), we used a calibration model to assess the ability of simple surrogate indices for insulin sensitivity [quantitative insulin sensitivity check index (QUICKI), homeostasis model assessment (HOMA2-IR), fasting insulin-to-glucose ratio (FIGR), and fasting insulin (FI)] to predict an insulin sensitivity index derived from the reference glucose clamp method (SI(Clamp)). Predictive accuracy was assessed by both root mean squared error (RMSE) of prediction as well as leave-one-out cross-validation-type RMSE of prediction (CVPE). QUICKI, FIGR, and FI, but not HOMA2-IR, had modest linear correlations with SI(Clamp) (QUICKI: r = 0.36; FIGR: r = -0.36; FI: r = -0.27; P < 0.05). No significant differences were noted among CVPE or RMSE from any of the surrogate indices when compared with QUICKI. Surrogate measurements of insulin sensitivity/resistance such as QUICKI, FIGR, and FI are easily obtainable in large clinical studies, but these may only be useful as secondary outcome measurements in assessing insulin sensitivity/resistance in clinical studies of Asian Indians.

Sediment transport and evaluation of sediment surrogate ratings in the Kootenai River near Bonners Ferry, Idaho, Water Years 2011–14

USGS Publications Warehouse

Wood, Molly S.; Fosness, Ryan L.; Etheridge, Alexandra B.

2015-12-14

Acoustic surrogate ratings were developed between backscatter data collected using acoustic Doppler velocity meters (ADVMs) and results of suspended-sediment samples. Ratings were successfully fit to various sediment size classes (total, fines, and sands) using ADVMs of different frequencies (1.5 and 3 megahertz). Surrogate ratings also were developed using variations of streamflow and seasonal explanatory variables. The streamflow surrogate ratings produced average annual sediment load estimates that were 8–32 percent higher, depending on site and sediment type, than estimates produced using the acoustic surrogate ratings. The streamflow surrogate ratings tended to overestimate suspended-sediment concentrations and loads during periods of elevated releases from Libby Dam as well as on the falling limb of the streamflow hydrograph. Estimates from the acoustic surrogate ratings more closely matched suspended-sediment sample results than did estimates from the streamflow surrogate ratings during these periods as well as for rating validation samples collected in water year 2014. Acoustic surrogate technologies are an effective means to obtain continuous, accurate estimates of suspended-sediment concentrations and loads for general monitoring and sediment-transport modeling. In the Kootenai River, continued operation of the acoustic surrogate sites and use of the acoustic surrogate ratings to calculate continuous suspended-sediment concentrations and loads will allow for tracking changes in sediment transport over time.

The US Food and Drug Administration's expedited approval programs: Evidentiary standards, regulatory trade-offs, and potential improvements.

PubMed

Wallach, Joshua D; Ross, Joseph S; Naci, Huseyin

2018-06-01

The US Food and Drug Administration has several regulatory programs and pathways to expedite the development and approval of therapeutic agents aimed at treating serious or life-debilitating conditions. A common feature of these programs is the regulatory flexibility, which allows for a customized approval approach that enables market authorization on the basis of less rigorous evidence, in exchange for requiring postmarket evidence generation. An increasing share of therapeutic agents approved by the Food and Drug Administration in recent years are associated with expedited programs. In this article, we provide an overview of the evidentiary standards required by the Food and Drug Administration's expedited development and review programs, summarize the findings of the recent academic literature demonstrating some of the limitations of these programs, and outline potential opportunities to address these limitations. Recent evidence suggests that therapeutic agents in the Food and Drug Administration's expedited programs are approved on the basis of fewer and smaller studies that may lack comparator groups and random allocation, and rather than focusing on clinical outcomes for study endpoints, rely instead on surrogate markers of disease. Once on the market, agents receiving expedited approvals are often quickly incorporated into clinical practice, and evidence generated in the postmarket period may not necessarily address the evidentiary limitations at the time of market entry. Furthermore, not all pathways require additional postmarket studies. Evidence suggests that drugs in expedited approval programs are associated with a greater likelihood that the Food and Drug Administration will take a safety action following market entry. There are several opportunities to improve the timeliness, information value, and validity of the pre- and postmarket studies of therapeutic agents receiving expedited approvals. When use of nonrandomized and uncontrolled studies cannot be avoided prior to market entry, randomized trials should be mandatory in the postmarket period, unless there are strong justifications for not carrying out such studies. In the premarket period, validity of the surrogate markers can be improved by more rigorously evaluating their correlation with patient-relevant clinical outcomes. Opportunities to reduce the duration, complexity, and cost of postmarket randomized trials should not compromise their validity and instead incorporate pragmatic "real-world" design elements. Despite recent enthusiasm for widely using real-world evidence, adaptive designs, and pragmatic trials in the regulatory setting, caution is warranted until large-scale empirical evaluations demonstrate their validity compared to more traditional trial designs.

Characteristics of efficacy evidence supporting approval of supplemental indications for prescription drugs in United States, 2005-14: systematic review.

PubMed

Wang, Bo; Kesselheim, Aaron S

2015-09-23

To characterize the types of comparators and endpoints used in efficacy trials for approvals of supplemental indications, compared with the data supporting these drugs' originally approved indications. Systematic review. Publicly accessible data on supplemental indications approved by the US Food and Drug Administration from 2005 to 2014. Types of comparators (active, placebo, historical, none) and endpoints (clinical outcomes, clinical scales, surrogate) in the efficacy trials for these drugs' supplemental and original indication approvals. The cohort included 295 supplemental indications. Thirty per cent (41/136) of supplemental approvals for new indications were supported by efficacy trials with active comparators, compared with 51% (47/93) of modified use approvals and 11% (7/65) of approvals expanding the patient population (P<0.001), almost all of which related to pediatric patients (61/65; 94%). Trials using clinical outcome endpoints led to approval for 32% (44/137) of supplemental approvals for new indications, 30% (28/93) of modified indication approvals, and 22% (14/65) of expanded population approvals (P=0.29). Orphan drugs had supplemental approvals for 40 non-orphan indications, which were supported by similar proportions of trials using active comparators (28% (11/40) for non-orphan supplemental indications versus 24% (10/42) for original orphan indications; P=0.70) and clinical outcome endpoints (25% (10/40) versus 31% (13/42); P=0.55). Wide variations were seen in the evidence supporting approval of supplemental indications, with the fewest active comparators and clinical outcome endpoints used in trials leading to supplemental approvals that expanded the patient population. © Wang et al 2015.

Safety and Efficacy Endpoints for Mesenchymal Stromal Cell Therapy in Renal Transplant Recipients.

PubMed

Bank, J R; Rabelink, T J; de Fijter, J W; Reinders, M E J

2015-01-01

Despite excellent short-term graft survival after renal transplantation, the long-term graft outcome remains compromised. It has become evident that a combination of sustained alloreactivity and calcineurin-inhibitor- (CNI-) related nephrotoxicity results in fibrosis and consequently dysfunction of the graft. New immunosuppressive regimens that can minimize or eliminate side effects, while maintaining efficacy, are required to improve long-term graft survival. In this perspective mesenchymal stromal cells (MSCs) are an interesting candidate, since MSCs have immunosuppressive and regenerative properties. The first clinical trials with MSCs in renal transplantation showed safety and feasibility and displayed promising results. Recently, the first phase II studies have been started. One of the most difficult and challenging aspects in those early phase trials is to define accurate endpoints that can measure safety and efficacy of MSC treatment. Since both graft losses and acute rejection rates declined, alternative surrogate markers such as renal function, histological findings, and immunological markers are used to measure efficacy and to provide mechanistic insight. In this review, we will discuss the current status of MSCs in renal transplantation with a focus on the endpoints used in the different experimental and clinical studies.

Sequential RAAS blockade: is it worth the risk?

PubMed

Persson, Frederik; Rossing, Peter

2014-03-01

Soon after the emergence of the renin-angiotensin-aldosterone system (RAAS) blocking treatment as the cornerstone of renoprotective treatment in the prevention and treatment of diabetic and nondiabetic CKD, it was investigated if a higher degree of achievable RAAS blockade by combining more than one compound is feasible and advantageous. Regardless of the benefits from using monotherapy for diabetic kidney disease, there is still much improvement to wish for in terms of kidney prognosis in these populations. A great deal of research has gone into evaluating combinations of the RAAS blocking treatments in different populations and with different drugs and doses. Studies have mostly been short-term and use surrogate endpoints such as albuminuria. Side effects have been well known and expected in terms of increasing potassium levels and hypotension, but to an acceptable extent. With recent disappointing results from major hard endpoint trials using dual RAAS blockade the concept is now under scrutiny. In this review we will discuss the pros and cons of dual RAAS blockade, with facts and findings from smaller studies, endpoint trials, and meta-analyses. Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Helicopter EMS: Research Endpoints and Potential Benefits

PubMed Central

Thomas, Stephen H.; Arthur, Annette O.

2012-01-01

Patients, EMS systems, and healthcare regions benefit from Helicopter EMS (HEMS) utilization. This article discusses these benefits in terms of specific endpoints utilized in research projects. The endpoint of interest, be it primary, secondary, or surrogate, is important to understand in the deployment of HEMS resources or in planning further HEMS outcomes research. The most important outcomes are those which show potential benefits to the patients, such as functional survival, pain relief, and earlier ALS care. Case reports are also important “outcomes” publications. The benefits of HEMS in the rural setting is the ability to provide timely access to Level I or Level II trauma centers and in nontrauma, interfacility transport of cardiac, stroke, and even sepsis patients. Many HEMS crews have pharmacologic and procedural capabilities that bring a different level of care to a trauma scene or small referring hospital, especially in the rural setting. Regional healthcare and EMS system's benefit from HEMS by their capability to extend the advanced level of care throughout a region, provide a “backup” for areas with limited ALS coverage, minimize transport times, make available direct transport to specialized centers, and offer flexibility of transport in overloaded hospital systems. PMID:22203905

[The Intentions Affecting the Medical Decision-Making Behavior of Surrogate Decision Makers of Critically Ill Patients and Related Factors].

PubMed

Su, Szu-Huei; Wu, Li-Min

2018-04-01

The severity of diseases and high mortality rates that typify the intensive care unit often make it difficult for surrogate decision makers to make decisions for critically ill patients regarding whether to continue medical treatments or to accept palliative care. To explore the behavioral intentions that underlie the medical decisions of surrogate decision makers of critically ill patients and the related factors. A cross-sectional, correlation study design was used. A total of 193 surrogate decision makers from six ICUs in a medical center in southern Taiwan were enrolled as participants. Three structured questionnaires were used, including a demographic datasheet, the Family Relationship Scale, and the Behavioral Intention of Medical Decisions Scale. Significantly positive correlations were found between the behavioral intentions underlying medical decisions and the following variables: the relationship of the participant to the patient (Eta = .343, p = .020), the age of the patient (r = .295, p < .01), and whether the patient had signed a currently valid advance healthcare directive (Eta = .223, p = .002). Furthermore, a significantly negative correlation was found between these intentions and length of stay in the ICU (r = -.263, p < .01). Patient age, whether the patient had signed a currently valid advance healthcare directive, and length of stay in the ICU were all predictive factors for the behavioral intentions underlying the medical decisions of the surrogate decision makers, explaining 13.9% of the total variance. In assessing the behavioral intentions underlying the medical decisions of surrogate decision makers, health providers should consider the relationship between critical patients and their surrogate decision makers, patient age, the length of ICU stay, and whether the patient has a pre-signed advance healthcare directive in order to maximize the effectiveness of medical care provided to critically ill patients.

An Empirical Assessment and Comparison of Species-Based and Habitat-Based Surrogates: A Case Study of Forest Vertebrates and Large Old Trees

PubMed Central

Lindenmayer, David B.; Barton, Philip S.; Lane, Peter W.; Westgate, Martin J.; McBurney, Lachlan; Blair, David; Gibbons, Philip; Likens, Gene E.

2014-01-01

A holy grail of conservation is to find simple but reliable measures of environmental change to guide management. For example, particular species or particular habitat attributes are often used as proxies for the abundance or diversity of a subset of other taxa. However, the efficacy of such kinds of species-based surrogates and habitat-based surrogates is rarely assessed, nor are different kinds of surrogates compared in terms of their relative effectiveness. We use 30-year datasets on arboreal marsupials and vegetation structure to quantify the effectiveness of: (1) the abundance of a particular species of arboreal marsupial as a species-based surrogate for other arboreal marsupial taxa, (2) hollow-bearing tree abundance as a habitat-based surrogate for arboreal marsupial abundance, and (3) a combination of species- and habitat-based surrogates. We also quantify the robustness of species-based and habitat-based surrogates over time. We then use the same approach to model overall species richness of arboreal marsupials. We show that a species-based surrogate can appear to be a valid surrogate until a habitat-based surrogate is co-examined, after which the effectiveness of the former is lost. The addition of a species-based surrogate to a habitat-based surrogate made little difference in explaining arboreal marsupial abundance, but altered the co-occurrence relationship between species. Hence, there was limited value in simultaneously using a combination of kinds of surrogates. The habitat-based surrogate also generally performed significantly better and was easier and less costly to gather than the species-based surrogate. We found that over 30 years of study, the relationships which underpinned the habitat-based surrogate generally remained positive but variable over time. Our work highlights why it is important to compare the effectiveness of different broad classes of surrogates and identify situations when either species- or habitat-based surrogates are likely to be superior. PMID:24587050

An empirical assessment and comparison of species-based and habitat-based surrogates: a case study of forest vertebrates and large old trees.

PubMed

Lindenmayer, David B; Barton, Philip S; Lane, Peter W; Westgate, Martin J; McBurney, Lachlan; Blair, David; Gibbons, Philip; Likens, Gene E

2014-01-01

A holy grail of conservation is to find simple but reliable measures of environmental change to guide management. For example, particular species or particular habitat attributes are often used as proxies for the abundance or diversity of a subset of other taxa. However, the efficacy of such kinds of species-based surrogates and habitat-based surrogates is rarely assessed, nor are different kinds of surrogates compared in terms of their relative effectiveness. We use 30-year datasets on arboreal marsupials and vegetation structure to quantify the effectiveness of: (1) the abundance of a particular species of arboreal marsupial as a species-based surrogate for other arboreal marsupial taxa, (2) hollow-bearing tree abundance as a habitat-based surrogate for arboreal marsupial abundance, and (3) a combination of species- and habitat-based surrogates. We also quantify the robustness of species-based and habitat-based surrogates over time. We then use the same approach to model overall species richness of arboreal marsupials. We show that a species-based surrogate can appear to be a valid surrogate until a habitat-based surrogate is co-examined, after which the effectiveness of the former is lost. The addition of a species-based surrogate to a habitat-based surrogate made little difference in explaining arboreal marsupial abundance, but altered the co-occurrence relationship between species. Hence, there was limited value in simultaneously using a combination of kinds of surrogates. The habitat-based surrogate also generally performed significantly better and was easier and less costly to gather than the species-based surrogate. We found that over 30 years of study, the relationships which underpinned the habitat-based surrogate generally remained positive but variable over time. Our work highlights why it is important to compare the effectiveness of different broad classes of surrogates and identify situations when either species- or habitat-based surrogates are likely to be superior.

Neoadjuvant rectal score as individual-level surrogate for disease-free survival in rectal cancer in the CAO/ARO/AIO-04 randomized phase 3 trial.

PubMed

Fokas, E; Fietkau, R; Hartmann, A; Hohenberger, W; Grützmann, R; Ghadimi, M; Liersch, T; Ströbel, P; Grabenbauer, G G; Graeven, U; Hofheinz, R-D; Köhne, C-H; Wittekind, C; Sauer, R; Kaufmann, M; Hothorn, T; Rödel, C

2018-04-27

Surrogate endpoints in rectal cancer after preoperative chemoradiation are lacking as their statistical validation poses major challenges, including confirmation based on large phase 3 trials. We examined the prognostic role and individual-level surrogacy of neoadjuvant rectal (NAR) score that incorporates weighted cT, ypT and ypN categories for disease-free survival (DFS) in 1191 patients with rectal carcinoma treated within the CAO/ARO/AIO-04 phase 3 trial. Cox regression models adjusted for treatment arm, resection status, and NAR score were used in multivariable analysis. The four Prentice criteria (PC1-4) were used to assess individual-level surrogacy of NAR for DFS. After a median follow-up of 50 months, the addition of oxaliplatin to fluorouracil-based chemoradiotherapy (CRT) significantly improved 3-year DFS (75.9% [95% CI 72.30-79.50] vs 71.3% [95% CI 67.60-74.90]; P = 0.034; PC 1) and resulted in a shift towards lower NAR groups (P = 0.034, PC 2) compared to fluorouracil-only CRT. The 3-year DFS was 91.7% (95% CI, 88.2 95.2), 81.8% (95% CI, 78.4-85.1) and 58.1 (95% CI 52.4-63.9) for low, intermediate and high NAR score, respectively (P < 0.001; PC 3). NAR score remained an independent prognostic factor for DFS (low vs high NAR: HR 4.670; 95% CI 3.106-7.020; P < 0.001; low vs intermediate NAR: HR 1.971; 95% CI 1.303-2.98; P = 0.001) in multivariable analysis. Notwithstanding the inherent methodological difficulty in interpretation of PC 4 to establish surrogacy, the treatment effect on DFS was captured by NAR, supporting satisfaction of individual-level PC4. Our study validates the prognostic role and individual-level surrogacy of NAR score for DFS within a large randomized phase 3 trial. NAR score could help oncologists to speed up response-adapted therapeutic decision, and further large phase 3 trial datasets should aim to confirm trial-level surrogacy.

Surrogate outcomes in health technology assessment: an international comparison.

PubMed

Velasco Garrido, Marcial; Mangiapane, Sandra

2009-07-01

Our aim was to review the recommendations given by health technology assessment (HTA) institutions in their methodological guidelines concerning the use of surrogate outcomes in their assessments. In a second step, we aimed at quantifying the role surrogate parameters take in assessment reports. We analyzed methodological papers and guidelines from HTA agencies with International Network of Agencies for Health Technology Assessment membership as well as from institutions related to pharmaceutical regulation (i.e., reimbursement, pricing). We analyzed the use of surrogate outcomes in a sample of HTA reports randomly drawn from the HTA database. We checked methods, results (including evidence tables), and conclusions sections and extracted the outcomes reported. We report descriptive statistics on the presence of surrogate outcomes in the reports. We identified thirty-four methodological guidelines, twenty of them addressing the issue of outcome parameter choice and the problematic of surrogate outcomes. Overall HTA agencies call on caution regarding the reliance on surrogate outcomes. None of the agencies has provided a list or catalog of acceptable and validated surrogate outcomes. We extracted the outcome parameter of 140 HTA reports. Only around half of the reports determined the outcomes for the assessment prospectively. Surrogate outcomes had been used in 62 percent of the reports. However, only 3.6 percent were based upon surrogate outcomes exclusively. All of them assessed diagnostic or screening technologies and the surrogate outcomes were predominantly test characteristics. HTA institutions seem to agree on a cautious approach to the use of surrogate outcomes in technology assessment. Thorough assessment of health technologies should not rely exclusively on surrogate outcomes.

Biomarkers and Surrogate Markers: An FDA Perspective

PubMed Central

Katz, Russell

2004-01-01

Summary: Interest is increasing rapidly in the use of surrogate markers as primary measures of the effectiveness of investigational drugs in definitive drug trials. Many such surrogate markers have been proposed as potential candidates for use in definitive effectiveness trials of agents to treat neurologic or psychiatric disease, but as of this date, there are no such markers that have been adequately “validated,” that is, shown to predict the effect of the treatment on the clinical outcome of interest. While the current law and regulations permit the United States Food and Drug Administration to base the approval of a drug product on a determination the effect of the drug on an unvalidated surrogate marker (that is, one for which it is not known that an effect on the surrogate actually predicts the desired clinical benefit), there are a number of difficulties in interpreting trials that use surrogate markers as primary measures of drug effect. In this article, the relevant regulatory context will be discussed, as well as the epistemological problems related to the interpretation of clinical trials in which unvalidated surrogate markers are used as primary outcomes. PMID:15717019

Using a gel/plastic surrogate to study the biomechanical response of the head under air shock loading: a combined experimental and numerical investigation.

PubMed

Zhu, Feng; Wagner, Christina; Dal Cengio Leonardi, Alessandra; Jin, Xin; Vandevord, Pamela; Chou, Clifford; Yang, King H; King, Albert I

2012-03-01

A combined experimental and numerical study was conducted to determine a method to elucidate the biomechanical response of a head surrogate physical model under air shock loading. In the physical experiments, a gel-filled egg-shaped skull/brain surrogate was exposed to blast overpressure in a shock tube environment, and static pressures within the shock tube and the surrogate were recorded throughout the event. A numerical model of the shock tube was developed using the Eulerian approach and validated against experimental data. An arbitrary Lagrangian-Eulerian (ALE) fluid-structure coupling algorithm was then utilized to simulate the interaction of the shock wave and the head surrogate. After model validation, a comprehensive series of parametric studies was carried out on the egg-shaped surrogate FE model to assess the effect of several key factors, such as the elastic modulus of the shell, bulk modulus of the core, head orientation, and internal sensor location, on pressure and strain responses. Results indicate that increasing the elastic modulus of the shell within the range simulated in this study led to considerable rise of the overpressures. Varying the bulk modulus of the core from 0.5 to 2.0 GPa, the overpressure had an increase of 7.2%. The curvature of the surface facing the shock wave significantly affected both the peak positive and negative pressures. Simulations of the head surrogate with the blunt end facing the advancing shock front had a higher pressure compared to the simulations with the pointed end facing the shock front. The influence of an opening (possibly mimicking anatomical apertures) on the peak pressures was evaluated using a surrogate head with a hole on the shell of the blunt end. It was revealed that the presence of the opening had little influence on the positive pressures but could affect the negative pressure evidently.

Measuring titratable alkalinity by single versus double endpoint titration: An evaluation in two cyprinodont species and implications for characterizing net H+ flux in aquatic organisms.

PubMed

Brix, Kevin V; Wood, Chris M; Grosell, Martin

2013-01-01

In this study, Na(+) uptake and acid-base balance in the euryhaline pupfish Cyprinodon variegatus variegatus were characterized when fish were exposed to pH 4.5 freshwater (7mM Na(+)). Similar to the related cyprinodont, Fundulus heteroclitus, Na(+) uptake was significantly inhibited when exposed to low pH water. However, it initially appeared that C. v. variegatus increased apparent net acid excretion at low pH relative to circumneutral pH. This result is opposite to previous observations for F. heteroclitus under similar conditions where fish were observed to switch from apparent net H(+) excretion at circumneutral pH to apparent net H(+) uptake at low pH. Further investigation revealed disparate observations between these studies were the result of using double endpoint titrations to measure titratable alkalinity fluxes in the current study, while the earlier study utilized single endpoint titrations to measure these fluxes (i.e.,. Cyprinodon acid-base transport is qualitatively similar to Fundulus when characterized using single endpoint titrations). This led to a comparative investigation of these two methods. We hypothesized that either the single endpoint methodology was being influenced by a change in the buffer capacity of the water (e.g., mucus being released by the fish) at low pH, or the double endpoint methodology was not properly accounting for ammonia flux by the fish. A series of follow-up experiments indicated that buffer capacity of the water did not change significantly, that excretion of protein (a surrogate for mucus) was actually reduced at low pH, and that the double endpoint methodology does not properly account for NH(3) excretion by fish under low pH conditions. As a result, it overestimates net H(+) excretion during low pH exposure. After applying the maximum possible correction for this error (i.e., assuming that all ammonia is excreted as NH(3)), the double endpoint methodology indicates that net H(+) transport was reduced to effectively zero in both species at pH 4.5. However, significant differences between the double endpoint (no net H(+) transport at low pH) and single endpoint titrations (net H(+) uptake at low pH) remain to be explained. Copyright © 2012 Elsevier Inc. All rights reserved.

Nonparametric Discrete Survival Function Estimation with Uncertain Endpoints Using an Internal Validation Subsample

PubMed Central

Zee, Jarcy; Xie, Sharon X.

2015-01-01

Summary When a true survival endpoint cannot be assessed for some subjects, an alternative endpoint that measures the true endpoint with error may be collected, which often occurs when obtaining the true endpoint is too invasive or costly. We develop an estimated likelihood function for the situation where we have both uncertain endpoints for all participants and true endpoints for only a subset of participants. We propose a nonparametric maximum estimated likelihood estimator of the discrete survival function of time to the true endpoint. We show that the proposed estimator is consistent and asymptotically normal. We demonstrate through extensive simulations that the proposed estimator has little bias compared to the naïve Kaplan-Meier survival function estimator, which uses only uncertain endpoints, and more efficient with moderate missingness compared to the complete-case Kaplan-Meier survival function estimator, which uses only available true endpoints. Finally, we apply the proposed method to a dataset for estimating the risk of developing Alzheimer's disease from the Alzheimer's Disease Neuroimaging Initiative. PMID:25916510

Do women who choose to become surrogate mothers have different psychological profiles compared to a normative female sample?

PubMed

Pizitz, Todd D; McCullaugh, Joseph; Rabin, Alexa

2013-03-01

Surrogate mothers are routinely assessed for their suitability to function in the role of surrogacy. Such assessments often include psychological testing including the Minnesota multiphasic personality inventory-revised (MMPI-2). There has been a paucity of research detailing the personality structures of these women, especially with the MMPI-2. The current study examined the validity and clinical profiles of surrogate mothers (N=43) compared to a non-patient, normative reference sample of women (N=40) using their MMPI-2 results. This study examined between group differences among the 68 scales of the MMPI-2. Independent-sample t-tests were conducted for each of the scales, with those violating homogeneity of variance assessed with a non-parametric, Mann-Whitney U test. The findings demonstrated that surrogate mothers produce profiles with lower values than normative samples across several MMPI-2 scales. For this unique group, elevations were observed on scales that assess profile validity, views on traditional gender roles, repression, ego strength, social obligation and duties, and contained hostility, relative to the normative group. The findings provide an initial examination of the profiles of surrogate mothers on the MMPI-2. The findings revealed that the psychological suitability of surrogate mother candidates appear to be a composite of being both tough-minded and sensitive, sufficiently resilient to manage the role of surrogacy, and aware of the importance of emotional boundary-setting related to pre-natal attachment. Copyright © 2012 Australian College of Midwives. Published by Elsevier Ltd. All rights reserved.

Comparison between Surrogate Indexes of Insulin Sensitivity/Resistance and Hyperinsulinemic Euglycemic Glucose Clamps in Rhesus Monkeys

PubMed Central

Lee, Ho-Won; Muniyappa, Ranganath; Yan, Xu; Yue, Lilly Q.; Linden, Ellen H.; Chen, Hui; Hansen, Barbara C.

2011-01-01

The euglycemic glucose clamp is the reference method for assessing insulin sensitivity in humans and animals. However, clamps are ill-suited for large studies because of extensive requirements for cost, time, labor, and technical expertise. Simple surrogate indexes of insulin sensitivity/resistance including quantitative insulin-sensitivity check index (QUICKI) and homeostasis model assessment (HOMA) have been developed and validated in humans. However, validation studies of QUICKI and HOMA in both rats and mice suggest that differences in metabolic physiology between rodents and humans limit their value in rodents. Rhesus monkeys are a species more similar to humans than rodents. Therefore, in the present study, we evaluated data from 199 glucose clamp studies obtained from a large cohort of 86 monkeys with a broad range of insulin sensitivity. Data were used to evaluate simple surrogate indexes of insulin sensitivity/resistance (QUICKI, HOMA, Log HOMA, 1/HOMA, and 1/Fasting insulin) with respect to linear regression, predictive accuracy using a calibration model, and diagnostic performance using receiver operating characteristic. Most surrogates had modest linear correlations with SIClamp (r ≈ 0.4–0.64) with comparable correlation coefficients. Predictive accuracy determined by calibration model analysis demonstrated better predictive accuracy of QUICKI than HOMA and Log HOMA. Receiver operating characteristic analysis showed equivalent sensitivity and specificity of most surrogate indexes to detect insulin resistance. Thus, unlike in rodents but similar to humans, surrogate indexes of insulin sensitivity/resistance including QUICKI and log HOMA may be reasonable to use in large studies of rhesus monkeys where it may be impractical to conduct glucose clamp studies. PMID:21209021

Translational research in addiction: toward a framework for the development of novel therapeutics.

PubMed

Paterson, Neil E

2011-06-15

The development of novel substance use disorder (SUD) therapeutics is insufficient to meet the medical needs of a growing SUD patient population. The identification of translatable SUD models and tests is a crucial step in establishing a framework for SUD therapeutic development programs. The present review begins by identifying the clinical features of SUDs and highlights the narrow regulatory end-point required for approval of a novel SUD therapeutic. A conceptual overview of dependence is provided, followed by identification of potential intervention targets in the addiction cycle. The main components of the addiction cycle provide the framework for a discussion of preclinical models and their clinical analogs, all of which are focused on isolated behavioral end-points thought to be relevant to the persistence of compulsive drug use. Thus, the greatest obstacle to successful development is the gap between the multiplicity of preclinical and early clinical end-points and the regulatory end-point of sustained abstinence. This review proposes two pathways to bridging this gap: further development and validation of the preclinical extended access self-administration model; inclusion of secondary end-points comprising all of the measures highlighted in the present discussion in Phase 3 trials. Further, completion of the postdictive validation of analogous preclinical and clinical assays is of high priority. Ultimately, demonstration of the relevance and validity of a variety of end-points to the ultimate goal of abstinence will allow researchers to identify truly relevant therapeutic mechanisms and intervention targets, and establish a framework for SUD therapeutic development that allows optimal decision-making and resource allocation. 2011 Elsevier Inc. All rights reserved.

Developing a Cognition Endpoint for Traumatic Brain Injury Clinical Trials

PubMed Central

Crane, Paul K.; Dams-O'Connor, Kristen; Holdnack, James; Ivins, Brian J.; Lange, Rael T.; Manley, Geoffrey T.; McCrea, Michael; Iverson, Grant L.

2017-01-01

Abstract Cognitive impairment is a core clinical feature of traumatic brain injury (TBI). After TBI, cognition is a key determinant of post-injury productivity, outcome, and quality of life. As a final common pathway of diverse molecular and microstructural TBI mechanisms, cognition is an ideal endpoint in clinical trials involving many candidate drugs and nonpharmacological interventions. Cognition can be reliably measured with performance-based neuropsychological tests that have greater granularity than crude rating scales, such as the Glasgow Outcome Scale-Extended, which remain the standard for clinical trials. Remarkably, however, there is no well-defined, widely accepted, and validated cognition endpoint for TBI clinical trials. A single cognition endpoint that has excellent measurement precision across a wide functional range and is sensitive to the detection of small improvements (and declines) in cognitive functioning would enhance the power and precision of TBI clinical trials and accelerate drug development research. We outline methodologies for deriving a cognition composite score and a research program for validation. Finally, we discuss regulatory issues and the limitations of a cognition endpoint. PMID:27188248

Investigating conflict in ICUs - Is the clinicians’ perspective enough?

PubMed Central

Schuster, Rachel A.; Hong, Seo Yeon; Arnold, Robert M.; White, Douglas B.

2013-01-01

Objective Most studies have assessed conflict between clinicians and surrogate decision makers in ICUs from only clinicians’ perspectives. It is unknown if surrogates’ perceptions differ from clinicians’. We sought to determine the degree of agreement between physicians and surrogates about conflict, and to identify predictors of physician-surrogate conflict. Design Prospective cohort study. Setting Four ICUs of two hospitals in San Francisco, California. Patients 230 surrogate decision makers and 100 physicians of 175 critically ill patients. Measurements Questionnaires addressing participants’ perceptions of whether there was physician-surrogate conflict, as well as attitudes and preferences about clinician-surrogate communication; kappa scores to quantify physician-surrogate concordance about the presence of conflict; and hierarchical multivariate modeling to determine predictors of conflict. Main Results Either the physician or surrogate identified conflict in 63% of cases. Physicians were less likely to perceive conflict than surrogates (27.8% vs 42.3%; p=0.007). Agreement between physicians and surrogates about conflict was poor (kappa = 0.14). Multivariable analysis with surrogate-assessed conflict as the outcome revealed that higher levels of surrogates’ satisfaction with physicians’ bedside manner were associated with lower odds of conflict (OR: 0.75 per 1 point increase in satisfaction, 95% CI 0.59–0.96). Multivariable analysis with physician-assessed conflict as the outcome revealed that the surrogate having felt discriminated against in the healthcare setting was associated with higher odds of conflict (OR 17.5, 95% CI 1.6–190.1) while surrogates’ satisfaction with physicians’ bedside manner was associated with lower odds of conflict (0–10 scale, OR 0.76 per 1 point increase, 95% CI 0.58–0.99). Conclusions Conflict between physicians and surrogates is common in ICUs. There is little agreement between physicians and surrogates about whether physician-surrogate conflict has occurred. Further work is needed to develop reliable and valid methods to assess conflict. In the interim, future studies should assess conflict from the perspective of both clinicians and surrogates. PMID:24434440

Development of a Conceptual Model of Disease Progression for Use in Economic Modeling of Chronic Obstructive Pulmonary Disease.

PubMed

Tabberer, Maggie; Gonzalez-McQuire, Sebastian; Muellerova, Hana; Briggs, Andrew H; Rutten-van Mölken, Maureen P M H; Chambers, Mike; Lomas, David A

2017-05-01

To develop and validate a new conceptual model (CM) of chronic obstructive pulmonary disease (COPD) for use in disease progression and economic modeling. The CM identifies and describes qualitative associations between disease attributes, progression and outcomes. A literature review was performed to identify any published CMs or literature reporting the impact and association of COPD disease attributes with outcomes. After critical analysis of the literature, a Steering Group of experts from the disciplines of health economics, epidemiology and clinical medicine was convened to develop a draft CM, which was refined using a Delphi process. The refined CM was validated by testing for associations between attributes using data from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). Disease progression attributes included in the final CM were history and occurrence of exacerbations, lung function, exercise capacity, signs and symptoms (cough, sputum, dyspnea), cardiovascular disease comorbidities, 'other' comorbidities (including depression), body composition (body mass index), fibrinogen as a biomarker, smoking and demographic characteristics (age, gender). Mortality and health-related quality of life were determined to be the most relevant final outcome measures for this model, intended to be the foundation of an economic model of COPD. The CM is being used as the foundation for developing a new COPD model of disease progression and to provide a framework for the analysis of patient-level data. The CM is available as a reference for the implementation of further disease progression and economic models.

Highly sensitive measurements of disease progression in rare disorders: Developing and validating a multimodal model of retinal degeneration in Stargardt disease.

PubMed

Lambertus, Stanley; Bax, Nathalie M; Fakin, Ana; Groenewoud, Joannes M M; Klevering, B Jeroen; Moore, Anthony T; Michaelides, Michel; Webster, Andrew R; van der Wilt, Gert Jan; Hoyng, Carel B

2017-01-01

Each inherited retinal disorder is rare, but together, they affect millions of people worldwide. No treatment is currently available for these blinding diseases, but promising new options-including gene therapy-are emerging. Arguably, the most prevalent retinal dystrophy is Stargardt disease. In each case, the specific combination of ABCA4 variants (> 900 identified to date) and modifying factors is virtually unique. It accounts for the vast phenotypic heterogeneity including variable rates of functional and structural progression, thereby potentially limiting the ability of phase I/II clinical trials to assess efficacy of novel therapies with few patients. To accommodate this problem, we developed and validated a sensitive and reliable composite clinical trial endpoint for disease progression based on structural measurements of retinal degeneration. We used longitudinal data from early-onset Stargardt patients from the Netherlands (development cohort, n = 14) and the United Kingdom (external validation cohort, n = 18). The composite endpoint was derived from best-corrected visual acuity, fundus autofluorescence, and spectral-domain optical coherence tomography. Weighting optimization techniques excluded visual acuity from the composite endpoint. After optimization, the endpoint outperformed each univariable outcome, and showed an average progression of 0.41° retinal eccentricity per year (95% confidence interval, 0.30-0.52). Comparing with actual longitudinal values, the model accurately predicted progression (R2, 0.904). These properties were largely preserved in the validation cohort (0.43°/year [0.33-0.53]; prediction: R2, 0.872). We subsequently ran a two-year trial simulation with the composite endpoint, which detected a 25% decrease in disease progression with 80% statistical power using only 14 patients. These results suggest that a multimodal endpoint, reflecting structural macular changes, provides a sensitive measurement of disease progression in Stargardt disease. It can be very useful in the evaluation of novel therapeutic modalities in rare disorders.

Highly sensitive measurements of disease progression in rare disorders: Developing and validating a multimodal model of retinal degeneration in Stargardt disease

PubMed Central

Bax, Nathalie M.; Fakin, Ana; Groenewoud, Joannes M. M.; Klevering, B. Jeroen; Moore, Anthony T.; Michaelides, Michel; Webster, Andrew R.; van der Wilt, Gert Jan; Hoyng, Carel B.

2017-01-01

Background Each inherited retinal disorder is rare, but together, they affect millions of people worldwide. No treatment is currently available for these blinding diseases, but promising new options—including gene therapy—are emerging. Arguably, the most prevalent retinal dystrophy is Stargardt disease. In each case, the specific combination of ABCA4 variants (> 900 identified to date) and modifying factors is virtually unique. It accounts for the vast phenotypic heterogeneity including variable rates of functional and structural progression, thereby potentially limiting the ability of phase I/II clinical trials to assess efficacy of novel therapies with few patients. To accommodate this problem, we developed and validated a sensitive and reliable composite clinical trial endpoint for disease progression based on structural measurements of retinal degeneration. Methods and findings We used longitudinal data from early-onset Stargardt patients from the Netherlands (development cohort, n = 14) and the United Kingdom (external validation cohort, n = 18). The composite endpoint was derived from best-corrected visual acuity, fundus autofluorescence, and spectral-domain optical coherence tomography. Weighting optimization techniques excluded visual acuity from the composite endpoint. After optimization, the endpoint outperformed each univariable outcome, and showed an average progression of 0.41° retinal eccentricity per year (95% confidence interval, 0.30–0.52). Comparing with actual longitudinal values, the model accurately predicted progression (R2, 0.904). These properties were largely preserved in the validation cohort (0.43°/year [0.33–0.53]; prediction: R2, 0.872). We subsequently ran a two-year trial simulation with the composite endpoint, which detected a 25% decrease in disease progression with 80% statistical power using only 14 patients. Conclusions These results suggest that a multimodal endpoint, reflecting structural macular changes, provides a sensitive measurement of disease progression in Stargardt disease. It can be very useful in the evaluation of novel therapeutic modalities in rare disorders. PMID:28355279

Pain management interventions in the nursing home: a structured review of the literature.

PubMed

Herman, Adam D; Johnson, Theodore M; Ritchie, Christine S; Parmelee, Patricia A

2009-07-01

Residents in nursing homes (NHs) experience pain that is underrecognized and undertreated. This pain contributes to a decline in quality of life. Although descriptive studies of pain assessment and management have been conducted, few have been published that critically evaluate interventions to improve pain management. Identification of the strengths and gaps in the current literature is required. A literature search was conducted of clinical trials that evaluated prospective interventions to improve pain management. Information on the intervention type, resident sample and setting, endpoints, and study design were extracted. Studies were classified based on a modification of Donabedian's model of healthcare quality. Four categories of interventions were identified: actor, decision support, treatment, and systems. The search strategy and selection criteria yielded 21 articles. Eleven studies used an actor intervention; of these, eight also employed a systems intervention, and one also used a treatment intervention. Two studies used a decision support intervention, seven used a treatment intervention, and one used a systems intervention. The overall quality of research was uneven in several areas: research design--nine studies were quasi-experimental in nature, endpoints measures were not consistent--three did not perform statistical analysis, and characteristics of the resident samples varied dramatically. In conclusion, the number of high-quality studies of pain management in NHs remains limited. Process endpoints are used as surrogate measures for resident endpoints. Systematic approaches are needed to understand how each type of intervention improves the quality of pain management at the resident level.

Characteristics of efficacy evidence supporting approval of supplemental indications for prescription drugs in United States, 2005-14: systematic review

PubMed Central

Wang, Bo

2015-01-01

Objective To characterize the types of comparators and endpoints used in efficacy trials for approvals of supplemental indications, compared with the data supporting these drugs’ originally approved indications. Design Systematic review. Setting Publicly accessible data on supplemental indications approved by the US Food and Drug Administration from 2005 to 2014. Main outcome measures Types of comparators (active, placebo, historical, none) and endpoints (clinical outcomes, clinical scales, surrogate) in the efficacy trials for these drugs’ supplemental and original indication approvals. Results The cohort included 295 supplemental indications. Thirty per cent (41/136) of supplemental approvals for new indications were supported by efficacy trials with active comparators, compared with 51% (47/93) of modified use approvals and 11% (7/65) of approvals expanding the patient population (P<0.001), almost all of which related to pediatric patients (61/65; 94%). Trials using clinical outcome endpoints led to approval for 32% (44/137) of supplemental approvals for new indications, 30% (28/93) of modified indication approvals, and 22% (14/65) of expanded population approvals (P=0.29). Orphan drugs had supplemental approvals for 40 non-orphan indications, which were supported by similar proportions of trials using active comparators (28% (11/40) for non-orphan supplemental indications versus 24% (10/42) for original orphan indications; P=0.70) and clinical outcome endpoints (25% (10/40) versus 31% (13/42); P=0.55). Conclusions Wide variations were seen in the evidence supporting approval of supplemental indications, with the fewest active comparators and clinical outcome endpoints used in trials leading to supplemental approvals that expanded the patient population. PMID:26400844

Endpoint-based parallel data processing with non-blocking collective instructions in a parallel active messaging interface of a parallel computer

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

Archer, Charles J; Blocksome, Michael A; Cernohous, Bob R

Methods, apparatuses, and computer program products for endpoint-based parallel data processing with non-blocking collective instructions in a parallel active messaging interface (`PAMI`) of a parallel computer are provided. Embodiments include establishing by a parallel application a data communications geometry, the geometry specifying a set of endpoints that are used in collective operations of the PAMI, including associating with the geometry a list of collective algorithms valid for use with the endpoints of the geometry. Embodiments also include registering in each endpoint in the geometry a dispatch callback function for a collective operation and executing without blocking, through a single onemore » of the endpoints in the geometry, an instruction for the collective operation.« less

Testing for nonlinearity in non-stationary physiological time series.

PubMed

Guarín, Diego; Delgado, Edilson; Orozco, Álvaro

2011-01-01

Testing for nonlinearity is one of the most important preprocessing steps in nonlinear time series analysis. Typically, this is done by means of the linear surrogate data methods. But it is a known fact that the validity of the results heavily depends on the stationarity of the time series. Since most physiological signals are non-stationary, it is easy to falsely detect nonlinearity using the linear surrogate data methods. In this document, we propose a methodology to extend the procedure for generating constrained surrogate time series in order to assess nonlinearity in non-stationary data. The method is based on the band-phase-randomized surrogates, which consists (contrary to the linear surrogate data methods) in randomizing only a portion of the Fourier phases in the high frequency domain. Analysis of simulated time series showed that in comparison to the linear surrogate data method, our method is able to discriminate between linear stationarity, linear non-stationary and nonlinear time series. Applying our methodology to heart rate variability (HRV) records of five healthy patients, we encountered that nonlinear correlations are present in this non-stationary physiological signals.

Approving cancer treatments based on endpoints other than overall survival: an analysis of historical data using the PACE Continuous Innovation Indicators™ (CII).

PubMed

Brooks, Neon; Campone, Mario; Paddock, Silvia; Shortenhaus, Scott; Grainger, David; Zummo, Jacqueline; Thomas, Samuel; Li, Rose

2017-01-01

There is an active debate about the role that endpoints other than overall survival (OS) should play in the drug approval process. Yet the term 'surrogate endpoint' implies that OS is the only critical metric for regulatory approval of cancer treatments. We systematically analyzed the relationship between U.S. Food and Drug Administration (FDA) approval and publication of OS evidence to understand better the risks and benefits of delaying approval until OS evidence is available. Using the PACE Continuous Innovation Indicators (CII) platform, we analyzed the effects of cancer type, treatment goal, and year of approval on the lag time between FDA approval and publication of first significant OS finding for 53 treatments approved between 1952 and 2016 for 10 cancer types (n = 71 approved indications). Greater than 59% of treatments were approved before significant OS data for the approved indication were published. Of the drugs in the sample, 31% had lags between approval and first published OS evidence of 4 years or longer. The average number of years between approval and first OS evidence varied by cancer type and did not reliably predict the eventual amount of OS evidence accumulated. Striking the right balance between early access and minimizing risk is a central challenge for regulators worldwide. We illustrate that endpoints other than OS have long helped to provide timely access to new medicines, including many current standards of care. We found that many critical drugs are approved many years before OS data are published, and that OS may not be the most appropriate endpoint in some treatment contexts. Our examination of approved treatments without significant OS data suggests contexts where OS may not be the most relevant endpoint and highlights the importance of using a wide variety of fit-for-purpose evidence types in the approval process.

Evaluation of Enterococcus faecium NRRL B-2354 as a Surrogate for Salmonella During Extrusion of Low-Moisture Food.

PubMed

Verma, Tushar; Wei, Xinyao; Lau, Soon Kiat; Bianchini, Andreia; Eskridge, Kent M; Subbiah, Jeyamkondan

2018-04-01

Salmonella in low-moisture foods is an emerging challenge due to numerous food product recalls and foodborne illness outbreaks. Identification of suitable surrogate is critical for process validation at industry level due to implementation of new Food Safety Modernization Act of 2011. The objective of this study was to evaluate Enterococcus faecium NRRL B-2354 as a surrogate for Salmonella during the extrusion of low-moisture food. Oat flour, a low-moisture food, was adjusted to different moisture (14% to 26% wet basis) and fat (5% to 15% w/w) contents and was inoculated with E. faecium NRRL B-2354. Inoculated material was then extruded in a lab-scale single-screw extruder running at different screw speeds (75 to 225 rpm) and different temperatures (75, 85, and 95 °C). A split-plot central composite 2nd order response surface design was used, with the central point replicated six times. The data from the selective media (m-Enterococcus agar) was used to build the response surface model for inactivation of E. faecium NRRL B-2354. Results indicated that E. faecium NRRL B-2354 always had higher heat resistance compared to Salmonella at all conditions evaluated in this study. However, the patterns of contour plots showing the effect of various product and process parameters on inactivation of E. faecium NRRL B-2354 was different from that of Salmonella. Although E. faecium NRRL B-2354 may be an acceptable surrogate for extrusion of low-moisture products due to higher resistance than Salmonella, another surrogate with similar inactivation behavior may be preferred and needs to be identified. Food Safety Modernization Act requires the food industry to validate processing interventions. This study validated extrusion processing and demonstrated that E. faecium NRRL B-2354 is an acceptable surrogate for extrusion of low-moisture products. The developed response surface model allows the industry to identify process conditions to achieve a desired lethality for their products based on composition. © 2018 Institute of Food Technologists®.

On the Use of Local Assessments for Monitoring Centrally Reviewed Endpoints with Missing Data in Clinical Trials*

PubMed Central

Brummel, Sean S.; Gillen, Daniel L.

2014-01-01

Due to ethical and logistical concerns it is common for data monitoring committees to periodically monitor accruing clinical trial data to assess the safety, and possibly efficacy, of a new experimental treatment. When formalized, monitoring is typically implemented using group sequential methods. In some cases regulatory agencies have required that primary trial analyses should be based solely on the judgment of an independent review committee (IRC). The IRC assessments can produce difficulties for trial monitoring given the time lag typically associated with receiving assessments from the IRC. This results in a missing data problem wherein a surrogate measure of response may provide useful information for interim decisions and future monitoring strategies. In this paper, we present statistical tools that are helpful for monitoring a group sequential clinical trial with missing IRC data. We illustrate the proposed methodology in the case of binary endpoints under various missingness mechanisms including missing completely at random assessments and when missingness depends on the IRC’s measurement. PMID:25540717

[HTA-Perspective: Challenges in the early assessment of new oncological drugs].

PubMed

Wild, Claudia; Nachtnebel, Anna

2013-01-01

Oncologic drug therapies have gained wide attention in the context of health policy priority setting for serious and socially significant diseases with high human and monetary costs. Due to uncertainties and scepticism about the actual therapeutic importance of newly approved oncology products, an early assessment programme was already established in Austria in 2007. The assessment of new oncology products is thereby faced with special challenges, since study populations are frequently not representative or the study design is laid out in such a manner that a definitive assessment of patient-relevant endpoints is not possible (cross-overs after interim assessments, surrogate parameters as primary endpoints, uncontrolled studies or those with unrealistic comparators, invalidated post-hoc identified biomarkers). On account of these major uncertainties, even the European Medicines Agency (EMA) is already contemplating multi-stage, "adaptive" approvals, and national reimbursement institutions are increasingly working with outcome-oriented, conditional reimbursement. (As supplied by publisher). Copyright © 2013. Published by Elsevier GmbH.

Reliable and developmentally appropriate study end points are needed to achieve drug development for treatment of pediatric pulmonary arterial hypertension.

PubMed

Sun, H; Stockbridge, N; Ariagno, R L; Murphy, D; Nelson, R M; Rodriguez, W

2016-12-01

To identify suitable end points and surrogates for pediatric pulmonary arterial hypertension (PAH) as the lack of developmentally appropriate end point and clinical trials contribute to the unmet medical need. Reviewed the efficacy end points and surrogates for all trials (1995 to 2013) that were submitted to the Food and Drug Administration (FDA) to support the approval of PAH therapy and conducted literature search. An increase in the 6 min walking distance (6MWD) was used as a primary end point in 8/9 adult PAH trials. This end point is not suitable for infants and young children because of performance limitations and lack of control data. One adult PAH trial used time to the first morbidity or mortality event as a primary end point, which could potentially be used in pediatric PAH trials. In the sildenafil pediatric PAH trial, the change in pulmonary vascular resistance index or mean pulmonary artery pressure was used as a surrogate for the 6MWD to assess exercise capacity. However, two deaths and three severe adverse events during the catheterizations made this an unacceptably high-risk surrogate. The INOmax persistent pulmonary hypertension of the newborn trial used a reduction in initiation of extracorporeal membrane oxygenation treatment as a primary end point, which is not feasible for other pediatric PAH trials. A Literature review revealed none of the existing noninvasive markers are fully validated as surrogates to assess PAH efficacy and long-term safety. For pediatric PAH trials, clinical end points are acceptable, and novel validated surrogates would be helpful. FDA seeks collaboration with academia, industry and parents to develop other suitable and possibly more efficient efficacy end points to facilitate pediatric PAH drug development.

Trends in improving the embryonic stem cell test (EST): an overview.

PubMed

Buesen, Roland; Visan, Anke; Genschow, Elke; Slawik, Birgitta; Spielmann, Horst; Seiler, Andrea

2004-01-01

The embryonic stem cell test (EST) is an in vitro assay that has been developed to assess the teratogenic and embryotoxic potential of drugs and chemicals. It is based on the capacity of murine ES cells (cell line D3) to differentiate into contracting myocardial cells under specific cell culture conditions. The appearance of beating cardiomyocytes in embryoid body (EB) outgrowths is used as a toxicological endpoint to assess the embryotoxic potential of a test substance. Applying linear analysis of discriminance, a biostatistical prediction model (PM) was developed to assign test chemicals to three classes of embryotoxicity. In an international validation study the EST predicted the embryotoxic potential of chemicals and drugs with the same reliability as two other in vitro embryotoxicity tests, which employed embryonic cells and tissues from pregnant animals. In a joint research project with German pharmaceutical companies we have successfully improved the EST by establishing molecular endpoints of differentiation in cultured ES cells. The quantification of cardiac-specific protein expression by intracellular flow cytometry has been studied in the presence of chemicals of different embryotoxic potential. The results obtained using molecular endpoints specific for differentiated cardiomyocytes employing FACS (fluorescence-activated cell sorting) analysis will be presented in comparison to the validated endpoint - the microscopic analysis of beating areas. FACS analysis provides a more objective endpoint for predicting the embryotoxic potential of chemicals than the validated method. Furthermore, flow cytometry promises to be suitable for high-throughput screening systems (HTS). In addition, our partners from the joint project have improved the EST by developing protocols that stimulate differentiation of ES cells into neural and endothelial cells, chondrocytes and osteoblasts, because some substances might have embryotoxic effects on specific cell-types other than cardiomyocytes. These protocols have been successfully established at ZEBET and in the participating laboratories. Additionally, molecular endpoints have been established for the detection of specific differentiation pathways. Furthermore, new prediction models (PMs) have been developed using single endpoints of the EST.

Testing Pairwise Association between Spatially Autocorrelated Variables: A New Approach Using Surrogate Lattice Data

PubMed Central

Deblauwe, Vincent; Kennel, Pol; Couteron, Pierre

2012-01-01

Background Independence between observations is a standard prerequisite of traditional statistical tests of association. This condition is, however, violated when autocorrelation is present within the data. In the case of variables that are regularly sampled in space (i.e. lattice data or images), such as those provided by remote-sensing or geographical databases, this problem is particularly acute. Because analytic derivation of the null probability distribution of the test statistic (e.g. Pearson's r) is not always possible when autocorrelation is present, we propose instead the use of a Monte Carlo simulation with surrogate data. Methodology/Principal Findings The null hypothesis that two observed mapped variables are the result of independent pattern generating processes is tested here by generating sets of random image data while preserving the autocorrelation function of the original images. Surrogates are generated by matching the dual-tree complex wavelet spectra (and hence the autocorrelation functions) of white noise images with the spectra of the original images. The generated images can then be used to build the probability distribution function of any statistic of association under the null hypothesis. We demonstrate the validity of a statistical test of association based on these surrogates with both actual and synthetic data and compare it with a corrected parametric test and three existing methods that generate surrogates (randomization, random rotations and shifts, and iterative amplitude adjusted Fourier transform). Type I error control was excellent, even with strong and long-range autocorrelation, which is not the case for alternative methods. Conclusions/Significance The wavelet-based surrogates are particularly appropriate in cases where autocorrelation appears at all scales or is direction-dependent (anisotropy). We explore the potential of the method for association tests involving a lattice of binary data and discuss its potential for validation of species distribution models. An implementation of the method in Java for the generation of wavelet-based surrogates is available online as supporting material. PMID:23144961

Endpoint-based parallel data processing with non-blocking collective instructions in a parallel active messaging interface of a parallel computer

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

Archer, Charles J; Blocksome, Michael A; Cernohous, Bob R

Endpoint-based parallel data processing with non-blocking collective instructions in a PAMI of a parallel computer is disclosed. The PAMI is composed of data communications endpoints, each including a specification of data communications parameters for a thread of execution on a compute node, including specifications of a client, a context, and a task. The compute nodes are coupled for data communications through the PAMI. The parallel application establishes a data communications geometry specifying a set of endpoints that are used in collective operations of the PAMI by associating with the geometry a list of collective algorithms valid for use with themore » endpoints of the geometry; registering in each endpoint in the geometry a dispatch callback function for a collective operation; and executing without blocking, through a single one of the endpoints in the geometry, an instruction for the collective operation.« less

Challenges in Development of Sperm Repositories for Biomedical Fishes: Quality Control in Small-Bodied Species.

PubMed

Torres, Leticia; Liu, Yue; Guitreau, Amy; Yang, Huiping; Tiersch, Terrence R

2017-12-01

Quality control (QC) is essential for reproducible and efficient functioning of germplasm repositories. However, many biomedical fish models present significant QC challenges due to small body sizes (<5 cm) and miniscule sperm volumes (<5 μL). Using minimal volumes of sperm, we used Zebrafish to evaluate common QC endpoints as surrogates for fertilization success along sequential steps of cryopreservation. First, concentrations of calibration bead suspensions were evaluated with a Makler ® counting chamber by using different sample volumes and mixing methods. For sperm analysis, samples were initially diluted at a 1:30 ratio with Hanks' balanced salt solution (HBSS). Motility was evaluated by using different ratios of sperm and activation medium, and membrane integrity was analyzed with flow cytometry at different concentrations. Concentration and sperm motility could be confidently estimated by using volumes as small as 1 μL, whereas membrane integrity required a minimum of 2 μL (at 1 × 10 6 cells/mL). Thus, <5 μL of sperm suspension (after dilution to 30-150 μL with HBSS) was required to evaluate sperm quality by using three endpoints. Sperm quality assessment using a combination of complementary endpoints enhances QC efforts during cryopreservation, increasing reliability and reproducibility, and reducing waste of time and resources.

Biomarkers of Host Response Predict Primary End-Point Radiological Pneumonia in Tanzanian Children with Clinical Pneumonia: A Prospective Cohort Study

PubMed Central

Erdman, Laura K.; D’Acremont, Valérie; Hayford, Kyla; Kilowoko, Mary; Kyungu, Esther; Hongoa, Philipina; Alamo, Leonor; Streiner, David L.; Genton, Blaise; Kain, Kevin C.

2015-01-01

Background Diagnosing pediatric pneumonia is challenging in low-resource settings. The World Health Organization (WHO) has defined primary end-point radiological pneumonia for use in epidemiological and vaccine studies. However, radiography requires expertise and is often inaccessible. We hypothesized that plasma biomarkers of inflammation and endothelial activation may be useful surrogates for end-point pneumonia, and may provide insight into its biological significance. Methods We studied children with WHO-defined clinical pneumonia (n = 155) within a prospective cohort of 1,005 consecutive febrile children presenting to Tanzanian outpatient clinics. Based on x-ray findings, participants were categorized as primary end-point pneumonia (n = 30), other infiltrates (n = 31), or normal chest x-ray (n = 94). Plasma levels of 7 host response biomarkers at presentation were measured by ELISA. Associations between biomarker levels and radiological findings were assessed by Kruskal-Wallis test and multivariable logistic regression. Biomarker ability to predict radiological findings was evaluated using receiver operating characteristic curve analysis and Classification and Regression Tree analysis. Results Compared to children with normal x-ray, children with end-point pneumonia had significantly higher C-reactive protein, procalcitonin and Chitinase 3-like-1, while those with other infiltrates had elevated procalcitonin and von Willebrand Factor and decreased soluble Tie-2 and endoglin. Clinical variables were not predictive of radiological findings. Classification and Regression Tree analysis generated multi-marker models with improved performance over single markers for discriminating between groups. A model based on C-reactive protein and Chitinase 3-like-1 discriminated between end-point pneumonia and non-end-point pneumonia with 93.3% sensitivity (95% confidence interval 76.5–98.8), 80.8% specificity (72.6–87.1), positive likelihood ratio 4.9 (3.4–7.1), negative likelihood ratio 0.083 (0.022–0.32), and misclassification rate 0.20 (standard error 0.038). Conclusions In Tanzanian children with WHO-defined clinical pneumonia, combinations of host biomarkers distinguished between end-point pneumonia, other infiltrates, and normal chest x-ray, whereas clinical variables did not. These findings generate pathophysiological hypotheses and may have potential research and clinical utility. PMID:26366571

Emotional experiences in surrogate mothers: A qualitative study

PubMed Central

Ahmari Tehran, Hoda; Tashi, Shohreh; Mehran, Nahid; Eskandari, Narges; Dadkhah Tehrani, Tahmineh

2014-01-01

Background: Surrogacy is one of the new techniques of assisted reproduction technology in which a woman carries and bears a child for another woman. In Iran, many Shia clerics and jurists considered it permissible so there is no religious prohibition for it. In addition to the risk of physical complications for complete surrogate mothers, the possibility of psychological complications resulted from emotional attachment to a living creature in the surrogate mother as another injury requires counseling and assessment prior to acceptance by infertile couples and complete surrogate mothers. Objective: The purpose of this study was to assess the emotional experiences of surrogate mothers. Materials and Methods: This was a qualitative, phenomenological study. We selected eight complete surrogate mothers in Isfahan. We used convenient sampling method and in-depth interview to collect the information. The data analysis was fulfilled via Colaizzi’s seven-stage method. Reliability and validity study of the roots in the four-axis was done. Results: The findings of these interviews were classified into two main themes and four sub themes: acquired experiences in pregnancy (feelings toward pregnancy, relationship with family, relatives and commissioning couple) and consequences of surrogacy (complications of pregnancy, religious and financial problems of surrogacy). Conclusion: Surrogacy pregnancy should be considered as high-risk emotional experience because many of surrogate mothers may face negative experiences. Therefore, it is recommended that surrogates should receive professional counseling prior to, during and following pregnancy. PMID:25114669

Emotional experiences in surrogate mothers: A qualitative study.

PubMed

Ahmari Tehran, Hoda; Tashi, Shohreh; Mehran, Nahid; Eskandari, Narges; Dadkhah Tehrani, Tahmineh

2014-07-01

Surrogacy is one of the new techniques of assisted reproduction technology in which a woman carries and bears a child for another woman. In Iran, many Shia clerics and jurists considered it permissible so there is no religious prohibition for it. In addition to the risk of physical complications for complete surrogate mothers, the possibility of psychological complications resulted from emotional attachment to a living creature in the surrogate mother as another injury requires counseling and assessment prior to acceptance by infertile couples and complete surrogate mothers. The purpose of this study was to assess the emotional experiences of surrogate mothers. This was a qualitative, phenomenological study. We selected eight complete surrogate mothers in Isfahan. We used convenient sampling method and in-depth interview to collect the information. The data analysis was fulfilled via Colaizzi's seven-stage method. Reliability and validity study of the roots in the four-axis was done. The findings of these interviews were classified into two main themes and four sub themes: acquired experiences in pregnancy (feelings toward pregnancy, relationship with family, relatives and commissioning couple) and consequences of surrogacy (complications of pregnancy, religious and financial problems of surrogacy). Surrogacy pregnancy should be considered as high-risk emotional experience because many of surrogate mothers may face negative experiences. Therefore, it is recommended that surrogates should receive professional counseling prior to, during and following pregnancy.

Assessing Exposure to Household Air Pollution: A Systematic Review and Pooled Analysis of Carbon Monoxide as a Surrogate Measure of Particulate Matter.

PubMed

Carter, Ellison; Norris, Christina; Dionisio, Kathie L; Balakrishnan, Kalpana; Checkley, William; Clark, Maggie L; Ghosh, Santu; Jack, Darby W; Kinney, Patrick L; Marshall, Julian D; Naeher, Luke P; Peel, Jennifer L; Sambandam, Sankar; Schauer, James J; Smith, Kirk R; Wylie, Blair J; Baumgartner, Jill

2017-07-28

Household air pollution from solid fuel burning is a leading contributor to disease burden globally. Fine particulate matter (PM 2.5 ) is thought to be responsible for many of these health impacts. A co-pollutant, carbon monoxide (CO) has been widely used as a surrogate measure of PM 2.5 in studies of household air pollution. The goal was to evaluate the validity of exposure to CO as a surrogate of exposure to PM 2.5 in studies of household air pollution and the consistency of the PM 2.5 -CO relationship across different study settings and conditions. We conducted a systematic review of studies with exposure and/or cooking area PM 2.5 and CO measurements and assembled 2,048 PM 2.5 and CO measurements from a subset of studies (18 cooking area studies and 9 personal exposure studies) retained in the systematic review. We conducted pooled multivariate analyses of PM 2.5 -CO associations, evaluating fuels, urbanicity, season, study, and CO methods as covariates and effect modifiers. We retained 61 of 70 studies for review, representing 27 countries. Reported PM 2.5 -CO correlations ( r ) were lower for personal exposure (range: 0.22-0.97; median=0.57) than for cooking areas (range: 0.10-0.96; median=0.71). In the pooled analyses of personal exposure and cooking area concentrations, the variation in ln(CO) explained 13% and 48% of the variation in ln(PM 2.5 ), respectively. Our results suggest that exposure to CO is not a consistently valid surrogate measure of exposure to PM 2.5 . Studies measuring CO exposure as a surrogate measure of PM exposure should conduct local validation studies for different stove/fuel types and seasons. https://doi.org/10.1289/EHP767.

Assessing Exposure to Household Air Pollution: A Systematic Review and Pooled Analysis of Carbon Monoxide as a Surrogate Measure of Particulate Matter

PubMed Central

Carter, Ellison; Norris, Christina; Dionisio, Kathie L.; Balakrishnan, Kalpana; Checkley, William; Clark, Maggie L.; Ghosh, Santu; Jack, Darby W.; Kinney, Patrick L.; Marshall, Julian D.; Naeher, Luke P.; Peel, Jennifer L.; Sambandam, Sankar; Schauer, James J.; Smith, Kirk R.; Wylie, Blair J.

2017-01-01

Background: Household air pollution from solid fuel burning is a leading contributor to disease burden globally. Fine particulate matter (PM2.5) is thought to be responsible for many of these health impacts. A co-pollutant, carbon monoxide (CO) has been widely used as a surrogate measure of PM2.5 in studies of household air pollution. Objective: The goal was to evaluate the validity of exposure to CO as a surrogate of exposure to PM2.5 in studies of household air pollution and the consistency of the PM2.5–CO relationship across different study settings and conditions. Methods: We conducted a systematic review of studies with exposure and/or cooking area PM2.5 and CO measurements and assembled 2,048 PM2.5 and CO measurements from a subset of studies (18 cooking area studies and 9 personal exposure studies) retained in the systematic review. We conducted pooled multivariate analyses of PM2.5–CO associations, evaluating fuels, urbanicity, season, study, and CO methods as covariates and effect modifiers. Results: We retained 61 of 70 studies for review, representing 27 countries. Reported PM2.5–CO correlations (r) were lower for personal exposure (range: 0.22–0.97; median=0.57) than for cooking areas (range: 0.10–0.96; median=0.71). In the pooled analyses of personal exposure and cooking area concentrations, the variation in ln(CO) explained 13% and 48% of the variation in ln(PM2.5), respectively. Conclusions: Our results suggest that exposure to CO is not a consistently valid surrogate measure of exposure to PM2.5. Studies measuring CO exposure as a surrogate measure of PM exposure should conduct local validation studies for different stove/fuel types and seasons. https://doi.org/10.1289/EHP767 PMID:28886596

Primary Sclerosing Cholangitis Risk Estimate Tool (PREsTo) Predicts Outcomes in PSC: A Derivation & Validation Study Using Machine Learning.

PubMed

Eaton, John E; Vesterhus, Mette; McCauley, Bryan M; Atkinson, Elizabeth J; Schlicht, Erik M; Juran, Brian D; Gossard, Andrea A; LaRusso, Nicholas F; Gores, Gregory J; Karlsen, Tom H; Lazaridis, Konstantinos N

2018-05-09

Improved methods are needed to risk stratify and predict outcomes in patients with primary sclerosing cholangitis (PSC). Therefore, we sought to derive and validate a new prediction model and compare its performance to existing surrogate markers. The model was derived using 509 subjects from a multicenter North American cohort and validated in an international multicenter cohort (n=278). Gradient boosting, a machine based learning technique, was used to create the model. The endpoint was hepatic decompensation (ascites, variceal hemorrhage or encephalopathy). Subjects with advanced PSC or cholangiocarcinoma at baseline were excluded. The PSC risk estimate tool (PREsTo) consists of 9 variables: bilirubin, albumin, serum alkaline phosphatase (SAP) times the upper limit of normal (ULN), platelets, AST, hemoglobin, sodium, patient age and the number of years since PSC was diagnosed. Validation in an independent cohort confirms PREsTo accurately predicts decompensation (C statistic 0.90, 95% confidence interval (CI) 0.84-0.95) and performed well compared to MELD score (C statistic 0.72, 95% CI 0.57-0.84), Mayo PSC risk score (C statistic 0.85, 95% CI 0.77-0.92) and SAP < 1.5x ULN (C statistic 0.65, 95% CI 0.55-0.73). PREsTo continued to be accurate among individuals with a bilirubin < 2.0 mg/dL (C statistic 0.90, 95% CI 0.82-0.96) and when the score was re-applied at a later course in the disease (C statistic 0.82, 95% CI 0.64-0.95). PREsTo accurately predicts hepatic decompensation in PSC and exceeds the performance among other widely available, noninvasive prognostic scoring systems. This article is protected by copyright. All rights reserved. © 2018 by the American Association for the Study of Liver Diseases.

Development of surrogate endpoint biomarkers for clinical trials of cancer chemopreventive agents: relationships to fundamental properties of preinvasive (intraepithelial) neoplasia.

PubMed

Boone, C W; Kelloff, G J

1994-01-01

The tissue changes offering the greatest immediate potential for development as surrogate endpoint biomarkers (SEBs) to be used in Phase II trials of cancer chemopreventive agents are those derived from the microscopic tissue changes pathologists use to make the diagnosis of preinvasive (intraepithelial) neoplasia. These changes comprise four categories: proliferative index, ploidy, nuclear morphometry (size, shape, texture, and pleomorphism), and nucleolar morphometry (number, size, shape, position, and pleomorphism). Computer-assisted image analysis (CIA) permits dozens of additional morphometric parameters to be developed. Other categories of candidate SEBs are: DNA and chromosomal structural changes associated with genomic instability, activation of oncogenes and inactivation of tumor suppressor genes, structural changes in differentiated molecules, and aberrations of growth factor/receptor structure and function. Self-perpetuating DNA breakage with secondary mutator mutations in genomic stability genes is a major mechanism by which the genomic instability characteristic of neoplasia occurs, and from which stem other basic neoplastic properties, including clonal evolution, along multiple pathways of genetic variation that are stochastically determined, continuously increasing proliferation, rate and extent of phenotypic heterogeneity. SEBs resulting from genomic instability include homogeneously staining regions, double minute chromosomes, micronuclei, dicentrics, gene amplification, loss of heterozygosity, and alterations in chromosome number. Newly developed assays for detecting genomic instability include comparative genomic hybridization using fluorescence in situ hybridization on > 20 micron-thick sections monitored by confocal laser scanning microscopy, assays for microsatellite instability, and restriction landmark genomic scanning. These assays offer promise for detecting the earliest molecular changes of neoplasia in normal-appearing epithelium prior to the onset of the dysplastic phase of intraepithelial neoplasia.

Relative Biological Effectiveness of HZE Particles for Chromosomal Exchanges and Other Surrogate Cancer Risk Endpoints.

PubMed

Cacao, Eliedonna; Hada, Megumi; Saganti, Premkumar B; George, Kerry A; Cucinotta, Francis A

2016-01-01

The biological effects of high charge and energy (HZE) particle exposures are of interest in space radiation protection of astronauts and cosmonauts, and estimating secondary cancer risks for patients undergoing Hadron therapy for primary cancers. The large number of particles types and energies that makeup primary or secondary radiation in HZE particle exposures precludes tumor induction studies in animal models for all but a few particle types and energies, thus leading to the use of surrogate endpoints to investigate the details of the radiation quality dependence of relative biological effectiveness (RBE) factors. In this report we make detailed RBE predictions of the charge number and energy dependence of RBE's using a parametric track structure model to represent experimental results for the low dose response for chromosomal exchanges in normal human lymphocyte and fibroblast cells with comparison to published data for neoplastic transformation and gene mutation. RBE's are evaluated against acute doses of γ-rays for doses near 1 Gy. Models that assume linear or non-targeted effects at low dose are considered. Modest values of RBE (<10) are found for simple exchanges using a linear dose response model, however in the non-targeted effects model for fibroblast cells large RBE values (>10) are predicted at low doses <0.1 Gy. The radiation quality dependence of RBE's against the effects of acute doses γ-rays found for neoplastic transformation and gene mutation studies are similar to those found for simple exchanges if a linear response is assumed at low HZE particle doses. Comparisons of the resulting model parameters to those used in the NASA radiation quality factor function are discussed.

Relative Biological Effectiveness of HZE Particles for Chromosomal Exchanges and Other Surrogate Cancer Risk Endpoints

DOE PAGES

Cacao, Eliedonna; Hada, Megumi; Saganti, Premkumar B.; ...

2016-04-25

The biological effects of high charge and energy (HZE) particle exposures are of interest in space radiation protection of astronauts and cosmonauts, and estimating secondary cancer risks for patients undergoing Hadron therapy for primary cancers. The large number of particles types and energies that makeup primary or secondary radiation in HZE particle exposures precludes tumor induction studies in animal models for all but a few particle types and energies, thus leading to the use of surrogate endpoints to investigate the details of the radiation quality dependence of relative biological effectiveness (RBE) factors. In this report we make detailed RBE predictionsmore » of the charge number and energy dependence of RBE’s using a parametric track structure model to represent experimental results for the low dose response for chromosomal exchanges in normal human lymphocyte and fibroblast cells with comparison to published data for neoplastic transformation and gene mutation. RBE’s are evaluated against acute doses of γ-rays for doses near 1 Gy. Models that assume linear or non-targeted effects at low dose are considered. Modest values of RBE (<10) are found for simple exchanges using a linear dose response model, however in the non-targeted effects model for fibroblast cells large RBE values (>10) are predicted at low doses <0.1 Gy. The radiation quality dependence of RBE’s against the effects of acute doses γ-rays found for neoplastic transformation and gene mutation studies are similar to those found for simple exchanges if a linear response is assumed at low HZE particle doses. Finally, we discuss comparisons of the resulting model parameters to those used in the NASA radiation quality factor function.« less

Safety and efficacy of autologous cell therapy in critical limb ischemia: a systematic review.

PubMed

Benoit, Eric; O'Donnell, Thomas F; Patel, Amit N

2013-01-01

Researchers have accumulated a decade of experience with autologous cell therapy in the treatment of critical limb ischemia (CLI). We conducted a systematic review of clinical trials in the literature to determine the safety and efficacy of cell therapy in CLI. We searched the literature for clinical trials of autologous cell therapy in CLI, including observational series of five or more patients to accrue a large pool of patients for safety analysis. Safety analysis included evaluation of death, cancer, unregulated angiogenesis, and procedural adverse events such as bleeding. Efficacy analysis included the clinical endpoints amputation and death as well as functional and surrogate endpoints. We identified 45 clinical trials, including seven RCTs, and 1,272 patients who received cell therapy. The overall adverse event rate was low (4.2%). Cell therapy patients did not have a higher mortality rate than control patients and demonstrated no increase in cancer incidence when analyzed against population rates. With regard to efficacy, cell therapy patients had a significantly lower amputation rate than control patients (OR 0.36, p = 0.0004). Cell therapy also demonstrated efficacy in a variety of functional and surrogate outcomes. Clinical trials differed in the proportion of patients with risk factors for clinical outcomes, and these influenced rates of amputation and death. Cell therapy presents a favorable safety profile with a low adverse event rate and no increase in severe events such as mortality and cancer and treatment with cell therapy decreases the risk of amputation. Cell therapy has a positive benefit-to-risk ratio in CLI and may be a valuable treatment option, particularly for those challenging patients who cannot undergo arterial reconstruction.

Relative Biological Effectiveness of HZE Particles for Chromosomal Exchanges and Other Surrogate Cancer Risk Endpoints

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

Cacao, Eliedonna; Hada, Megumi; Saganti, Premkumar B.

The biological effects of high charge and energy (HZE) particle exposures are of interest in space radiation protection of astronauts and cosmonauts, and estimating secondary cancer risks for patients undergoing Hadron therapy for primary cancers. The large number of particles types and energies that makeup primary or secondary radiation in HZE particle exposures precludes tumor induction studies in animal models for all but a few particle types and energies, thus leading to the use of surrogate endpoints to investigate the details of the radiation quality dependence of relative biological effectiveness (RBE) factors. In this report we make detailed RBE predictionsmore » of the charge number and energy dependence of RBE’s using a parametric track structure model to represent experimental results for the low dose response for chromosomal exchanges in normal human lymphocyte and fibroblast cells with comparison to published data for neoplastic transformation and gene mutation. RBE’s are evaluated against acute doses of γ-rays for doses near 1 Gy. Models that assume linear or non-targeted effects at low dose are considered. Modest values of RBE (<10) are found for simple exchanges using a linear dose response model, however in the non-targeted effects model for fibroblast cells large RBE values (>10) are predicted at low doses <0.1 Gy. The radiation quality dependence of RBE’s against the effects of acute doses γ-rays found for neoplastic transformation and gene mutation studies are similar to those found for simple exchanges if a linear response is assumed at low HZE particle doses. Finally, we discuss comparisons of the resulting model parameters to those used in the NASA radiation quality factor function.« less

Development and validation of optimal cut-off value in inter-arm systolic blood pressure difference for prediction of cardiovascular events.

PubMed

Hirono, Akira; Kusunose, Kenya; Kageyama, Norihito; Sumitomo, Masayuki; Abe, Masahiro; Fujinaga, Hiroyuki; Sata, Masataka

2018-01-01

An inter-arm systolic blood pressure difference (IAD) is associated with cardiovascular disease. The aim of this study was to develop and validate the optimal cut-off value of IAD as a predictor of major adverse cardiac events in patients with arteriosclerosis risk factors. From 2009 to 2014, 1076 patients who had at least one cardiovascular risk factor were included in the analysis. We defined 700 randomly selected patients as a development cohort to confirm that IAD was the predictor of cardiovascular events and to determine optimal cut-off value of IAD. Next, we validated outcomes in the remaining 376 patients as a validation cohort. The blood pressure (BP) of both arms measurements were done simultaneously using the ankle-brachial blood pressure index (ABI) form of automatic device. The primary endpoint was the cardiovascular event and secondary endpoint was the all-cause mortality. During a median period of 2.8 years, 143 patients reached the primary endpoint in the development cohort. In the multivariate Cox proportional hazards analysis, IAD was the strong predictor of cardiovascular events (hazard ratio: 1.03, 95% confidence interval: 1.01-1.05, p=0.005). The receiver operating characteristic curve revealed that 5mmHg was the optimal cut-off point of IAD to predict cardiovascular events (p<0.001). In the validation cohort, the presence of a large IAD (IAD ≥5mmHg) was significantly associated with the primary endpoint (p=0.021). IAD is significantly associated with future cardiovascular events in patients with arteriosclerosis risk factors. The optimal cut-off value of IAD is 5mmHg. Copyright © 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Quantitative Medical Image Analysis for Clinical Development of Therapeutics

NASA Astrophysics Data System (ADS)

Analoui, Mostafa

There has been significant progress in development of therapeutics for prevention and management of several disease areas in recent years, leading to increased average life expectancy, as well as of quality of life, globally. However, due to complexity of addressing a number of medical needs and financial burden of development of new class of therapeutics, there is a need for better tools for decision making and validation of efficacy and safety of new compounds. Numerous biological markers (biomarkers) have been proposed either as adjunct to current clinical endpoints or as surrogates. Imaging biomarkers are among rapidly increasing biomarkers, being examined to expedite effective and rational drug development. Clinical imaging often involves a complex set of multi-modality data sets that require rapid and objective analysis, independent of reviewer's bias and training. In this chapter, an overview of imaging biomarkers for drug development is offered, along with challenges that necessitate quantitative and objective image analysis. Examples of automated and semi-automated analysis approaches are provided, along with technical review of such methods. These examples include the use of 3D MRI for osteoarthritis, ultrasound vascular imaging, and dynamic contrast enhanced MRI for oncology. Additionally, a brief overview of regulatory requirements is discussed. In conclusion, this chapter highlights key challenges and future directions in this area.

Doubt and belief in physicians' ability to prognosticate during critical illness: The perspective of surrogate decision makers

PubMed Central

Zier, Lucas S.; Burack, Jeffrey H.; Micco, Guy; Chipman, Anne K.; Frank, James A.; Luce, John M.; White, Douglas B.

2009-01-01

Objectives: Although discussing a prognosis is a duty of physicians caring for critically ill patients, little is known about surrogate decision-makers' beliefs about physicians' ability to prognosticate. We sought to determine: 1) surrogates' beliefs about whether physicians can accurately prognosticate for critically ill patients; and 2) how individuals use prognostic information in their role as surrogate decision-makers. Design, Setting, and Patients: Multicenter study in intensive care units of a public hospital, a tertiary care hospital, and a veterans' hospital. We conducted semistructured interviews with 50 surrogate decision-makers of critically ill patients. We analyzed the interview transcripts using grounded theory methods to inductively develop a framework to describe surrogates' beliefs about physicians' ability to prognosticate. Validation methods included triangulation by multidisciplinary analysis and member checking. Measurements and Main Results: Overall, 88% (44 of 50) of surrogates expressed doubt about physicians' ability to prognosticate for critically ill patients. Four distinct themes emerged that explained surrogates' doubts about prognostic accuracy: a belief that God could alter the course of the illness, a belief that predicting the future is inherently uncertain, prior experiences where physicians' prognostications were inaccurate, and experiences with prognostication during the patient's intensive care unit stay. Participants also identified several factors that led to belief in physicians' prognostications, such as receiving similar prognostic estimates from multiple physicians and prior experiences with accurate prognostication. Surrogates' doubts about prognostic accuracy did not prevent them from wanting prognostic information. Instead, most surrogate decision-makers view physicians' prognostications as rough estimates that are valuable in informing decisions, but are not determinative. Surrogates identified the act of prognostic disclosure as a key step in preparing emotionally and practically for the possibility that a patient may not survive. Conclusions: Although many surrogate decision-makers harbor some doubt about the accuracy of physicians' prognostications, they highly value discussions about prognosis and use the information for multiple purposes. (Crit Care Med 2008; 36: 2341–2347) PMID:18596630

Legal regulation of surrogate motherhood in Israel.

PubMed

Frenkel, D A

2001-01-01

The Israeli Law on surrogate motherhood demands a preconception agreement to include payments to be made to the surrogate mother. Surrogacy arrangements with family members are forbidden. Commercial surrogacy is allowed and encouraged. The Law causes many problems. Validity of consent given by surrogate mothers is doubtful. Possible future psychological harm are ignored. There is a danger of "commodification" of children. Abusing women of low socio-economic status as breeding machines may be another outcome. No clear responsibility is imposed on the "intended parents" for an impaired child. The law ignores possibility of divorce or death of the "intended parents" before the child's birth. Splitting motherhood is another social problem that has to be dealt with. So far the sperm of the husband from the "intended parents" has to be used, but further steps may follow. It is not certain that a policy of "positive eugenics" will not develop.

Validation of Baking To Control Salmonella Serovars in Hamburger Bun Manufacturing, and Evaluation of Enterococcus faecium ATCC 8459 and Saccharomyces cerevisiae as Nonpathogenic Surrogate Indicators.

PubMed

Channaiah, Lakshmikantha H; Holmgren, Elizabeth S; Michael, Minto; Sevart, Nicholas J; Milke, Donka; Schwan, Carla L; Krug, Matthew; Wilder, Amanda; Phebus, Randall K; Thippareddi, Harshavardhan; Milliken, George

2016-04-01

This study was conducted to validate a simulated commercial baking process for hamburger buns to destroy Salmonella serovars and to determine the appropriateness of using nonpathogenic surrogates (Enterococcus faecium ATCC 8459 or Saccharomyces cerevisiae) for in-plant process validation studies. Wheat flour was inoculated (∼6 log CFU/g) with three Salmonella serovars (Typhimurium, Newport, or Senftenberg 775W) or with E. faecium. Dough was formed, proofed, and baked to mimic commercial manufacturing conditions. Buns were baked for up to 13 min in a conventional oven (218.3°C), with internal crumb temperature increasing to ∼100°C during the first 8 min of baking and remaining at this temperature until removal from the oven. Salmonella and E. faecium populations were undetectable by enrichment (>6-log CFU/g reductions) after 9.0 and 11.5 min of baking, respectively, and ≥5-log-cycle reductions were achieved by 6.0 and 7.75 min, respectively. D-values of Salmonella (three-serovar cocktail) and E. faecium 8459 in dough were 28.64 and 133.33, 7.61 and 55.67, and 3.14 and 14.72 min at 55, 58, and 61°C, respectively, whereas D-values of S. cerevisiae were 18.73, 5.67, and 1.03 min at 52, 55, and 58°C, respectivly. The z-values of Salmonella, E. faecium, and S. cerevisiae were 6.58, 6.25, and 4.74°C, respectively. A high level of thermal lethality was observed for baking of typical hamburger bun dough, resulting in rapid elimination of high levels of the three-strain Salmonella cocktail; however, the lethality and microbial destruction kinetics should not be extrapolated to other bakery products without further research. E. faecium demonstrated greater thermal resistance compared with Salmonella during bun baking and could serve as a conservative surrogate to validate thermal process lethality in commercial bun baking operations. Low thermal tolerance of S. cerevisiae relative to Salmonella serovars limits its usefulness as a surrogate for process validations.

Validation of intermediate end points in cancer research.

PubMed

Schatzkin, A; Freedman, L S; Schiffman, M H; Dawsey, S M

1990-11-21

Investigations using intermediate end points as cancer surrogates are quicker, smaller, and less expensive than studies that use malignancy as the end point. We present a strategy for determining whether a given biomarker is a valid intermediate end point between an exposure and incidence of cancer. Candidate intermediate end points may be selected from case series, ecologic studies, and animal experiments. Prospective cohort and sometimes case-control studies may be used to quantify the intermediate end point-cancer association. The most appropriate measure of this association is the attributable proportion. The intermediate end point is a valid cancer surrogate if the attributable proportion is close to 1.0, but not if it is close to 0. Usually, the attributable proportion is close to neither 1.0 nor 0; in this case, valid surrogacy requires that the intermediate end point mediate an established exposure-cancer relation. This would in turn imply that the exposure effect would vanish if adjusted for the intermediate end point. We discuss the relative advantages of intervention and observational studies for the validation of intermediate end points. This validation strategy also may be applied to intermediate end points for adverse reproductive outcomes and chronic diseases other than cancer.

The Validity of Left Ventricular Mass as a Surrogate End Point for All-Cause and Cardiovascular Mortality Outcomes in People With CKD: A Systematic Review and Meta-analysis.

PubMed

Badve, Sunil V; Palmer, Suetonia C; Strippoli, Giovanni F M; Roberts, Matthew A; Teixeira-Pinto, Armando; Boudville, Neil; Cass, Alan; Hawley, Carmel M; Hiremath, Swapnil S; Pascoe, Elaine M; Perkovic, Vlado; Whalley, Gillian A; Craig, Jonathan C; Johnson, David W

2016-10-01

Left ventricular mass (LVM) is a widely used surrogate end point in randomized trials involving people with chronic kidney disease (CKD) because treatment-induced LVM reductions are assumed to lower cardiovascular risk. The aim of this study was to assess the validity of LVM as a surrogate end point for all-cause and cardiovascular mortality in CKD. Systematic review and meta-analysis. Participants with any stages of CKD. Randomized controlled trials with 3 or more months' follow-up that reported LVM data. Any pharmacologic or nonpharmacologic intervention. The surrogate outcome of interest was LVM change from baseline to last measurement, and clinical outcomes of interest were all-cause and cardiovascular mortality. Standardized mean differences (SMDs) of LVM change and relative risk for mortality were estimated using pairwise random-effects meta-analysis. Correlations between surrogate and clinical outcomes were summarized across all interventions combined using bivariate random-effects Bayesian models, and 95% credible intervals were computed. 73 trials (6,732 participants) covering 25 intervention classes were included in the meta-analysis. Overall, risk of bias was uncertain or high. Only 3 interventions reduced LVM: erythropoiesis-stimulating agents (9 trials; SMD, -0.13; 95% CI, -0.23 to -0.03), renin-angiotensin-aldosterone system inhibitors (13 trials; SMD, -0.28; 95% CI, -0.45 to -0.12), and isosorbide mononitrate (2 trials; SMD, -0.43; 95% CI, -0.72 to -0.14). All interventions had uncertain effects on all-cause and cardiovascular mortality. There were weak and imprecise associations between the effects of interventions on LVM change and all-cause (32 trials; 5,044 participants; correlation coefficient, 0.28; 95% credible interval, -0.13 to 0.59) and cardiovascular mortality (13 trials; 2,327 participants; correlation coefficient, 0.30; 95% credible interval, -0.54 to 0.76). Limited long-term data, suboptimal quality of included studies. There was no clear and consistent association between intervention-induced LVM change and mortality. Evidence for LVM as a valid surrogate end point in CKD is currently lacking. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

A validated LC-MS/MS method for the quantitative measurement of creatinine as an endogenous biomarker in human plasma.

PubMed

Zhao, Yue; Liu, Guowen; Angeles, Aida; Christopher, Lisa J; Wang, Zhaoqing; Arnold, Mark E; Shen, Jim X

2016-10-01

Creatinine is an endogenous compound generated from creatine by normal muscular metabolism. It is an important indicator of renal function and the serum level is routinely monitored in clinical labs. Results & methodology: Surrogate analyte (d3-creatinine) was used for calibration standard and quality control preparation and the relative instrument response ratio between creatinine and d3-creatinine was used to calculate the endogenous creatinine concentrations. A fit-for-purpose strategy of using a surrogate analyte and authentic matrix was adopted for this validation. The assay was the first human plasma assay using such strategy and was successfully applied to a clinical study to confirm a transient elevation of creatinine observed using an existing clinical assay.

Clinical trial designs to obtain marketing authorization of drugs for haematological malignancy in Japan, the EU and the US.

PubMed

Nagai, Sumimasa; Ozawa, Keiya

2016-07-01

Differences in regulatory actions between Japan, the European Union (EU) and the United States (US) regarding the approval date and primary endpoints of pivotal trials have never been analysed comprehensively. This study aimed to examine such differences in haematological malignancy indications not only in applications for new molecular entity agents but also in supplemental applications for additional indications. A total of 101 haematological malignancy indications were examined for 58 drugs. Only 30 indications were approved by the regulatory agencies of all three regions with 25, 9 and 67 indications being first approved in Japan, the EU and the US, respectively. Regarding the 18 indications approved only in the US, 13 were approved based on results of single-arm trials. The approval of all nine indications approved first in the EU was based on results of comparative trials. The primary endpoints were different between the EU and the US in 4 of 49 indications approved by both regulatory agencies, all of which were approved earlier in the US than in the EU. This analysis shows that the US Food and Drug Administration has taken the most active attitude to acceptance of surrogate endpoints in single-arm trials. Therefore, not only shorter review time but also this attitude may lead to earlier approval in US. © 2016 John Wiley & Sons Ltd.

Profiling clinical cancer research across the Atlantic: a review of research and its characteristics presented at ASCO and ESMO Congresses during the last decade.

PubMed

Pentheroudakis, George; Krikelis, Dimitrios; Cervantes, Andres; Vermorken, Jan; Pavlidis, Nicholas

2012-10-01

The comparison of clinical cancer research characteristics across the Atlantic and their evolution over time have not been studied to date. We collected oral presentations on breast, lung and colorectal cancer at ASCO (n=506) and ESMO (n=239) Congresses in years 2000-2010. EU-originated research constituted 52% of all ASCO presentations while US-research 26.7% of ESMO Congress presentations. Industry sponsorship was reported in 24.8% of ASCO vs. 31.8% of ESMO Congress trials. ASCO-presented trials were larger with longer follow-up periods but were blinded less often. ESMO-presented trials used Event-Free Survival (EFS, 38.1%) and Surrogate (18.4%) primary endpoints and reported positive primary endpoints (65%) more often than ASCO-presented trials. Interim analysis resulted in discontinuation of a trial more often at ASCO Congress (8.3% vs. 3.2%). ASCO Congress-presented research was more often published (69.2% vs. 59.8% at ESMO) at higher impact factor journals. Strong trends over the decade were seen for more frequent industry sponsorship, blinded design, larger sample size, early interim discontinuation, use of EFS endpoints and biomarker evaluation. Cancer clinical research is a complex scientific activity with common global but also distinct characteristics at the two sides of the Atlantic. Copyright © 2011 Elsevier Ltd. All rights reserved.

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

Zhao, T; Ruan, D

Purpose: The growing size and heterogeneity in training atlas necessitates sophisticated schemes to identify only the most relevant atlases for the specific multi-atlas-based image segmentation problem. This study aims to develop a model to infer the inaccessible oracle geometric relevance metric from surrogate image similarity metrics, and based on such model, provide guidance to atlas selection in multi-atlas-based image segmentation. Methods: We relate the oracle geometric relevance metric in label space to the surrogate metric in image space, by a monotonically non-decreasing function with additive random perturbations. Subsequently, a surrogate’s ability to prognosticate the oracle order for atlas subset selectionmore » is quantified probabilistically. Finally, important insights and guidance are provided for the design of fusion set size, balancing the competing demands to include the most relevant atlases and to exclude the most irrelevant ones. A systematic solution is derived based on an optimization framework. Model verification and performance assessment is performed based on clinical prostate MR images. Results: The proposed surrogate model was exemplified by a linear map with normally distributed perturbation, and verified with several commonly-used surrogates, including MSD, NCC and (N)MI. The derived behaviors of different surrogates in atlas selection and their corresponding performance in ultimate label estimate were validated. The performance of NCC and (N)MI was similarly superior to MSD, with a 10% higher atlas selection probability and a segmentation performance increase in DSC by 0.10 with the first and third quartiles of (0.83, 0.89), compared to (0.81, 0.89). The derived optimal fusion set size, valued at 7/8/8/7 for MSD/NCC/MI/NMI, agreed well with the appropriate range [4, 9] from empirical observation. Conclusion: This work has developed an efficacious probabilistic model to characterize the image-based surrogate metric on atlas selection. Analytical insights lead to valid guiding principles on fusion set size design.« less

The Role of Neoadjuvant Trials in Drug Development for Solid Tumors.

PubMed

Funt, Samuel A; Chapman, Paul B

2016-05-15

The relatively low success rate of phase II oncology trials in predicting success of novel drugs in phase III trials and in gaining regulatory approval may be due to reliance on the endpoint of response rate defined by the RECIST. The neoadjuvant treatment paradigm allows the antitumor activity of a novel therapy to be determined on a pathologic basis at the time of surgery instead of by RECIST, which was not developed to guide clinical decision making or correlate with long-term outcomes. Indeed, the FDA endorsed pathologic complete response (pCR) as a surrogate for overall survival (OS) in early-stage breast cancer and granted accelerated approval to pertuzumab based on this endpoint. We propose that pCR is a biologically rational method of determining treatment effect that may be more likely to predict OS. We discuss some advantages of the neoadjuvant trial design, review the use of neoadjuvant therapy as standards of care, and consider the neoadjuvant platform as a method for drug development. Clin Cancer Res; 22(10); 2323-8. ©2016 AACR. ©2016 American Association for Cancer Research.

Selection of response criteria for clinical trials of sarcoma treatment.

PubMed

Schuetze, Scott M; Baker, Laurence H; Benjamin, Robert S; Canetta, Renzo

2008-01-01

Soft tissue sarcomas are a heterogeneous group of malignancies arising from mesenchymal tissues. A large number of new therapies are being evaluated in patients with sarcomas, and consensus criteria defining treatment responses are essential for comparison of results from studies completed by different research groups. The 1979 World Health Organization (WHO) handbook set forth operationally defined criteria for response evaluation in solid tumors that were updated in 2000 with the publication of the Response Evaluation Criteria in Solid Tumors (RECIST). There have been significant advances in tumor imaging, however, that are not reflected in the RECIST. For example, computed tomography (CT) slice thickness has been reduced from 10 mm to < or =2.5 mm, allowing for more reproducible and accurate measurement of smaller lesions. Combination of imaging techniques, such as positron emission tomography with fluorine-18-fluorodeoxyglucose (18FDG-PET) and CT can provide investigators and clinicians with both anatomical and functional information regarding tumors, and there is now a large body of evidence demonstrating the effectiveness of PET/CT and other newer imaging methods for the detection and staging of tumors as well as early determination of responses to therapy. The application of newer imaging methods has the potential to decrease both the sample sizes required for, and duration of, clinical trials by providing an early indication of therapeutic response that is well correlated with clinical outcomes, such as time to tumor progression or overall survival. The results summarized in this review support the conclusion that the RECIST and the WHO criteria for evaluation of response in solid tumors need to be modernized. In addition, there is a current need for prospective trials to compare new response criteria with established endpoints and to validate imaging-based response rates as surrogate endpoints for clinical trials of new agents for sarcoma and other solid tumors.

Serum S100B is a useful surrogate marker for long-term outcomes in photochemically-induced thrombotic stroke rat models.

PubMed

Tanaka, Yu; Koizumi, Chie; Marumo, Toshiyuki; Omura, Tomohiro; Yoshida, Shigeru

2007-08-02

In recent years, serum S100B has been used as a secondary endpoint in some clinical trials, in which serum S100B has successfully indicated the benefits or harm done by the tested agents. Compared to clinical stroke studies, few experimental stroke studies report using serum S100B as a surrogate marker for estimating the long-term effects of neuroprotectants. This study sought to observe serum S100B kinetics in PIT stroke models and to clarify the association between serum S100B and both final infarct volumes and long-term neurological outcomes. Furthermore, to demonstrate that early elevations in serum S100B reflect successful neuroprotective treatment, a pharmacological study was performed with a non-competitive NMDA glutamate receptor antagonist, MK-801. Serum S100B levels were significantly elevated after PIT stroke, reaching peak values 48 h after the onset and declining thereafter. Single measurements of serum S100B as early as 48 h after PIT stroke correlated significantly with final infarct volumes and long-term neurological outcomes. Elevated serum S100B was significantly attenuated by MK-801, correlating significantly with long-term beneficial effects of MK-801 on infarct volumes and neurological outcomes. Our results showed that single measurements of serum S100B 48 h after PIT stroke would serve as an early and simple surrogate marker for long-term evaluation of histological and neurological outcomes in PIT stroke rat models.

Using 171,173Yb(d,p) to benchmark a surrogate reaction for neutron capture

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

Hatarik, R; Bersntein, L; Burke, J

2008-08-08

Neutron capture cross sections on unstable nuclei are important for many applications in nuclear structure and astrophysics. Measuring these cross sections directly is a major challenge and often impossible. An indirect approach for measuring these cross sections is the surrogate reaction method, which makes it possible to relate the desired cross section to a cross section of an alternate reaction that proceeds through the same compound nucleus. To benchmark the validity of using the (d,p{gamma}) reaction as a surrogate for (n,{gamma}), the {sup 171,173}Yb(d,p{gamma}) reactions were measured with the goal to reproduce the known [1] neutron capture cross section ratiosmore » of these nuclei.« less

Post hoc analyses: after the facts.

PubMed

Srinivas, Titte R; Ho, Bing; Kang, Joseph; Kaplan, Bruce

2015-01-01

Prospective clinical trials are constructed with high levels of internal validity. Sample size and power considerations usually address primary endpoints. Primary endpoints have traditionally included events that are becoming increasingly less common and thus have led to growing use of composite endpoints and noninferiority trial designs in transplantation. This approach may mask real clinical benefit in one or the other domain with regard to either clinically relevant secondary endpoints or other unexpected findings. In addition, endpoints solely chosen based on power considerations are prone to misjudgment of actual treatment effect size as well as consistency of that effect. In the instances where treatment effects may have been underestimated, valuable information may be lost if buried within a composite endpoint. In all these cases, analyses and post hoc analyses of data become relevant in informing practitioners about clinical benefits or safety signals that may not be captured by the primary endpoint. On the other hand, there are many pitfalls in using post hoc determined endpoints. This short review is meant to allow readers to appreciate post hoc analysis not as an entity with a single approach, but rather as an analysis with unique limitations and strengths that often raise new questions to be addressed in further inquiries.

Histological Image Feature Mining Reveals Emergent Diagnostic Properties for Renal Cancer

PubMed Central

Kothari, Sonal; Phan, John H.; Young, Andrew N.; Wang, May D.

2016-01-01

Computer-aided histological image classification systems are important for making objective and timely cancer diagnostic decisions. These systems use combinations of image features that quantify a variety of image properties. Because researchers tend to validate their diagnostic systems on specific cancer endpoints, it is difficult to predict which image features will perform well given a new cancer endpoint. In this paper, we define a comprehensive set of common image features (consisting of 12 distinct feature subsets) that quantify a variety of image properties. We use a data-mining approach to determine which feature subsets and image properties emerge as part of an “optimal” diagnostic model when applied to specific cancer endpoints. Our goal is to assess the performance of such comprehensive image feature sets for application to a wide variety of diagnostic problems. We perform this study on 12 endpoints including 6 renal tumor subtype endpoints and 6 renal cancer grade endpoints. Keywords-histology, image mining, computer-aided diagnosis PMID:28163980

Runoff load estimation of particulate and dissolved nitrogen in Lake Inba watershed using continuous monitoring data on turbidity and electric conductivity.

PubMed

Kim, J; Nagano, Y; Furumai, H

2012-01-01

Easy-to-measure surrogate parameters for water quality indicators are needed for real time monitoring as well as for generating data for model calibration and validation. In this study, a novel linear regression model for estimating total nitrogen (TN) based on two surrogate parameters is proposed based on evaluation of pollutant loads flowing into a eutrophic lake. Based on their runoff characteristics during wet weather, electric conductivity (EC) and turbidity were selected as surrogates for particulate nitrogen (PN) and dissolved nitrogen (DN), respectively. Strong linear relationships were established between PN and turbidity and DN and EC, and both models subsequently combined for estimation of TN. This model was evaluated by comparison of estimated and observed TN runoff loads during rainfall events. This analysis showed that turbidity and EC are viable surrogates for PN and DN, respectively, and that the linear regression model for TN concentration was successful in estimating TN runoff loads during rainfall events and also under dry weather conditions.

Reduced-order surrogate models for Green's functions in black hole spacetimes

NASA Astrophysics Data System (ADS)

Galley, Chad; Wardell, Barry

2016-03-01

The fundamental nature of linear wave propagation in curved spacetime is encoded in the retarded Green's function (or propagator). Green's functions are useful tools because almost any field quantity of interest can be computed via convolution integrals with a source. In addition, perturbation theories involving nonlinear wave propagation can be expressed in terms of multiple convolutions of the Green's function. Recently, numerical solutions for propagators in black hole spacetimes have been found that are globally valid and accurate for computing physical quantities. However, the data generated is too large for practical use because the propagator depends on two spacetime points that must be sampled finely to yield accurate convolutions. I describe how to build a reduced-order model that can be evaluated as a substitute, or surrogate, for solutions of the curved spacetime Green's function equation. The resulting surrogate accurately and quickly models the original and out-of-sample data. I discuss applications of the surrogate, including self-consistent evolutions and waveforms of extreme mass ratio binaries. Green's function surrogate models provide a new and practical way to handle many old problems involving wave propagation and motion in curved spacetimes.

Do Firms Underinvest in Long-Term Research? Evidence from Cancer Clinical Trials.

PubMed

Budish, Eric; Roin, Benjamin N; Williams, Heidi

2015-07-01

We investigate whether private research investments are distorted away from long-term projects. Our theoretical model highlights two potential sources of this distortion: short-termism and the fixed patent term. Our empirical context is cancer research, where clinical trials--and hence, project durations--are shorter for late-stage cancer treatments relative to early-stage treatments or cancer prevention. Using newly constructed data, we document several sources of evidence that together show private research investments are distorted away from long-term projects. The value of life-years at stake appears large. We analyze three potential policy responses: surrogate (non-mortality) clinical-trial endpoints, targeted R&D subsidies, and patent design.

Do firms underinvest in long-term research? Evidence from cancer clinical trials

PubMed Central

Budish, Eric; Roin, Benjamin N.

2015-01-01

We investigate whether private research investments are distorted away from long-term projects. Our theoretical model highlights two potential sources of this distortion: short-termism and the fixed patent term. Our empirical context is cancer research, where clinical trials – and hence, project durations – are shorter for late-stage cancer treatments relative to early-stage treatments or cancer prevention. Using newly constructed data, we document several sources of evidence that together show private research investments are distorted away from long-term projects. The value of life-years at stake appears large. We analyze three potential policy responses: surrogate (non-mortality) clinicaltrial endpoints, targeted R&D subsidies, and patent design. PMID:26345455

Do firms underinvest in long-term research? Evidence from cancer clinical trials.

PubMed

Budish, Eric; Roin, Benjamin N; Williams, Heidi

2015-07-01

We investigate whether private research investments are distorted away from long-term projects. Our theoretical model highlights two potential sources of this distortion: short-termism and the fixed patent term. Our empirical context is cancer research, where clinical trials - and hence, project durations - are shorter for late-stage cancer treatments relative to early-stage treatments or cancer prevention. Using newly constructed data, we document several sources of evidence that together show private research investments are distorted away from long-term projects. The value of life-years at stake appears large. We analyze three potential policy responses: surrogate (non-mortality) clinicaltrial endpoints, targeted R&D subsidies, and patent design.

Opportunities and pitfalls in clinical proof-of-concept: principles and examples.

PubMed

Chen, Chao

2018-04-01

Clinical proof-of-concept trials crucially inform major resource deployment decisions. This paper discusses several mechanisms for enhancing their rigour and efficiency. The importance of careful consideration when using a surrogate endpoint is illustrated; situational effectiveness of run-in patient enrichment is explored; a versatile tool is introduced to ensure a strong pharmacological underpinning; the benefits of dose-titration are revealed by simulation; and the importance of adequately scheduled observations is shown. The general process of model-based trial design and analysis is described and several examples demonstrate the value in historical data, simulation-guided design, model-based analysis and trial adaptation informed by interim analysis. Copyright © 2018 Elsevier Ltd. All rights reserved.

The inverse benefit law: how drug marketing undermines patient safety and public health.

PubMed

Brody, Howard; Light, Donald W

2011-03-01

Recent highly publicized withdrawals of drugs from the market because of safety concerns raise the question of whether these events are random failures or part of a recurring pattern. The inverse benefit law, inspired by Hart's inverse care law, states that the ratio of benefits to harms among patients taking new drugs tends to vary inversely with how extensively the drugs are marketed. The law is manifested through 6 basic marketing strategies: reducing thresholds for diagnosing disease, relying on surrogate endpoints, exaggerating safety claims, exaggerating efficacy claims, creating new diseases, and encouraging unapproved uses. The inverse benefit law highlights the need for comparative effectiveness research and other reforms to improve evidence-based prescribing.

Blood eosinophil count thresholds and exacerbations in patients with chronic obstructive pulmonary disease.

PubMed

Yun, Jeong H; Lamb, Andrew; Chase, Robert; Singh, Dave; Parker, Margaret M; Saferali, Aabida; Vestbo, Jørgen; Tal-Singer, Ruth; Castaldi, Peter J; Silverman, Edwin K; Hersh, Craig P

2018-06-01

Eosinophilic airway inflammation in patients with chronic obstructive pulmonary disease (COPD) is associated with exacerbations and responsivity to steroids, suggesting potential shared mechanisms with eosinophilic asthma. However, there is no consistent blood eosinophil count that has been used to define the increased exacerbation risk. We sought to investigate blood eosinophil counts associated with exacerbation risk in patients with COPD. Blood eosinophil counts and exacerbation risk were analyzed in patients with moderate-to-severe COPD by using 2 independent studies of former and current smokers with longitudinal data. The Genetic Epidemiology of COPD (COPDGene) study was analyzed for discovery (n = 1,553), and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study was analyzed for validation (n = 1,895). A subset of the ECLIPSE study subjects were used to assess the stability of blood eosinophil counts over time. COPD exacerbation risk increased with higher eosinophil counts. An eosinophil count threshold of 300 cells/μL or greater showed adjusted incidence rate ratios for exacerbations of 1.32 in the COPDGene study (95% CI, 1.10-1.63). The cutoff of 300 cells/μL or greater was validated for prospective risk of exacerbation in the ECLIPSE study, with adjusted incidence rate ratios of 1.22 (95% CI, 1.06-1.41) using 3-year follow-up data. Stratified analysis confirmed that the increased exacerbation risk associated with an eosinophil count of 300 cells/μL or greater was driven by subjects with a history of frequent exacerbations in both the COPDGene and ECLIPSE studies. Patients with moderate-to-severe COPD and blood eosinophil counts of 300 cells/μL or greater had an increased risk exacerbations in the COPDGene study, which was prospectively validated in the ECLIPSE study. Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Validity of response assessment criteria in neoadjuvant chemotherapy for gastric cancer (JCOG0507-A).

PubMed

Kurokawa, Yukinori; Shibata, Taro; Sasako, Mitsuru; Sano, Takeshi; Tsuburaya, Akira; Iwasaki, Yoshiaki; Fukuda, Haruhiko

2014-01-01

Neoadjuvant chemotherapy may improve outcomes in gastric cancer. Tumor responses can be evaluated with RECIST, Japanese Classification of Gastric Carcinoma (JCGC), and histological criteria. These approaches have not yet been compared. We analyzed two phase II trials of neoadjuvant chemotherapy using S-1 plus cisplatin. JCOG0210 included patients with linitis plastica and large ulcero-invasive tumors, whereas JCOG0405 comprised those with para-aortic or bulky lymph node metastases. Radiologic evaluations were conducted using RECIST in JCOG0405 and JCGC criteria in JCOG0210, because the latter included many patients without measurable lesions. A histological responder was defined as a patient in whom one third or more of the tumor was affected. The hazard ratios (HR) for death between responders and non-responders and response rate differences between short- and long-term survivors were estimated. In JCOG0210 (n = 49), HR was 0.54 in JCGC responders (P = 0.059) and 0.40 in histological responders (P = 0.005). The difference in response rates between short- and long-term survivors using histological criteria (34 %, P = 0.023) was greater than that using JCGC criteria (24 %, P = 0.15). In JCOG0405 (n = 51), HR was 0.67 in RECIST responders (P = 0.35) and 0.39 in histological responders (P = 0.030). In short- and long-term survivors, respectively, RECIST response rates were 62  and 67 % (P = 0.77), whereas histological response rates were 33  and 63 % (P = 0.048). Histological criteria showed higher response assessment validity than RECIST or JCGC criteria and yielded the best surrogate endpoint for overall survival.

A surrogate analyte method to determine D-serine in mouse brain using liquid chromatography-tandem mass spectrometry.

PubMed

Kinoshita, Kohnosuke; Jingu, Shigeji; Yamaguchi, Jun-ichi

2013-01-15

A bioanalytical method for determining endogenous d-serine levels in the mouse brain using a surrogate analyte and liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed. [2,3,3-(2)H]D-serine and [(15)N]D-serine were used as a surrogate analyte and an internal standard, respectively. The surrogate analyte was spiked into brain homogenate to yield calibration standards and quality control (QC) samples. Both endogenous and surrogate analytes were extracted using protein precipitation followed by solid phase extraction. Enantiomeric separation was achieved on a chiral crown ether column with an analysis time of only 6 min without any derivatization. The column eluent was introduced into an electrospray interface of a triple-quadrupole mass spectrometer. The calibration range was 1.00 to 300 nmol/g, and the method showed acceptable accuracy and precision at all QC concentration levels from a validation point of view. In addition, the brain d-serine levels of normal mice determined using this method were the same as those obtained by a standard addition method, which is time-consuming but is often used for the accurate measurement of endogenous substances. Thus, this surrogate analyte method should be applicable to the measurement of d-serine levels as a potential biomarker for monitoring certain effects of drug candidates on the central nervous system. Copyright © 2012 Elsevier Inc. All rights reserved.

Challenges of advanced hepatocellular carcinoma

PubMed Central

Colagrande, Stefano; Inghilesi, Andrea L; Aburas, Sami; Taliani, Gian G; Nardi, Cosimo; Marra, Fabio

2016-01-01

Hepatocellular carcinoma (HCC) is an aggressive malignancy, resulting as the third cause of death by cancer each year. The management of patients with HCC is complex, as both the tumour stage and any underlying liver disease must be considered conjointly. Although surveillance by imaging, clinical and biochemical parameters is routinely performed, a lot of patients suffering from cirrhosis have an advanced stage HCC at the first diagnosis. Advanced stage HCC includes heterogeneous groups of patients with different clinical condition and radiological features and sorafenib is the only approved treatment according to Barcelona Clinic Liver Cancer. Since the introduction of sorafenib in clinical practice, several phase III clinical trials have failed to demonstrate any superiority over sorafenib in the frontline setting. Loco-regional therapies have also been tested as first line treatment, but their role in advanced HCC is still matter of debate. No single agent or combination therapies have been shown to impact outcomes after sorafenib failure. Therefore this review will focus on the range of experimental therapeutics for patients with advanced HCC and highlights the successes and failures of these treatments as well as areas for future development. Specifics such as dose limiting toxicity and safety profile in patients with liver dysfunction related to the underlying chronic liver disease should be considered when developing therapies in HCC. Finally, robust validated and reproducible surrogate end-points as well as predictive biomarkers should be defined in future randomized trials. PMID:27678348

Validation of a deformable MRI to CT registration algorithm employing same day planning MRI for surrogate analysis.

PubMed

Padgett, Kyle R; Stoyanova, Radka; Pirozzi, Sara; Johnson, Perry; Piper, Jon; Dogan, Nesrin; Pollack, Alan

2018-03-01

Validating deformable multimodality image registrations is challenging due to intrinsic differences in signal characteristics and their spatial intensity distributions. Evaluating multimodality registrations using these spatial intensity distributions is also complicated by the fact that these metrics are often employed in the registration optimization process. This work evaluates rigid and deformable image registrations of the prostate in between diagnostic-MRI and radiation treatment planning-CT by utilizing a planning-MRI after fiducial marker placement as a surrogate. The surrogate allows for the direct quantitative analysis that can be difficult in the multimodality domain. For thirteen prostate patients, T2 images were acquired at two different time points, the first several weeks prior to planning (diagnostic-MRI) and the second on the same day as the planning-CT (planning-MRI). The diagnostic-MRI was deformed to the planning-CT utilizing a commercially available algorithm which synthesizes a deformable image registration (DIR) algorithm from local rigid registrations. The planning-MRI provided an independent surrogate for the planning-CT for assessing registration accuracy using image similarity metrics, including Pearson correlation and normalized mutual information (NMI). A local analysis was performed by looking only within the prostate, proximal seminal vesicles, penile bulb, and combined areas. The planning-MRI provided an excellent surrogate for the planning-CT with residual error in fiducial alignment between the two datasets being submillimeter, 0.78 mm. DIR was superior to the rigid registration in 11 of 13 cases demonstrating a 27.37% improvement in NMI (P < 0.009) within a regional area surrounding the prostate and associated critical organs. Pearson correlations showed similar results, demonstrating a 13.02% improvement (P < 0.013). By utilizing the planning-MRI as a surrogate for the planning-CT, an independent evaluation of registration accuracy is possible. This population provides an ideal testing ground for MRI to CT DIR by obviating the need for multimodality comparisons which are inherently more challenging. © 2018 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

Surrogate analyte approach for quantitation of endogenous NAD(+) in human acidified blood samples using liquid chromatography coupled with electrospray ionization tandem mass spectrometry.

PubMed

Liu, Liling; Cui, Zhiyi; Deng, Yuzhong; Dean, Brian; Hop, Cornelis E C A; Liang, Xiaorong

2016-02-01

A high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) assay for the quantitative determination of NAD(+) in human whole blood using a surrogate analyte approach was developed and validated. Human whole blood was acidified using 0.5N perchloric acid at a ratio of 1:3 (v:v, blood:perchloric acid) during sample collection. 25μL of acidified blood was extracted using a protein precipitation method and the resulting extracts were analyzed using reverse-phase chromatography and positive electrospray ionization mass spectrometry. (13)C5-NAD(+) was used as the surrogate analyte for authentic analyte, NAD(+). The standard curve ranging from 0.250 to 25.0μg/mL in acidified human blood for (13)C5-NAD(+) was fitted to a 1/x(2) weighted linear regression model. The LC-MS/MS response between surrogate analyte and authentic analyte at the same concentration was obtained before and after the batch run. This response factor was not applied when determining the NAD(+) concentration from the (13)C5-NAD(+) standard curve since the percent difference was less than 5%. The precision and accuracy of the LC-MS/MS assay based on the five analytical QC levels were well within the acceptance criteria from both FDA and EMA guidance for bioanalytical method validation. Average extraction recovery of (13)C5-NAD(+) was 94.6% across the curve range. Matrix factor was 0.99 for both high and low QC indicating minimal ion suppression or enhancement. The validated assay was used to measure the baseline level of NAD(+) in 29 male and 21 female human subjects. This assay was also used to study the circadian effect of endogenous level of NAD(+) in 10 human subjects. Copyright © 2015 Elsevier B.V. All rights reserved.

Evaluation of Overall Response Rate and Progression-Free Survival as Potential Surrogate Endpoints for Overall Survival in Immunotherapy Trials.

PubMed

Mushti, Sirisha L; Mulkey, Flora; Sridhara, Rajeshwari

2018-05-15

Purpose: With the approval of immunotherapies for a variety of indications, methods to assess treatment benefit addressing the response patterns observed are important. We evaluated RECIST criteria-based overall response rate (ORR) and progression-free survival (PFS) as potential surrogate endpoints of overall survival (OS), and explored a modified definition of PFS by altering the threshold percentage determining disease progression to assess the association with survival benefit in immunotherapy trials. Experimental Design: Thirteen randomized, multicenter, active-control trials containing immunotherapeutic agents submitted to the FDA were analyzed. Associations between treatment effects of ORR, PFS, modified PFS, and OS were evaluated at individual and trial levels. Patient-level responder analysis was performed for PFS and OS. Results: The coefficient of determination ( R ²) measured the strength of associations, where values near 1 imply surrogacy and values close to 0 suggest no association. At the trial level, the association between hazard ratios (HR) of PFS and OS was R 2 = 0.1303, and between the odds ratio (OR) of ORR and HR of OS was R 2 = 0.1277. At the individual level, the Spearman rank correlation coefficient between PFS and OS was 0.61. Trial-level associations between modified PFS and OS ranged between 0.07 and 0.1, and individual-level correlations were approximately 0.6. HRs of PFS and OS for responders versus nonresponders were 0.129 [95% confidence interval (CI), 0.11-0.15] and 0.118 (95% CI, 0.11-0.13), respectively. Conclusions: Although responders exhibited longer survival and PFS than nonresponders, the trial-level and individual-level associations were weak between PFS/ORR and OS. Modifications to PFS did not improve associations. Clin Cancer Res; 24(10); 2268-75. ©2018 AACR See related commentary by Korn and Freidlin, p. 2239 . ©2018 American Association for Cancer Research.

Unlocking the relationship of biotic integrity of impaired waters to anthropogenic stresses.

PubMed

Novotny, Vladimir; Bartosová, Alena; O'Reilly, Neal; Ehlinger, Timothy

2005-01-01

The Clean Water Act expressed its goals in terms of restoring and preserving the physical, chemical and biological integrity of the Nation's waters. Integrity has been defined as the ability of the water body's ecological system to support and maintain a balanced integrated, adaptive community of organisms comparable to that of a natural biota of the region. Several indices of biotic integrity (IBIs) have been developed to measure quantitatively the biotic composition and, hence, the integrity. Integrity can be impaired by discharges of pollutants from point and nonpoint sources and by other pollution-related to watershed/landscape and channel stresses, including channel and riparian zone modifications and habitat impairment. Various models that link the stressors to the biotic assessment endpoints, i.e., the IBIs, have been presented and discussed. Simple models that link IBIs directly to single or multiple surrogate stressors such as percent imperviousness are inadequate because they may not represent a true cause-effect proximate relationship. Furthermore, some surrogate landscape parameters are irreversible and the relationships cannot be used for development of plans for restoration of the water body integrity. A concept of a layered hierarchical model that will link the watershed, landscape and stream morphology pollution stressors to the biotic assessment endpoints (IBIs) is described. The key groups of structural components of the model are: IBIs and their metrics in the top layer, chemical water and sediment risks and a habitat quality index in the layer below, in-stream concentrations in water and sediments and channel/habitat impairment parameters in the third layer, and watershed/landscaper pollution generating stressors, land use change rates, and hydrology in the lowest layer of stressors. A modified and expanded Maximum Species Richness concept is developed and used to reveal quantitatively the functional relationships between the top two layers of the structural components and parameters of the model.

Systemic, Local, and Imaging Biomarkers of Brain Injury: More Needed, and Better Use of Those Already Established?

PubMed Central

Carpenter, Keri L. H.; Czosnyka, Marek; Jalloh, Ibrahim; Newcombe, Virginia F. J.; Helmy, Adel; Shannon, Richard J.; Budohoski, Karol P.; Kolias, Angelos G.; Kirkpatrick, Peter J.; Carpenter, Thomas Adrian; Menon, David K.; Hutchinson, Peter J.

2015-01-01

Much progress has been made over the past two decades in the treatment of severe acute brain injury, including traumatic brain injury and subarachnoid hemorrhage, resulting in a higher proportion of patients surviving with better outcomes. This has arisen from a combination of factors. These include improvements in procedures at the scene (pre-hospital) and in the hospital emergency department, advances in neuromonitoring in the intensive care unit, both continuously at the bedside and intermittently in scans, evolution and refinement of protocol-driven therapy for better management of patients, and advances in surgical procedures and rehabilitation. Nevertheless, many patients still experience varying degrees of long-term disabilities post-injury with consequent demands on carers and resources, and there is room for improvement. Biomarkers are a key aspect of neuromonitoring. A broad definition of a biomarker is any observable feature that can be used to inform on the state of the patient, e.g., a molecular species, a feature on a scan, or a monitoring characteristic, e.g., cerebrovascular pressure reactivity index. Biomarkers are usually quantitative measures, which can be utilized in diagnosis and monitoring of response to treatment. They are thus crucial to the development of therapies and may be utilized as surrogate endpoints in Phase II clinical trials. To date, there is no specific drug treatment for acute brain injury, and many seemingly promising agents emerging from pre-clinical animal models have failed in clinical trials. Large Phase III studies of clinical outcomes are costly, consuming time and resources. It is therefore important that adequate Phase II clinical studies with informative surrogate endpoints are performed employing appropriate biomarkers. In this article, we review some of the available systemic, local, and imaging biomarkers and technologies relevant in acute brain injury patients, and highlight gaps in the current state of knowledge. PMID:25741315

Validity of body mass index as a measurement of adiposity in infancy

USDA-ARS?s Scientific Manuscript database

To assess the validity of body mass index (BMI) and age- and sex-standardized BMI z-score (BMIZ) as surrogates for adiposity (body fat percentage [BF%], fat mass, and fat mass index [kg/m2]) at 3 time points in infancy (1, 4, and 7 months) and to assess the extent to which the change in BMIZ represe...

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

Ratkiewicz, A.; Cizewski, J.A.; Pain, S.D.

The r-process is responsible for creating roughly half of the elements heavier than iron. It has recently become understood that the rates at which neutron capture reactions proceed at late times in the r-process may dramatically affect the final abundance pattern. However, direct measurements of neutron capture reaction rates on exotic nuclei are exceptionally difficult, necessitating the development of indirect approaches such as the surrogate technique. The (d,pγ) reaction at low energies was identified as a promising surrogate for the (n,γ) reaction, as both reactions share many characteristics. We report on a program to validate (d,pγ) as a surrogate formore » (n,γ) using 95Mo as a target. The experimental campaign includes direct measurements of the γ-ray intensities from the decay of excited states populated in the 95Mo(n,γ) and 95Mo(d,pγ) reactions.« less

Downstage migration after neoadjuvant chemoradiotherapy for rectal cancer: the reverse of the Will Rogers phenomenon?

PubMed

Fokas, Emmanouil; Liersch, Torsten; Fietkau, Rainer; Hohenberger, Werner; Hess, Clemens; Becker, Heinz; Sauer, Rolf; Wittekind, Christian; Rödel, Claus

2015-06-01

Downstaging after neoadjuvant treatment is increasingly used as a prognostic factor and surrogate endpoint in clinical trials. However, in recent trials of neoadjuvant 5-fluorouracil-based chemoradiotherapy for rectal cancer, downstaging did not translate into a benefit with regard to either disease-free survival (DFS) or overall survival. By analyzing the 10-year outcome data of the German CAO/ARO/AIO-94 phase 3 trial, the authors demonstrated that significantly fewer patients had poor prognostic features (eg, ypT3-4, ypN1-2) after preoperative 5-fluorouracil-based chemoradiotherapy. Nevertheless, these patients with International Union for Cancer Control stage II disease were found to be at a higher risk of developing distant metastases and had poorer DFS compared with patients with corresponding TNM tumor (sub)groups in the postoperative treatment arm, whereas patients with International Union for Cancer Control stage III disease demonstrated a nonsignificant trend toward a worse outcome after preoperative treatment. Overall, DFS remained identical in both treatment arms. Thus, "downstage migration" after neoadjuvant treatment resembles the reverse of the Will Rogers phenomenon and therefore may not be a reliable endpoint for long-term outcomes. © 2015 American Cancer Society.

Meta-analysis of randomized clinical trials in the era of individual patient data sharing.

PubMed

Kawahara, Takuya; Fukuda, Musashi; Oba, Koji; Sakamoto, Junichi; Buyse, Marc

2018-06-01

Individual patient data (IPD) meta-analysis is considered to be a gold standard when the results of several randomized trials are combined. Recent initiatives on sharing IPD from clinical trials offer unprecedented opportunities for using such data in IPD meta-analyses. First, we discuss the evidence generated and the benefits obtained by a long-established prospective IPD meta-analysis in early breast cancer. Next, we discuss a data-sharing system that has been adopted by several pharmaceutical sponsors. We review a number of retrospective IPD meta-analyses that have already been proposed using this data-sharing system. Finally, we discuss the role of data sharing in IPD meta-analysis in the future. Treatment effects can be more reliably estimated in both types of IPD meta-analyses than with summary statistics extracted from published papers. Specifically, with rich covariate information available on each patient, prognostic and predictive factors can be identified or confirmed. Also, when several endpoints are available, surrogate endpoints can be assessed statistically. Although there are difficulties in conducting, analyzing, and interpreting retrospective IPD meta-analysis utilizing the currently available data-sharing systems, data sharing will play an important role in IPD meta-analysis in the future.

Exposure assessment in investigations of waterborne illness: a quantitative estimate of measurement error

PubMed Central

Jones, Andria Q; Dewey, Catherine E; Doré, Kathryn; Majowicz, Shannon E; McEwen, Scott A; Waltner-Toews, David

2006-01-01

Background Exposure assessment is typically the greatest weakness of epidemiologic studies of disinfection by-products (DBPs) in drinking water, which largely stems from the difficulty in obtaining accurate data on individual-level water consumption patterns and activity. Thus, surrogate measures for such waterborne exposures are commonly used. Little attention however, has been directed towards formal validation of these measures. Methods We conducted a study in the City of Hamilton, Ontario (Canada) in 2001–2002, to assess the accuracy of two surrogate measures of home water source: (a) urban/rural status as assigned using residential postal codes, and (b) mapping of residential postal codes to municipal water systems within a Geographic Information System (GIS). We then assessed the accuracy of a commonly-used surrogate measure of an individual's actual drinking water source, namely, their home water source. Results The surrogates for home water source provided good classification of residents served by municipal water systems (approximately 98% predictive value), but did not perform well in classifying those served by private water systems (average: 63.5% predictive value). More importantly, we found that home water source was a poor surrogate measure of the individuals' actual drinking water source(s), being associated with high misclassification errors. Conclusion This study demonstrated substantial misclassification errors associated with a surrogate measure commonly used in studies of drinking water disinfection byproducts. Further, the limited accuracy of two surrogate measures of an individual's home water source heeds caution in their use in exposure classification methodology. While these surrogates are inexpensive and convenient, they should not be substituted for direct collection of accurate data pertaining to the subjects' waterborne disease exposure. In instances where such surrogates must be used, estimation of the misclassification and its subsequent effects are recommended for the interpretation and communication of results. Our results also lend support for further investigation into the quantification of the exposure misclassification associated with these surrogate measures, which would provide useful estimates for consideration in interpretation of waterborne disease studies. PMID:16729887

Carotid Plaque Lipid Content and Fibrous Cap Status Predict Systemic CV Outcomes: The MRI Substudy in AIM-HIGH.

PubMed

Sun, Jie; Zhao, Xue-Qiao; Balu, Niranjan; Neradilek, Moni B; Isquith, Daniel A; Yamada, Kiyofumi; Cantón, Gádor; Crouse, John R; Anderson, Todd J; Huston, John; O'Brien, Kevin; Hippe, Daniel S; Polissar, Nayak L; Yuan, Chun; Hatsukami, Thomas S

2017-03-01

The aim of this study was to investigate whether and what carotid plaque characteristics predict systemic cardiovascular outcomes in patients with clinically established atherosclerotic disease. Advancements in atherosclerosis imaging have allowed assessment of various plaque characteristics, some of which are more directly linked to the pathogenesis of acute cardiovascular events compared to plaque burden. As part of the event-driven clinical trial AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes), subjects with clinically established atherosclerotic disease underwent multicontrast carotid magnetic resonance imaging (MRI) to detect plaque tissue composition and high-risk features. Prospective associations between MRI measurements and the AIM-HIGH primary endpoint (fatal and nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, and symptom-driven revascularization) were analyzed using Cox proportional hazards survival models. Of the 232 subjects recruited, 214 (92.2%) with diagnostic image quality constituted the study population (82% male, mean age 61 ± 9 years, 94% statin use). During median follow-up of 35.1 months, 18 subjects (8.4%) reached the AIM-HIGH endpoint. High lipid content (hazard ratio [HR] per 1 SD increase in percent lipid core volume: 1.57; p = 0.002) and thin/ruptured fibrous cap (HR: 4.31; p = 0.003) in carotid plaques were strongly associated with the AIM-HIGH endpoint. Intraplaque hemorrhage had a low prevalence (8%) and was marginally associated with the AIM-HIGH endpoint (HR: 3.00; p = 0.053). High calcification content (HR per 1 SD increase in percent calcification volume: 0.66; p = 0.20), plaque burden metrics, and clinical risk factors were not significantly associated with the AIM-HIGH endpoint. The associations between carotid plaque characteristics and the AIM-HIGH endpoint changed little after adjusting for clinical risk factors, plaque burden, or AIM-HIGH randomized treatment assignment. Among patients with clinically established atherosclerotic disease, carotid plaque lipid content and fibrous cap status were strongly associated with systemic cardiovascular outcomes. Markers of carotid plaque vulnerability may serve as novel surrogate markers for systemic atherothrombotic risk. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

An urban observatory for quantifying phosphorus and suspended solid loads in combined natural and stormwater conveyances.

PubMed

Melcher, Anthony A; Horsburgh, Jeffery S

2017-06-01

Water quality in urban streams and stormwater systems is highly dynamic, both spatially and temporally, and can change drastically during storm events. Infrequent grab samples commonly collected for estimating pollutant loadings are insufficient to characterize water quality in many urban water systems. In situ water quality measurements are being used as surrogates for continuous pollutant load estimates; however, relatively few studies have tested the validity of surrogate indicators in urban stormwater conveyances. In this paper, we describe an observatory aimed at demonstrating the infrastructure required for surrogate monitoring in urban water systems and for capturing the dynamic behavior of stormwater-driven pollutant loads. We describe the instrumentation of multiple, autonomous water quality and quantity monitoring sites within an urban observatory. We also describe smart and adaptive sampling procedures implemented to improve data collection for developing surrogate relationships and for capturing the temporal and spatial variability of pollutant loading events in urban watersheds. Results show that the observatory is able to capture short-duration storm events within multiple catchments and, through inter-site communication, sampling efforts can be synchronized across multiple monitoring sites.

Partnership for Edge Physics (EPSI), University of Texas Final Report

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

Moser, Robert; Carey, Varis; Michoski, Craig

Simulations of tokamak plasmas require a number of inputs whose values are uncertain. The effects of these input uncertainties on the reliability of model predictions is of great importance when validating predictions by comparison to experimental observations, and when using the predictions for design and operation of devices. However, high fidelity simulation of tokamak plasmas, particular those aimed at characterization of the edge plasma physics, are computationally expensive, so lower cost surrogates are required to enable practical uncertainty estimates. Two surrogate modeling techniques have been explored in the context of tokamak plasma simulations using the XGC family of plasma simulationmore » codes. The first is a response surface surrogate, and the second is an augmented surrogate relying on scenario extrapolation. In addition, to reduce the costs of the XGC simulations, a particle resampling algorithm was developed, which allows marker particle distributions to be adjusted to maintain optimal importance sampling. This means that the total number of particles in and therefore the cost of a simulation can be reduced while maintaining the same accuracy.« less

Mimicking Retention and Transport of Rotavirus and Adenovirus in Sand Media Using DNA-labeled, Protein-coated Silica Nanoparticles

NASA Astrophysics Data System (ADS)

Pang, Liping; Farkas, Kata; Bennett, Grant; Varsani, Arvind; Easingwood, Richard; Tilley, Richard; Nowostawska, Urszula; Lin, Susan

2014-05-01

Rotavirus (RoV) and adenovirus (AdV) are important viral pathogens for the risk analysis of drinking water. Despite this, little is known about their retention and transport behaviors in porous media (e.g. sand filtered used for water treatment and groundwater aquifers due to a lack of representative surrogates. In this study, we developed RoV and AdV surrogates by covalently coating 70-nm sized silica nanoparticles with specific proteins and a DNA marker for sensitive detection. Filtration experiments using beach sand columns demonstrated the similarity of the surrogates' concentrations, attachment, and filtration efficiencies to the target viruses. The surrogates showed the same magnitude of concentration reduction as the viruses. Conversely, MS2 phage (a traditional virus model) over predicted concentrations of AdV and RoV by 1- and 2-orders of magnitude, respectively. The surrogates remained stable in size, surface charge and DNA concentration for at least one year. They can be easily and rapidly detected at concentrations down to one particle per PCR reaction and are readily detectable in natural waters and even in effluent. With up-scaling validation in pilot trials, the surrogates can be a useful cost-effective new tool for studying virus retention and transport in porous media, e.g. for assessing filter efficiency in water and wastewater treatment, tracking virus migration in groundwater after effluent land disposal, and establishing safe setback distances for groundwater protection.

Recommendations for the development of rare disease drugs using the accelerated approval pathway and for qualifying biomarkers as primary endpoints.

PubMed

Kakkis, Emil D; O'Donovan, Mary; Cox, Gerald; Hayes, Mark; Goodsaid, Federico; Tandon, P K; Furlong, Pat; Boynton, Susan; Bozic, Mladen; Orfali, May; Thornton, Mark

2015-02-10

For rare serious and life-threatening disorders, there is a tremendous challenge of transforming scientific discoveries into new drug treatments. This challenge has been recognized by all stakeholders who endorse the need for flexibility in the regulatory review process for novel therapeutics to treat rare diseases. In the United States, the best expression of this flexibility was the creation of the Accelerated Approval (AA) pathway. The AA pathway is critically important for the development of treatments for diseases with high unmet medical need and has been used extensively for drugs used to treat cancer and infectious diseases like HIV.In 2012, the AA provisions were amended to enhance the application of the AA pathway to expedite the development of drugs for rare disorders under the Food and Drug Administration Safety and Innovation Act (FDASIA). FDASIA, among many provisions, requires the development of a more relevant FDA guidance on the types of evidence that may be acceptable in support of using a novel surrogate endpoint. The application of AA to rare diseases requires more predictability to drive greater access to appropriate use of AA for more rare disease treatments that might not be developed otherwise.This white paper proposes a scientific framework for assessing biomarker endpoints to enhance the development of novel therapeutics for rare and devastating diseases currently without adequate treatment and is based on the opinions of experts in drug development and rare disease patient groups. Specific recommendations include: 1) Establishing regulatory rationale for increased AA access in rare disease programs; 2) Implementing a Biomarker Qualification Request Process to provide the opportunity for an early determination of biomarker acceptance; and 3) A proposed scientific framework for qualifying biomarkers as primary endpoints. The paper's final section highlights case studies of successful examples that have incorporated biomarker endpoints into FDA approvals for rare disease therapies. The focus of this paper is on the situation in the Unites States, but the recommendations are reasonably applicable to any jurisdiction.

Validation of intracranial area as a surrogate measure of intracranial volume when using clinical MRI.

PubMed

Nandigam, R N Kaveer; Chen, Yu-Wei; Gurol, Mahmut E; Rosand, Jonathan; Greenberg, Steven M; Smith, Eric E

2007-01-01

We sought to determine whether mid-sagittal intracranial area (ICA) is a valid surrogate of intracranial volume (ICV) when using retrospective data with relatively thick (6-7 mm) sagittal slices. Data were retrospectively analyzed from 47 subjects who had two MRI scans taken at least nine months apart. Twenty-three subjects had manual segmentation of ICV on the T2-weighted sequence for comparison. Intraclass correlation coefficient (ICC) for intraobserver, interobserver, and intraobserver scan-rescan comparisons were 0.96, 0.97 and 0.95. Pearson correlation coefficients between ICV and ICA, averaging the cumulative 1, 2, 3, and 4 most midline slices, were 0.89, 0.94, 0.93, and 0.95. There was a significant marginal increase in explained variance of ICV by measuring two, rather than one, slices (P= 0.001). These data suggest that ICA, even measured without high-resolution imaging, is a reasonable substitute for ICV.

The Inverse Benefit Law: How Drug Marketing Undermines Patient Safety and Public Health

PubMed Central

Light, Donald W.

2011-01-01

Recent highly publicized withdrawals of drugs from the market because of safety concerns raise the question of whether these events are random failures or part of a recurring pattern. The inverse benefit law, inspired by Hart's inverse care law, states that the ratio of benefits to harms among patients taking new drugs tends to vary inversely with how extensively the drugs are marketed. The law is manifested through 6 basic marketing strategies: reducing thresholds for diagnosing disease, relying on surrogate endpoints, exaggerating safety claims, exaggerating efficacy claims, creating new diseases, and encouraging unapproved uses. The inverse benefit law highlights the need for comparative effectiveness research and other reforms to improve evidence-based prescribing. PMID:21233426

Testing for qualitative heterogeneity: An application to composite endpoints in survival analysis.

PubMed

Oulhaj, Abderrahim; El Ghouch, Anouar; Holman, Rury R

2017-01-01

Composite endpoints are frequently used in clinical outcome trials to provide more endpoints, thereby increasing statistical power. A key requirement for a composite endpoint to be meaningful is the absence of the so-called qualitative heterogeneity to ensure a valid overall interpretation of any treatment effect identified. Qualitative heterogeneity occurs when individual components of a composite endpoint exhibit differences in the direction of a treatment effect. In this paper, we develop a general statistical method to test for qualitative heterogeneity, that is to test whether a given set of parameters share the same sign. This method is based on the intersection-union principle and, provided that the sample size is large, is valid whatever the model used for parameters estimation. We propose two versions of our testing procedure, one based on a random sampling from a Gaussian distribution and another version based on bootstrapping. Our work covers both the case of completely observed data and the case where some observations are censored which is an important issue in many clinical trials. We evaluated the size and power of our proposed tests by carrying out some extensive Monte Carlo simulations in the case of multivariate time to event data. The simulations were designed under a variety of conditions on dimensionality, censoring rate, sample size and correlation structure. Our testing procedure showed very good performances in terms of statistical power and type I error. The proposed test was applied to a data set from a single-center, randomized, double-blind controlled trial in the area of Alzheimer's disease.

Evaluating the Efficacy of Three U.S. Department of Agriculture-Approved Antimicrobial Sprays for Reducing Shiga Toxin-Producing Escherichia coli Surrogate Populations on Bob Veal Carcasses.

PubMed

2016-06-01

Effective antimicrobial intervention strategies to reduce Shiga toxin-producing Escherichia coli (STEC) risks associated with veal are needed. This study evaluated the efficacy of lactic acid (4.5%, pH 2.0), Citrilow (pH 1.2), and Beefxide (2.25%, pH 2.3) for reducing STEC surrogates on prerigor and chilled bob veal carcasses and monitored the effects of these interventions on chilled carcass color. Dehided bob veal carcasses were inoculated with a five-strain cocktail of rifampin-resistant, surrogate E. coli bacteria.E. coli surrogates were enumerated after inoculation, after water wash, after prechill carcass antimicrobial spray application, after chilling for 24 h, and after postchill carcass antimicrobial spray application; carcass color was measured throughout the process. A standard carcass water wash (∼50°C) reduced the STEC surrogate population by 0.9 log CFU/cm(2) (P ≤ 0.05). All three antimicrobial sprays applied to prerigor carcasses delivered an additional ∼0.5-log reduction (P ≤ 0.05) of the surrogates. Chilling of carcasses for 24 h reduced (P ≤ 0.05) the surrogate population by an additional ∼0.4 log cycles. The postchill application of the antimicrobial sprays provided no further reductions. Carcass L*, a*, and b* color values were not different (P > 0.05) among carcass treatments. Generally, the types and concentrations of the antimicrobial sprays evaluated herein did not negatively impact visual or instrumental color of chilled veal carcasses. This study demonstrates that warm water washing, followed by a prechill spray treatment with a low-pH chemical intervention, can effectively reduce STEC risks associated with veal carcasses; this provides processors a validated control point in slaughter operations.

Surrogate Model Application to the Identification of Optimal Groundwater Exploitation Scheme Based on Regression Kriging Method—A Case Study of Western Jilin Province

PubMed Central

An, Yongkai; Lu, Wenxi; Cheng, Weiguo

2015-01-01

This paper introduces a surrogate model to identify an optimal exploitation scheme, while the western Jilin province was selected as the study area. A numerical simulation model of groundwater flow was established first, and four exploitation wells were set in the Tongyu county and Qian Gorlos county respectively so as to supply water to Daan county. Second, the Latin Hypercube Sampling (LHS) method was used to collect data in the feasible region for input variables. A surrogate model of the numerical simulation model of groundwater flow was developed using the regression kriging method. An optimization model was established to search an optimal groundwater exploitation scheme using the minimum average drawdown of groundwater table and the minimum cost of groundwater exploitation as multi-objective functions. Finally, the surrogate model was invoked by the optimization model in the process of solving the optimization problem. Results show that the relative error and root mean square error of the groundwater table drawdown between the simulation model and the surrogate model for 10 validation samples are both lower than 5%, which is a high approximation accuracy. The contrast between the surrogate-based simulation optimization model and the conventional simulation optimization model for solving the same optimization problem, shows the former only needs 5.5 hours, and the latter needs 25 days. The above results indicate that the surrogate model developed in this study could not only considerably reduce the computational burden of the simulation optimization process, but also maintain high computational accuracy. This can thus provide an effective method for identifying an optimal groundwater exploitation scheme quickly and accurately. PMID:26264008

Surrogate biochemical markers: precise measurement for strategic drug and biologics development.

PubMed

Lee, J W; Hulse, J D; Colburn, W A

1995-05-01

More efficient drug and biologics development is necessary for future success of pharmaceutical and biotechnology companies. One way to achieve this objective is to use rationally selected surrogate markers to improve the early decision-making process. Using typical clinical chemistry methods to measure biochemical markers may not ensure adequate precision and reproducibility. In contrast, using analytical methods that meet good laboratory practices along with rational selection and validation of biochemical markers can give those who use them a competitive advantage over those who do not by providing meaningful data for earlier decision making.

An European inter-laboratory validation of alternative endpoints of the murine local lymph node assay: 2nd round.

PubMed

Ehling, G; Hecht, M; Heusener, A; Huesler, J; Gamer, A O; van Loveren, H; Maurer, Th; Riecke, K; Ullmann, L; Ulrich, P; Vandebriel, R; Vohr, H-W

2005-08-15

The original local lymph node assay (LLNA) is based on the use of radioactive labelling to measure cell proliferation. Other endpoints for the assessment of proliferation are also authorized by the OECD Guideline 429 provided there is appropriate scientific support, including full citations and description of the methodology (OECD, 2002. OECD Guideline for the Testing of Chemicals; Skin Sensitization: Local Lymph Node Assay, Guideline 429. Paris, adopted 24th April 2002.). Here, we describe the outcome of the second round of an inter-laboratory validation of alternative endpoints in the LLNA conducted in nine laboratories in Europe. The validation study was managed and supervised by the Swiss Agency for Therapeutic Products (Swissmedic) in Bern. Ear-draining lymph node (LN) weight and cell counts were used to assess LN cell proliferation instead of [3H]TdR incorporation. In addition, the acute inflammatory skin reaction was measured by ear weight determination of circular biopsies of the ears to identify skin irritation properties of the test items. The statistical analysis was performed in the department of statistics at the university of Bern. Similar to the EC(3) values defined for the radioactive method, threshold values were calculated for the endpoints measured in this modification of the LLNA. It was concluded that all parameters measured have to be taken into consideration for the categorisation of compounds due to their sensitising potencies. Therefore, an assessment scheme has been developed which turned out to be of great importance to consistently assess sensitisation versus irritancy based on the data of the different parameters. In contrast to the radioactive method, irritants have been picked up by all the laboratories applying this assessment scheme.

An European inter-laboratory validation of alternative endpoints of the murine local lymph node assay: first round.

PubMed

Ehling, G; Hecht, M; Heusener, A; Huesler, J; Gamer, A O; van Loveren, H; Maurer, Th; Riecke, K; Ullmann, L; Ulrich, P; Vandebriel, R; Vohr, H-W

2005-08-15

The new OECD guideline 429 (skin sensitization: local lymph node assay) is based upon a protocol, which utilises the incorporation of radioactivity into DNA as a measure for cell proliferation in vivo. The guideline also enables the use of alternative endpoints in order to assess draining lymph node (LN) cell proliferation. Here we describe the first round of an inter-laboratory validation of alternative endpoints in the LLNA conducted in seven laboratories. The validation study was managed and supervised by the Swiss Agency for Therapeutic Products, Swissmedic. Statistical analyses of all data were performed by an independent centre at the University of Bern, Department of Statistics. Ear-draining, LN weight and cell count were used to assess proliferation instead of radioactive labeling of lymph node cells. In addition, the acute inflammatory skin reaction was measured by ear swelling and weight of circular biopsies of the ears to identify skin irritating properties of the test items. Hexylcinnamaldehyde (HCA) and three blinded test items were applied to female, 8--10 weeks old NMRI and BALB/c mice. Results were sent via the independent study coordinator to the statistician. The results of this first round showed that the alternative endpoints of the LLNA are sensitive and robust parameters. The use of ear weights added an important parameter assessing the skin irritation potential, which supports the differentiation of pure irritative from contact allergenic potential. There were absolute no discrepancies between the categorisation of the three test substances A--C determined by each single participating laboratories. The results highlighted also that many parameters do have an impact on the strength of the responses. Therefore, such parameters have to be taken into consideration for the categorisation of compounds due to their relative sensitizing potencies.

Human neuron-astrocyte 3D co-culture-based assay for evaluation of neuroprotective compounds.

PubMed

Terrasso, Ana Paula; Silva, Ana Carina; Filipe, Augusto; Pedroso, Pedro; Ferreira, Ana Lúcia; Alves, Paula Marques; Brito, Catarina

Central nervous system drug development has registered high attrition rates, mainly due to the lack of efficacy of drug candidates, highlighting the low reliability of the models used in early-stage drug development and the need for new in vitro human cell-based models and assays to accurately identify and validate drug candidates. 3D human cell models can include different tissue cell types and represent the spatiotemporal context of the original tissue (co-cultures), allowing the establishment of biologically-relevant cell-cell and cell-extracellular matrix interactions. Nevertheless, exploitation of these 3D models for neuroprotection assessment has been limited due to the lack of data to validate such 3D co-culture approaches. In this work we combined a 3D human neuron-astrocyte co-culture with a cell viability endpoint for the implementation of a novel in vitro neuroprotection assay, over an oxidative insult. Neuroprotection assay robustness and specificity, and the applicability of Presto Blue, MTT and CytoTox-Glo viability assays to the 3D co-culture were evaluated. Presto Blue was the adequate endpoint as it is non-destructive and is a simpler and reliable assay. Semi-automation of the cell viability endpoint was performed, indicating that the assay setup is amenable to be transferred to automated screening platforms. Finally, the neuroprotection assay setup was applied to a series of 36 test compounds and several candidates with higher neuroprotective effect than the positive control, Idebenone, were identified. The robustness and simplicity of the implemented neuroprotection assay with the cell viability endpoint enables the use of more complex and reliable 3D in vitro cell models to identify and validate drug candidates. Copyright © 2016 Elsevier Inc. All rights reserved.

Improving medical decisions for incapacitated persons: does focusing on "accurate predictions" lead to an inaccurate picture?

PubMed

Kim, Scott Y H

2014-04-01

The Patient Preference Predictor (PPP) proposal places a high priority on the accuracy of predicting patients' preferences and finds the performance of surrogates inadequate. However, the quest to develop a highly accurate, individualized statistical model has significant obstacles. First, it will be impossible to validate the PPP beyond the limit imposed by 60%-80% reliability of people's preferences for future medical decisions--a figure no better than the known average accuracy of surrogates. Second, evidence supports the view that a sizable minority of persons may not even have preferences to predict. Third, many, perhaps most, people express their autonomy just as much by entrusting their loved ones to exercise their judgment than by desiring to specifically control future decisions. Surrogate decision making faces none of these issues and, in fact, it may be more efficient, accurate, and authoritative than is commonly assumed.

Determination of Diethyl Phthalate and Polyhexamethylene Guanidine in Surrogate Alcohol from Russia

PubMed Central

Monakhova, Yulia B.; Kuballa, Thomas; Leitz, Jenny; Lachenmeier, Dirk W.

2011-01-01

Analytical methods based on spectroscopic techniques were developed and validated for the determination of diethyl phthalate (DEP) and polyhexamethylene guanidine (PHMG), which may occur in unrecorded alcohol. Analysis for PHMG was based on UV-VIS spectrophotometry after derivatization with Eosin Y and 1H NMR spectroscopy of the DMSO extract. Analysis of DEP was performed with direct UV-VIS and 1H NMR methods. Multivariate curve resolution and spectra computation methods were used to confirm the presence of PHMG and DEP in the investigated beverages. Of 22 analysed alcohol samples, two contained DEP or PHMG. 1H NMR analysis also revealed the presence of signals of hawthorn extract in three medicinal alcohols used as surrogate alcohol. The simple and cheap UV-VIS methods can be used for rapid screening of surrogate alcohol samples for impurities, while 1H NMR is recommended for specific confirmatory analysis if required. PMID:21647285

Determination of diethyl phthalate and polyhexamethylene guanidine in surrogate alcohol from Russia.

PubMed

Monakhova, Yulia B; Kuballa, Thomas; Leitz, Jenny; Lachenmeier, Dirk W

2011-01-01

Analytical methods based on spectroscopic techniques were developed and validated for the determination of diethyl phthalate (DEP) and polyhexamethylene guanidine (PHMG), which may occur in unrecorded alcohol. Analysis for PHMG was based on UV-VIS spectrophotometry after derivatization with Eosin Y and (1)H NMR spectroscopy of the DMSO extract. Analysis of DEP was performed with direct UV-VIS and (1)H NMR methods. Multivariate curve resolution and spectra computation methods were used to confirm the presence of PHMG and DEP in the investigated beverages. Of 22 analysed alcohol samples, two contained DEP or PHMG. (1)H NMR analysis also revealed the presence of signals of hawthorn extract in three medicinal alcohols used as surrogate alcohol. The simple and cheap UV-VIS methods can be used for rapid screening of surrogate alcohol samples for impurities, while (1)H NMR is recommended for specific confirmatory analysis if required.

Is there a conflicted surrogate syndrome affecting quality of care in nursing homes?

PubMed

Kidder, Samuel W; Smith, David A

2006-03-01

Is there a point at which family complaints about care cease to be constructive and become excessive and counterproductive? Do excessive complaint behaviors represent a "conflicted surrogate syndrome" that is indicative of psychopathology in the family member or family system? Can this psychopathology result in avoidance behavior by the nursing staff sufficient to result in poor care? While many family/resident complaints are valid and should be viewed as constructive there are occasions when excessive complaints by the family of a nursing facility resident are a result of psychiatric illness or psychological problems in the family member(s) or are evidence of an abnormality in the family system. This series of brief case reports is offered to create discussion of what might be termed a "conflicted surrogate syndrome" that may result in avoidance behavior by staff and consequent poor care.

Surrogate measures: A proposed alternative in human factors assessment of operational measures of performance

NASA Technical Reports Server (NTRS)

Kennedy, Robert S.; Lane, Norman E.; Kuntz, Lois A.

1987-01-01

Surrogate measures are proposed as an alternative to direct assessment of operational performance for purposes of screening agents who may have to work under unusual stresses or in exotic environments. Such measures are particularly proposed when the surrogate can be empirically validated against the operational criterion. The focus is on cognitive (or throughput) performances in humans as opposed to sensory (input) or motor (output) measures, but the methods should be applicable for development of batteries which will tap input/output functions. A menu of performance tasks is under development for implementation on a battery-operated portable microcomputer, with 21 tests currently available. The tasks are reliable and become stable in minimum amounts of time; appear sensitive to some agents; comprise constructs related to actual job tasks; and are easily administered in most environments. Implications for human factors engineering studies in environmental stress are discussed.

Assessment of abdominal muscle function using the Biodex System-4. Validity and reliability in healthy volunteers and patients with giant ventral hernia.

PubMed

Gunnarsson, U; Johansson, M; Strigård, K

2011-08-01

The decrease in recurrence rates in ventral hernia surgery have led to a redirection of focus towards other important patient-related endpoints. One such endpoint is abdominal wall function. The aim of the present study was to evaluate the reliability and external validity of abdominal wall strength measurement using the Biodex System-4 with a back abdomen unit. Ten healthy volunteers and ten patients with ventral hernias exceeding 10 cm were recruited. Test-retest reliability, both with and without girdle, was evaluated by comparison of measurements at two test occasions 1 week apart. Reliability was calculated by the interclass correlation coefficients (ICC) method. Validity was evaluated by correlation with the well-established International Physical Activity Questionnaire (IPAQ) and a self-assessment of abdominal wall strength. One person in the healthy group was excluded after the first test due to neck problems following minor trauma. The reliability was excellent (>0.75), with ICC values between 0.92 and 0.97 for the different modalities tested. No differences were seen between testing with and without a girdle. Validity was also excellent both when calculated as correlation to self-assessment of abdominal wall strength, and to IPAQ, giving Kendall tau values of 0.51 and 0.47, respectively, and corresponding P values of 0.002 and 0.004. Measurement of abdominal muscle function using the Biodex System-4 is a reliable and valid method to assess this important patient-related endpoint. Further investigations will be made to explore the potential of this technique in the evaluation of the results of ventral hernia surgery, and to compare muscle function after different abdominal wall reconstruction techniques.

Prospective multicenter randomized intermediate biomarker study of oral contraceptive versus depo-provera for prevention of endometrial cancer in women with Lynch syndrome.

PubMed

Lu, Karen H; Loose, David S; Yates, Melinda S; Nogueras-Gonzalez, Graciela M; Munsell, Mark F; Chen, Lee-May; Lynch, Henry; Cornelison, Terri; Boyd-Rogers, Stephanie; Rubin, Mary; Daniels, Molly S; Conrad, Peggy; Milbourne, Andrea; Gershenson, David M; Broaddus, Russell R

2013-08-01

Women with Lynch syndrome have a 40% to 60% lifetime risk for developing endometrial cancer, a cancer associated with estrogen imbalance. The molecular basis for endometrial-specific tumorigenesis is unclear. Progestins inhibit estrogen-driven proliferation, and epidemiologic studies have shown that progestin-containing oral contraceptives (OCP) reduce the risk of endometrial cancer by 50% in women at general population risk. It is unknown whether they are effective in women with Lynch syndrome. Asymptomatic women ages 25 to 50 with Lynch syndrome were randomized to receive the progestin compounds Depo-Provera (depo-MPA) or OCP for three months. An endometrial biopsy and transvaginal ultrasound were conducted before and after treatment. Endometrial proliferation was evaluated as the primary endpoint. Histology and a panel of surrogate endpoint biomarkers were evaluated for each endometrial biopsy as secondary endpoints. A total of 51 women were enrolled, and 46 completed treatment. Two of the 51 women had complex hyperplasia with atypia at the baseline endometrial biopsy and were excluded from the study. Overall, both depo-MPA and OCP induced a dramatic decrease in endometrial epithelial proliferation and microscopic changes in the endometrium characteristic of progestin action. Transvaginal ultrasound measurement of endometrial stripe was not a useful measure of endometrial response or baseline hyperplasia. These results show that women with Lynch syndrome do show an endometrial response to short-term exogenous progestins, suggesting that OCP and depo-MPA may be reasonable chemopreventive agents in this high-risk patient population.

Prospective, Multi-center Randomized Intermediate Biomarker Study of Oral Contraceptive vs. Depo-Provera for Prevention of Endometrial Cancer in Women with Lynch Syndrome

PubMed Central

Lu, Karen H.; Loose, David S.; Yates, Melinda S.; Nogueras-Gonzalez, Graciela M.; Munsell, Mark F.; Chen, Lee-may; Lynch, Henry; Cornelison, Terri; Boyd-Rogers, Stephanie; Rubin, Mary; Daniels, Molly S.; Conrad, Peggy; Milbourne, Andrea; Gershenson, David M.; Broaddus, Russell R.

2013-01-01

Women with Lynch syndrome have a 40–60% lifetime risk for developing endometrial cancer, a cancer associated with estrogen imbalance. The molecular basis for endometrial-specific tumorigenesis is unclear. Progestins inhibit estrogen-driven proliferation, and epidemiologic studies have demonstrated that progestin-containing oral contraceptives (OCP) reduce the risk of endometrial cancer by 50% in women at general population risk. It is unknown if they are effective in women with Lynch syndrome. Asymptomatic women age 25–50 with Lynch syndrome were randomized to receive the progestin compounds depo-Provera (depoMPA) or OCP for three months. An endometrial biopsy and transvaginal ultrasound were performed before and after treatment. Endometrial proliferation was evaluated as the primary endpoint. Histology and a panel of surrogate endpoint biomarkers were evaluated for each endometrial biopsy as secondary endpoints. A total of 51 women were enrolled, and 46 completed treatment. Two of the 51 women had complex hyperplasia with atypia at the baseline endometrial biopsy and were excluded from the study. Overall, both depoMPA and OCP induced a dramatic decrease in endometrial epithelial proliferation and microscopic changes in the endometrium characteristic of progestin action. Transvaginal ultrasound measurement of endometrial stripe was not a useful measure of endometrial response or baseline hyperplasia. These results demonstrate that women with Lynch syndrome do show an endometrial response to short term exogenous progestins, suggesting that OCP and depoMPA may be reasonable chemopreventive agents in this high-risk patient population. PMID:23639481

Effects of Antibiotics on the Growth and Physiology of Chlorophytes, Cyanobacteria, and a Diatom.

PubMed

Guo, Jiahua; Selby, Katherine; Boxall, Alistair B A

2016-11-01

The occurrence of antibiotics in surface waters has been reported worldwide with concentrations ranging from ng L -1 to low µg L -1 levels. During environmental risk assessments, effects of antibiotics on algal species are assessed using standard test protocols (e.g., the OECD 201 guideline), where the cell number endpoint is used as a surrogate for growth. However, the use of photosynthetic related endpoints, such as oxygen evolution rate, and the assessment of effects on algal pigments could help to inform our understanding of the impacts of antibiotics on algal species. This study explored the effects of three major usage antibiotics (tylosin, lincomycin, and trimethoprim) on the growth and physiology of two chlorophytes (Desmodesmus subspicatus and Pseudokirchneriella subcapitata), a cyanobacteria (Anabaena flos-aquae), and a diatom (Navicula pelliculosa) using a battery of parameters, including cell density, oxygen evolution rate, total chlorophyll content, carotenoids, and the irradiance-photosynthesis relationship. The results indicated that photosynthesis of chlorophytes was a more sensitive endpoint than growth (i.e., EC 50 derived based on the effects of tylosin on the growth of D. subspicatus was 38.27 µmol L -1 compared with an EC 50 of 17.6 µmol L -1 based on photosynthetic rate), but the situation was reversed when testing cyanobacteria and the diatom (i.e., EC 50 derived based on the effects of tylosin on the growth of A. flos-aquae was 0.06 µmol L -1 ; EC 50 0.33 µmol L -1 based on photosynthetic rate). The pigment contents of algal cells were affected by the three antibiotics for D. subspicatus. However, in some cases, pigment content was stimulated for P. subcapitata, N. pelliculosa, and A. flos-aquae. The light utilization efficiency of chlorophytes and diatom was decreased markedly in the presence of antibiotics. The results demonstrated that the integration of these additional endpoints into existing standardised protocols could provide useful insights into the impacts of antibiotics on algal species.

Rationale, application and clinical qualification for NT-proBNP as a surrogate end point in pivotal clinical trials in patients with AL amyloidosis.

PubMed

Merlini, G; Lousada, I; Ando, Y; Dispenzieri, A; Gertz, M A; Grogan, M; Maurer, M S; Sanchorawala, V; Wechalekar, A; Palladini, G; Comenzo, R L

2016-10-01

Amyloid light-chain (LC) amyloidosis (AL amyloidosis) is a rare and fatal disease for which there are no approved therapies. In patients with AL amyloidosis, LC aggregates progressively accumulate in organs, resulting in organ failure that is particularly lethal when the heart is involved. A significant obstacle in the development of treatments for patients with AL amyloidosis, as well as for those with any disease that is rare, severe and heterogeneous, has been satisfying traditional clinical trial end points (for example, overall survival or progression-free survival). It is for this reason that many organizations, including the United States Food and Drug Administration through its Safety and Innovation Act Accelerated Approval pathway, have recognized the need for biomarkers as surrogate end points. The international AL amyloidosis expert community is in agreement that the N-terminal fragment of the pro-brain natriuretic peptide (NT-proBNP) is analytically validated and clinically qualified as a biomarker for use as a surrogate end point for survival in patients with AL amyloidosis. Underlying this consensus is the demonstration that NT-proBNP is an indicator of cardiac response in all interventional studies in which it has been assessed, despite differences in patient population, treatment type and treatment schedule. Furthermore, NT-proBNP expression is directly modulated by amyloidogenic LC-elicited signal transduction pathways in cardiomyocytes. The use of NT-proBNP will greatly facilitate the development of targeted therapies for AL amyloidosis. Here, we review the data supporting the use of NT-proBNP, a biomarker that is analytically validated, clinically qualified, directly modulated by LC and universally accepted by AL amyloidosis specialists, as a surrogate end point for survival.

Rationale, application and clinical qualification for NT-proBNP as a surrogate end point in pivotal clinical trials in patients with AL amyloidosis

PubMed Central

Merlini, G; Lousada, I; Ando, Y; Dispenzieri, A; Gertz, M A; Grogan, M; Maurer, M S; Sanchorawala, V; Wechalekar, A; Palladini, G; Comenzo, R L

2016-01-01

Amyloid light-chain (LC) amyloidosis (AL amyloidosis) is a rare and fatal disease for which there are no approved therapies. In patients with AL amyloidosis, LC aggregates progressively accumulate in organs, resulting in organ failure that is particularly lethal when the heart is involved. A significant obstacle in the development of treatments for patients with AL amyloidosis, as well as for those with any disease that is rare, severe and heterogeneous, has been satisfying traditional clinical trial end points (for example, overall survival or progression-free survival). It is for this reason that many organizations, including the United States Food and Drug Administration through its Safety and Innovation Act Accelerated Approval pathway, have recognized the need for biomarkers as surrogate end points. The international AL amyloidosis expert community is in agreement that the N-terminal fragment of the pro-brain natriuretic peptide (NT-proBNP) is analytically validated and clinically qualified as a biomarker for use as a surrogate end point for survival in patients with AL amyloidosis. Underlying this consensus is the demonstration that NT-proBNP is an indicator of cardiac response in all interventional studies in which it has been assessed, despite differences in patient population, treatment type and treatment schedule. Furthermore, NT-proBNP expression is directly modulated by amyloidogenic LC-elicited signal transduction pathways in cardiomyocytes. The use of NT-proBNP will greatly facilitate the development of targeted therapies for AL amyloidosis. Here, we review the data supporting the use of NT-proBNP, a biomarker that is analytically validated, clinically qualified, directly modulated by LC and universally accepted by AL amyloidosis specialists, as a surrogate end point for survival. PMID:27416985

Evaluation of the validity of treatment decisions based on surrogate country models before introduction of the Polish FRAX and recommendations in comparison to current practice

PubMed Central

Narloch, Jerzy; Glinkowska, Bożena; Bandura, Małgorzata

2016-01-01

Introduction Patients diagnosed before the Polish FRAX was introduced may require re-evaluation and treatment changes if the diagnosis was established according to a surrogate country FRAX score. The aim of the study was to evaluate the validity of treatment decisions based on the surrogate country model before introduction of the Polish FRAX and to provide recommendations based on the current practice. Material and methods We evaluated a group of 142 postmenopausal women (70.7 ±8.9 years) who underwent bone mineral density measurements. We used 22 country-specific FRAX models and compared these to the Polish model. Results The mean risk values for hip and major osteoporotic fractures within 10 years were 4.575 (from 0.82 to 8.46) and 12.47% (from 2.18 to 21.65), respectively. In the case of a major fracture, 94.4% of women would receive lifestyle advice, and 5.6% would receive treatment according to the Polish FRAX using the guidelines of the National Osteoporosis Foundation (NOF). Polish treatment thresholds would implement pharmacotherapy in 32.4% of the study group. In the case of hip fractures, 45% of women according to the NOF would require pharmacotherapy but only 9.8% of women would qualify according to Polish guidelines. Nearly all surrogate FRAX calculator scores proved significantly different form Polish (p > 0.05). Conclusions More patients might have received antiresorptive medication before the Polish FRAX. This study recommends re-evaluation of patients who received medical therapy before the Polish FRAX was introduced and a review of the recommendations, considering the side effects of antiresorptive medication. PMID:29593808

Evaluation of the validity of treatment decisions based on surrogate country models before introduction of the Polish FRAX and recommendations in comparison to current practice.

PubMed

Glinkowski, Wojciech M; Narloch, Jerzy; Glinkowska, Bożena; Bandura, Małgorzata

2018-03-01

Patients diagnosed before the Polish FRAX was introduced may require re-evaluation and treatment changes if the diagnosis was established according to a surrogate country FRAX score. The aim of the study was to evaluate the validity of treatment decisions based on the surrogate country model before introduction of the Polish FRAX and to provide recommendations based on the current practice. We evaluated a group of 142 postmenopausal women (70.7 ±8.9 years) who underwent bone mineral density measurements. We used 22 country-specific FRAX models and compared these to the Polish model. The mean risk values for hip and major osteoporotic fractures within 10 years were 4.575 (from 0.82 to 8.46) and 12.47% (from 2.18 to 21.65), respectively. In the case of a major fracture, 94.4% of women would receive lifestyle advice, and 5.6% would receive treatment according to the Polish FRAX using the guidelines of the National Osteoporosis Foundation (NOF). Polish treatment thresholds would implement pharmacotherapy in 32.4% of the study group. In the case of hip fractures, 45% of women according to the NOF would require pharmacotherapy but only 9.8% of women would qualify according to Polish guidelines. Nearly all surrogate FRAX calculator scores proved significantly different form Polish ( p > 0.05). More patients might have received antiresorptive medication before the Polish FRAX. This study recommends re-evaluation of patients who received medical therapy before the Polish FRAX was introduced and a review of the recommendations, considering the side effects of antiresorptive medication.

Hormone therapy and clinical and surrogate cardiovascular endpoints in women with chronic kidney disease: a systematic review and meta-analysis.

PubMed

Ramesh, Sharanya; Mann, Michelle C; Holroyd-Leduc, Jayna M; Wilton, Stephen B; James, Matthew T; Seely, Ellen W; Ahmed, Sofia B

2016-09-01

Women with chronic kidney disease (CKD) experience kidney dysfunction-mediated premature menopause. The role of postmenopausal hormone therapy (HT) in this population is unclear. We sought to summarize current knowledge regarding use of postmenopausal HT and cardiovascular (CV) outcomes, and established surrogate measures of CV risk in women with CKD. This is a systematic review and meta-analysis of adult women with CKD. We searched electronic bibliographic databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials) (inception to 2014 December), relevant conference proceedings, tables of contents of journals, and review articles. Randomized controlled trials and observational studies examining postmenopausal HT compared with either placebo or untreated control groups were included. The intervention of interest was postmenopausal HT, and the outcome measures were all-cause and CV mortality, nonfatal CV event (myocardial infarction, stroke), and surrogate measures of CV risk (serum lipids, blood pressure). Of 12,482 references retrieved, four randomized controlled trials and two cohort studies (N = 1,666 participants) were identified. No studies reported on CV outcomes or mortality. Compared with placebo, postmenopausal HT was associated with decreased low-density lipoprotein cholesterol (-13.2 mg/dL [95% CI, -23.32 to -3.00 mg/dL]), and increased high-density lipoprotein (8.73 mg/dL [95% CI, 4.72-12.73 mg/dL]) and total cholesterol (7.96 mg/dL [95% CI, 0.07-15.84 mg/dL]). No associations were observed between postmenopausal HT triglyceride levels and blood pressure. Studies examining the effect of postmenopausal HT on CV outcomes in women with CKD are lacking. Further prospective study of the role of postmenopausal HT in this high-risk group is required.

Progression-free survival as a surrogate endpoint for overall survival in glioblastoma: a literature-based meta-analysis from 91 trials

PubMed Central

Han, Kelong; Ren, Melanie; Wick, Wolfgang; Abrey, Lauren; Das, Asha; Jin, Jin; Reardon, David A.

2014-01-01

Background The aim of this study was to determine correlations between progression-free survival (PFS) and the objective response rate (ORR) with overall survival (OS) in glioblastoma and to evaluate their potential use as surrogates for OS. Method Published glioblastoma trials reporting OS and ORR and/or PFS with sufficient detail were included in correlative analyses using weighted linear regression. Results Of 274 published unique glioblastoma trials, 91 were included. PFS and OS hazard ratios were strongly correlated; R2 = 0.92 (95% confidence interval [CI], 0.71–0.99). Linear regression determined that a 10% PFS risk reduction would yield an 8.1% ± 0.8% OS risk reduction. R2 between median PFS and median OS was 0.70 (95% CI, 0.59–0.79), with a higher value in trials using Response Assessment in Neuro-Oncology (RANO; R2 = 0.96, n = 8) versus Macdonald criteria (R2 = 0.70; n = 83). No significant differences were demonstrated between temozolomide- and bevacizumab-containing regimens (P = .10) or between trials using RANO and Macdonald criteria (P = .49). The regression line slope between median PFS and OS was significantly higher in newly diagnosed versus recurrent disease (0.58 vs 0.35, P = .04). R2 for 6-month PFS with 1-year OS and median OS were 0.60 (95% CI, 0.37–0.77) and 0.64 (95% CI, 0.42–0.77), respectively. Objective response rate and OS were poorly correlated (R2 = 0.22). Conclusion In glioblastoma, PFS and OS are strongly correlated, indicating that PFS may be an appropriate surrogate for OS. Compared with OS, PFS offers earlier assessment and higher statistical power at the time of analysis. PMID:24335699

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

PubMed Central

2014-01-01

SUMMARY Bacteria adapt to growth in lungs of patients with cystic fibrosis (CF) by selection of heterogeneously resistant variants that are not detected by conventional susceptibility testing but are selected for rapidly during antibacterial treatment. Therefore, total bacterial counts and antibiotic susceptibilities are misleading indicators of infection and are not helpful as guides for therapy decisions or efficacy endpoints. High drug concentrations delivered by aerosol may maximize efficacy, as decreased drug susceptibilities of the pathogens are compensated for by high target site concentrations. However, reductions of the bacterial load in sputum and improvements in lung function were within the same ranges following aerosolized and conventional therapies. Furthermore, the use of conventional pharmacokinetic/pharmacodynamic (PK/PD) surrogates correlating pharmacokinetics in serum with clinical cure and presumed or proven eradication of the pathogen as a basis for PK/PD investigations in CF patients is irrelevant, as minimization of systemic exposure is one of the main objectives of aerosolized therapy; in addition, bacterial pathogens cannot be eradicated, and chronic infection cannot be cured. Consequently, conventional PK/PD surrogates are not applicable to CF patients. It is nonetheless obvious that systemic exposure of patients, with all its sequelae, is minimized and that the burden of oral treatment for CF patients suffering from chronic infections is reduced. PMID:25278574

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

Lafata, K; Ren, L; Wu, Q

Purpose: To develop a data-mining methodology based on quantum clustering and machine learning to predict expected dosimetric endpoints for lung SBRT applications based on patient-specific anatomic features. Methods: Ninety-three patients who received lung SBRT at our clinic from 2011–2013 were retrospectively identified. Planning information was acquired for each patient, from which various features were extracted using in-house semi-automatic software. Anatomic features included tumor-to-OAR distances, tumor location, total-lung-volume, GTV and ITV. Dosimetric endpoints were adopted from RTOG-0195 recommendations, and consisted of various OAR-specific partial-volume doses and maximum point-doses. First, PCA analysis and unsupervised quantum-clustering was used to explore the feature-space tomore » identify potentially strong classifiers. Secondly, a multi-class logistic regression algorithm was developed and trained to predict dose-volume endpoints based on patient-specific anatomic features. Classes were defined by discretizing the dose-volume data, and the feature-space was zero-mean normalized. Fitting parameters were determined by minimizing a regularized cost function, and optimization was performed via gradient descent. As a pilot study, the model was tested on two esophageal dosimetric planning endpoints (maximum point-dose, dose-to-5cc), and its generalizability was evaluated with leave-one-out cross-validation. Results: Quantum-Clustering demonstrated a strong separation of feature-space at 15Gy across the first-and-second Principle Components of the data when the dosimetric endpoints were retrospectively identified. Maximum point dose prediction to the esophagus demonstrated a cross-validation accuracy of 87%, and the maximum dose to 5cc demonstrated a respective value of 79%. The largest optimized weighting factor was placed on GTV-to-esophagus distance (a factor of 10 greater than the second largest weighting factor), indicating an intuitively strong correlation between this feature and both endpoints. Conclusion: This pilot study shows that it is feasible to predict dose-volume endpoints based on patient-specific anatomic features. The developed methodology can potentially help to identify patients at risk for higher OAR doses, thus improving the efficiency of treatment planning. R01-184173.« less

The Surgeon Volume-outcome Relationship: Not Yet Ready for Policy.

PubMed

Modrall, J Gregory; Minter, Rebecca M; Minhajuddin, Abu; Eslava-Schmalbach, Javier; Joshi, Girish P; Patel, Shivani; Rosero, Eric B

2018-05-01

Increasing surgeon volume may improve outcomes for index operations. We hypothesized that there may be surrogate operative experiences that yield similar outcomes for surgeons with a low-volume experience with a specific index operation, such as esophagectomy. The relationship between surgeon volume and outcomes has potential implications for credentialing of surgeons. Restrictions of privileges based on surgeon volume are only reasonable if there is no substitute for direct experience with the index operation. This study was aimed at determining whether there are valid surrogates for direct experience with a sample index operation-open esophagectomy. The Nationwide Inpatient Sample (2003-2009) was utilized. Surgeons were stratified into low and high-volume groups based on annual volume of esophagectomy. Surrogate volume was defined as the aggregate annual volume per surgeon of upper gastrointestinal operations including excision of esophageal diverticulum, gastrectomy, gastroduodenectomy, and repair of diaphragmatic hernia. In all, 26,795 esophagectomies were performed nationwide (2003-2009), with a crude inhospital mortality rate of 5.2%. Inhospital mortality decreased with increasing volume of esophagectomies performed annually: 7.7% and 3.8% for low and high-volume surgeons, respectively (P < 0.0001). Among surgeons with a low-volume esophagectomy experience, increasing volume of surrogate operations improved the outcomes observed for esophagectomy: 9.7%, 7.1%, and 4.3% for low, medium, and high-surrogate-volume surgeons, respectively (P = 0.016). Both operation-specific volume and surrogate volume are significant predictors of inhospital mortality for esophagectomy. Based on these observations, it would be premature to limit hospital privileges based solely on operation-specific surgeon volume criteria.

A toxin-free enzyme-linked immunosorbent assay for the analysis of aflatoxins based on a VHH surrogate standard.

PubMed

Wang, Yanru; Li, Peiwu; Zhang, Qi; Hu, Xiaofeng; Zhang, Wen

2016-09-01

A toxin-free enzyme-linked immunosorbent assay (ELISA) for aflatoxins was developed using an anti-idiotype nanobody VHH 2-5 as surrogate standard. Anti-idiotype nanobody VHH 2-5 was generated by immunizing an alpaca with anti-aflatoxin monoclonal antibody 1C11. This assay was used to detect aflatoxins in agro-products after a simple extraction with 75 % methanol/H2O. Aflatoxin concentration was calculated by a two-step approach: the concentration of VHH 2-5 was first obtained by a four-parameter logistic regression from the detected absorbance value at 450 nm, and then converted to aflatoxin concentration by a linear equation. The assay exhibits a limit of detection (LOD) of 0.015 ng mL(-1), which is better than or comparable with conventional immunoassays. The performance of our VHH surrogate-based ELISA was further validated with a high-performance liquid chromatography (HPLC) method for total aflatoxins determination in 20 naturally contaminated peanut samples, displaying a good correlation (R (2) = 0.988). In conclusion, the proposed assay represents a first example applying an anti-idiotype VHH antibody as a standard surrogate in ELISA. With the advantages of high stability and ease of production, the VHH antibody-based standard surrogate can be extended in the future to immunoassays for other highly toxic compounds. Graphical Abstract ᅟ.

The fish embryo toxicity test as an animal alternative method in hazard and risk assessment and scientific research.

PubMed

Embry, Michelle R; Belanger, Scott E; Braunbeck, Thomas A; Galay-Burgos, Malyka; Halder, Marlies; Hinton, David E; Léonard, Marc A; Lillicrap, Adam; Norberg-King, Teresa; Whale, Graham

2010-04-15

Animal alternatives research has historically focused on human safety assessments and has only recently been extended to environmental testing. This is particularly for those assays that involve the use of fish. A number of alternatives are being pursued by the scientific community including the fish embryo toxicity (FET) test, a proposed replacement alternative to the acute fish test. Discussion of the FET methodology and its application in environmental assessments on a global level was needed. With this emerging issue in mind, the ILSI Health and Environmental Sciences Institute (HESI) and the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) held an International Workshop on the Application of the Fish Embryo Test as an Animal Alternative Method in Hazard and Risk Assessment and Scientific Research in March, 2008. The workshop included approximately 40 scientists and regulators representing government, industry, academia, and non-governmental organizations from North America, Europe, and Asia. The goal was to review the state of the science regarding the investigation of fish embryonic tests, pain and distress in fish, emerging approaches utilizing fish embryos, and the use of fish embryo toxicity test data in various types of environmental assessments (e.g., hazard, risk, effluent, and classification and labeling of chemicals). Some specific key outcomes included agreement that risk assessors need fish data for decision-making, that extending the FET to include eluethereombryos was desirable, that relevant endpoints are being used, and that additional endpoints could facilitate additional uses beyond acute toxicity testing. The FET was, however, not yet considered validated sensu OECD. An important action step will be to provide guidance on how all fish tests can be used to assess chemical hazard and to harmonize the diverse terminology used in test guidelines adopted over the past decades. Use of the FET in context of effluent assessments was considered and it is not known if fish embryos are sufficiently sensitive for consideration as a surrogate to the sub-chronic 7-day larval fish growth and survival test used in the United States, for example. Addressing these needs by via workshops, research, and additional data reviews were identified for future action by scientists and regulators.

Evaluation of lactic acid as an initial and secondary subprimal intervention for Escherichia coli O157:H7, non-O157 Shiga toxin-producing E. coli, and a nonpathogenic E. coli surrogate for E. coli O157:H7.

PubMed

Pittman, C I; Geornaras, I; Woerner, D R; Nightingale, K K; Sofos, J N; Goodridge, L; Belk, K E

2012-09-01

Lactic acid can reduce microbial contamination on beef carcass surfaces when used as a food safety intervention, but effectiveness when applied to the surface of chilled beef subprimal sections is not well documented. Studies characterizing bacterial reduction on subprimals after lactic acid treatment would be useful for validations of hazard analysis critical control point (HACCP) systems. The objective of this study was to validate initial use of lactic acid as a subprimal intervention during beef fabrication followed by a secondary application to vacuum-packaged product that was applied at industry operating parameters. Chilled beef subprimal sections (100 cm(2)) were either left uninoculated or were inoculated with 6 log CFU/cm(2) of a 5-strain mixture of Escherichia coli O157:H7, a 12-strain mixture of non-O157 Shiga toxin-producing E. coli (STEC), or a 5-strain mixture of nonpathogenic (biotype I) E. coli that are considered surrogates for E. coli O157:H7. Uninoculated and inoculated subprimal sections received only an initial or an initial and a second "rework" application of lactic acid in a custombuilt spray cabinet at 1 of 16 application parameters. After the initial spray, total inoculum counts were reduced from 6.0 log CFU/cm(2) to 3.6, 4.4, and 4.4 log CFU/cm(2) for the E. coli surrogates, E. coli O157:H7, and non-O157 STEC inoculation groups, respectively. After the second (rework) application, total inoculum counts were 2.6, 3.2, and 3.6 log CFU/cm(2) for the E. coli surrogates, E. coli O157:H7, and non-O157 STEC inoculation groups, respectively. Both the initial and secondary lactic acid treatments effectively reduced counts of pathogenic and nonpathogenic strains of E. coli and natural microflora on beef subprimals. These data will be useful to the meat industry as part of the HACCP validation process.

End points for adjuvant therapy trials: has the time come to accept disease-free survival as a surrogate end point for overall survival?

PubMed

Gill, Sharlene; Sargent, Daniel

2006-06-01

The intent of adjuvant therapy is to eradicate micro-metastatic residual disease following curative resection with the goal of preventing or delaying recurrence. The time-honored standard for demonstrating efficacy of new adjuvant therapies is an improvement in overall survival (OS). This typically requires phase III trials of large sample size with lengthy follow-up. With the intent of reducing the cost and time of completing such trials, there is considerable interest in developing alternative or surrogate end points. A surrogate end point may be employed as a substitute to directly assess the effects of an intervention on an already accepted clinical end point such as mortality. When used judiciously, surrogate end points can accelerate the evaluation of new therapies, resulting in the more timely dissemination of effective therapies to patients. The current review provides a perspective on the suitability and validity of disease-free survival (DFS) as an alternative end point for OS. Criteria for establishing surrogacy and the advantages and limitations associated with the use of DFS as a primary end point in adjuvant clinical trials and as the basis for approval of new adjuvant therapies are discussed.

IVGTT-based simple assessment of glucose tolerance in the Zucker fatty rat: Validation against minimal models.

PubMed

Morettini, Micaela; Faelli, Emanuela; Perasso, Luisa; Fioretti, Sandro; Burattini, Laura; Ruggeri, Piero; Di Nardo, Francesco

2017-01-01

For the assessment of glucose tolerance from IVGTT data in Zucker rat, minimal model methodology is reliable but time- and money-consuming. This study aimed to validate for the first time in Zucker rat, simple surrogate indexes of insulin sensitivity and secretion against the glucose-minimal-model insulin sensitivity index (SI) and against first- (Φ1) and second-phase (Φ2) β-cell responsiveness indexes provided by C-peptide minimal model. Validation of the surrogate insulin sensitivity index (ISI) and of two sets of coupled insulin-based indexes for insulin secretion, differing from the cut-off point between phases (FPIR3-SPIR3, t = 3 min and FPIR5-SPIR5, t = 5 min), was carried out in a population of ten Zucker fatty rats (ZFR) and ten Zucker lean rats (ZLR). Considering the whole rat population (ZLR+ZFR), ISI showed a significant strong correlation with SI (Spearman's correlation coefficient, r = 0.88; P<0.001). Both FPIR3 and FPIR5 showed a significant (P<0.001) strong correlation with Φ1 (r = 0.76 and r = 0.75, respectively). Both SPIR3 and SPIR5 showed a significant (P<0.001) strong correlation with Φ2 (r = 0.85 and r = 0.83, respectively). ISI is able to detect (P<0.001) the well-recognized reduction in insulin sensitivity in ZFRs, compared to ZLRs. The insulin-based indexes of insulin secretion are able to detect in ZFRs (P<0.001) the compensatory increase of first- and second-phase secretion, associated to the insulin-resistant state. The ability of the surrogate indexes in describing glucose tolerance in the ZFRs was confirmed by the Disposition Index analysis. The model-based validation performed in the present study supports the utilization of low-cost, insulin-based indexes for the assessment of glucose tolerance in Zucker rat, reliable animal model of human metabolic syndrome.

Surrogate Safety Assessment Model and Validation : Final Report

DOT National Transportation Integrated Search

2008-06-01

Safety of traffic facilities is most often measured by counting the number (and severity) of crashes that occur. It is not possible to apply such a measurement technique to traffic facility designs that have not yet been built or deployed in the real...

Using Bovine Viral Diarrhea Virus (BVDV) As Surrogate for Human Hepatitis C Virus

EPA Pesticide Factsheets

This test is designed to validate virucidal effectiveness claims for a product to be registered as a virucide. It determines the potential of the test agent to disinfect hard surfaces contaminated with human Hepatitis C virus (HCV).

Use of endpoint adjudication to improve the quality and validity of endpoint assessment for medical device development and post marketing evaluation: Rationale and best practices. A report from the cardiac safety research consortium.

PubMed

Seltzer, Jonathan H; Heise, Ted; Carson, Peter; Canos, Daniel; Hiatt, Jo Carol; Vranckx, Pascal; Christen, Thomas; Cutlip, Donald E

2017-08-01

This white paper provides a summary of presentations, discussions and conclusions of a Thinktank entitled "The Role of Endpoint Adjudication in Medical Device Clinical Trials". The think tank was cosponsored by the Cardiac Safety Research Committee, MDEpiNet and the US Food and Drug Administration (FDA) and was convened at the FDA's White Oak headquarters on March 11, 2016. Attention was focused on tailoring best practices for evaluation of endpoints in medical device clinical trials, practical issues in endpoint adjudication of therapeutic, diagnostic, biomarker and drug-device combinations, and the role of adjudication in regulatory and reimbursement issues throughout the device lifecycle. Attendees included representatives from medical device companies, the FDA, Centers for Medicare and Medicaid Services (CMS), end point adjudication specialist groups, clinical research organizations, and active, academically based adjudicators. The manuscript presents recommendations from the think tank regarding (1) rationale for when adjudication is appropriate, (2) best practices establishment and operation of a medical device adjudication committee and (3) the role of endpoint adjudication for post market evaluation in the emerging era of real world evidence. Copyright © 2017. Published by Elsevier Inc.

Tumor Cell-Free DNA Copy Number Instability Predicts Therapeutic Response to Immunotherapy.

PubMed

Weiss, Glen J; Beck, Julia; Braun, Donald P; Bornemann-Kolatzki, Kristen; Barilla, Heather; Cubello, Rhiannon; Quan, Walter; Sangal, Ashish; Khemka, Vivek; Waypa, Jordan; Mitchell, William M; Urnovitz, Howard; Schütz, Ekkehard

2017-09-01

Purpose: Chromosomal instability is a fundamental property of cancer, which can be quantified by next-generation sequencing (NGS) from plasma/serum-derived cell-free DNA (cfDNA). We hypothesized that cfDNA could be used as a real-time surrogate for imaging analysis of disease status as a function of response to immunotherapy and as a more reliable tool than tumor biomarkers. Experimental Design: Plasma cfDNA sequences from 56 patients with diverse advanced cancers were prospectively collected and analyzed in a single-blind study for copy number variations, expressed as a quantitative chromosomal number instability (CNI) score versus 126 noncancer controls in a training set of 23 and a blinded validation set of 33. Tumor biomarker concentrations and a surrogate marker for T regulatory cells (Tregs) were comparatively analyzed. Results: Elevated CNI scores were observed in 51 of 56 patients prior to therapy. The blinded validation cohort provided an overall prediction accuracy of 83% (25/30) and a positive predictive value of CNI score for progression of 92% (11/12). The combination of CNI score before cycle (Cy) 2 and 3 yielded a correct prediction for progression in all 13 patients. The CNI score also correctly identified cases of pseudo-tumor progression from hyperprogression. Before Cy2 and Cy3, there was no significant correlation for protein tumor markers, total cfDNA, or surrogate Tregs. Conclusions: Chromosomal instability quantification in plasma cfDNA can serve as an early indicator of response to immunotherapy. The method has the potential to reduce health care costs and disease burden for cancer patients following further validation. Clin Cancer Res; 23(17); 5074-81. ©2017 AACR . ©2017 American Association for Cancer Research.

Validity of ambient levels of fine particles as surrogate for personal exposure to outdoor air pollution--results of the European EXPOLIS-EAS Study (Swiss Center Basel).

PubMed

Oglesby, L; Künzli, N; Röösli, M; Braun-Fahrländer, C; Mathys, P; Stern, W; Jantunen, M; Kousa, A

2000-07-01

To evaluate the validity of fixed-site fine particle levels as exposure surrogates in air pollution epidemiology, we considered four indicator groups: (1) PM2.5 total mass concentrations, (2) sulfur and potassium for regional air pollution, (3) lead and bromine for traffic-related particles, and (4) calcium for crustal particles. Using data from the European EXPOLIS (Air Pollution Exposure Distribution within Adult Urban Populations in Europe) study, we assessed the associations between 48-hr personal exposures and home outdoor levels of the indicators. Furthermore, within-city variability of fine particle levels was evaluated. Personal exposures to PM2.5 mass were not correlated to corresponding home outdoor levels (n = 44, rSpearman (Sp) = 0.07). In the group reporting neither relevant indoor sources nor relevant activities, personal exposures and home outdoor levels of sulfur were highly correlated (n = 40, rSp = 0.85). In contrast, the associations were weaker for traffic (Pb: n = 44, rSp = 0.53; Br: n = 44, rSp = 0.21) and crustal (Ca: n = 44, rSp = 0.12) indicators. This contrast is consistent with spatially homogeneous regional pollution and higher spatial variability of traffic and crustal indicators observed in Basel, Switzerland. We conclude that for regional air pollution, fixed-site fine particle levels are valid exposure surrogates. For source-specific exposures, however, fixed-site data are probably not the optimal measure. Still, in air pollution epidemiology, ambient PM2.5 levels may be more appropriate exposure estimates than total personal PM2.5 exposure, since the latter reflects a mixture of indoor and outdoor sources.

Validity of Ambient Levels of Fine Particles as Surrogate for Personal Exposure to Outdoor Air Pollution-Results of the European EXPOLIS-EAS Study (Swiss Center Basel).

PubMed

Oglesby, Lucy; Künzli, Nino; Röösli, Martin; Braun-Fahrländer, Charlotte; Mathys, Patrick; Stern, Willem; Jantunen, Matti; Kousa, Anu

2000-07-01

To evaluate the validity of fixed-site fine particle levels as exposure surrogates in air pollution epidemiology, we considered four indicator groups: (1) PM 25 total mass concentrations, (2) sulfur and potassium for regional air pollution, (3) lead and bromine for traffic-related particles, and (4) calcium for crustal particles. Using data from the European EXPOLIS (Air Pollution Exposure Distribution within Adult Urban Populations in Europe) study, we assessed the associations between 48-hr personal exposures and home outdoor levels of the indicators. Furthermore, within-city variability of fine particle levels was evaluated. Personal exposures to PM 2.5 mass were not correlated to corresponding home outdoor levels (n = 44, r S (S) =r o v ' Spearman (Sp) 0.07). In the group reporting neither relevant indoor sources nor relevant activities, personal exposures and home outdoor levels of sulfur were highly correlated (n = 40, r Sp = 0.85). In contrast, the associations were weaker for traffic (Pb: n = 44, r Sp = 0.53; Br: n = 44, r Sp = 0.21) and crustal (Ca: n = 44, r Sp = 0.12) indicators. This contrast is consistent with spatially homogeneous regional pollution and higher spatial variability of traffic and crustal indicators observed in Basel, Switzerland. We conclude that for regional air pollution, fixed-site fine particle levels are valid exposure surrogates. For source-specific exposures, however, fixed-site data are probably not the optimal measure. Still, in air pollution epidemiology, ambient PM 2.5 levels may be more appropriate exposure estimates than total personal PM 2.5 exposure, since the latter reflects a mixture of indoor and outdoor sources.

ASME V\\&V challenge problem: Surrogate-based V&V

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

Beghini, Lauren L.; Hough, Patricia D.

2015-12-18

The process of verification and validation can be resource intensive. From the computational model perspective, the resource demand typically arises from long simulation run times on multiple cores coupled with the need to characterize and propagate uncertainties. In addition, predictive computations performed for safety and reliability analyses have similar resource requirements. For this reason, there is a tradeoff between the time required to complete the requisite studies and the fidelity or accuracy of the results that can be obtained. At a high level, our approach is cast within a validation hierarchy that provides a framework in which we perform sensitivitymore » analysis, model calibration, model validation, and prediction. The evidence gathered as part of these activities is mapped into the Predictive Capability Maturity Model to assess credibility of the model used for the reliability predictions. With regard to specific technical aspects of our analysis, we employ surrogate-based methods, primarily based on polynomial chaos expansions and Gaussian processes, for model calibration, sensitivity analysis, and uncertainty quantification in order to reduce the number of simulations that must be done. The goal is to tip the tradeoff balance to improving accuracy without increasing the computational demands.« less

Mathematical modeling and growth kinetics of Clostridium sporogenes in cooked beef

USDA-ARS?s Scientific Manuscript database

Clostridium sporogenes PA 3679 is a common surrogate for proteolytic Clostridium botulinum for thermal process development and validation. However, little information is available concerning the growth kinetics of C. sporogenes in food. Therefore, the objective of this study was to investigate the...

HSP27 as a biomarker for predicting skin irritation in human skin and reconstructed organotypic skin model.

PubMed

Chen, Hongxia; Li, Shuhua; Meng, Tian; Zhang, Lei; Dai, Taoli; Xiang, Qi; Su, Zhijian; Zhang, Qihao; Huang, Yadong

2014-04-21

In vitro alternative tests aiming at replacing the traditional animal test for predicting the irritant potential of chemicals have been developed, but the assessing parameters or endpoints are still not sufficient. To discover novel endpoints for skin irritation responses, 2DE-based proteomics was used to analyze the protein expression in human skin exposed to sodium lauryl sulfate (SLS) following the test protocol of the European Centre for the Validation of Alternative Methods (ECVAM) in the present study. HSP27 was up-regulated most significantly among the eight identified proteins, consistent with our previous reports. Acid and basic chemicals were applied on human skin for further validation and results showed that the up-regulated expression of HSP27 was induced in 24h after the exposure. Skin-equivalent constructed with fibroblasts, basement membrane and keratinocytes was used to investigate the potential of HSP27 as a biomarker or additional endpoint for the hazard assessment of skin irritation. Our skin-equivalent (Reconstructed Organotypic Skin Model, ROSM) had excellent epidermal differentiation and was suitable for the skin irritation test. HSP27 also displayed an up-regulated expression in the ROSM in 24h after the irritants exposure for 15min. All these results suggest that HSP27 may represent a potential marker or additional endpoint for the hazard assessment of skin irritation caused by chemical products. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

A review on design of experiments and surrogate models in aircraft real-time and many-query aerodynamic analyses

NASA Astrophysics Data System (ADS)

Yondo, Raul; Andrés, Esther; Valero, Eusebio

2018-01-01

Full scale aerodynamic wind tunnel testing, numerical simulation of high dimensional (full-order) aerodynamic models or flight testing are some of the fundamental but complex steps in the various design phases of recent civil transport aircrafts. Current aircraft aerodynamic designs have increase in complexity (multidisciplinary, multi-objective or multi-fidelity) and need to address the challenges posed by the nonlinearity of the objective functions and constraints, uncertainty quantification in aerodynamic problems or the restrained computational budgets. With the aim to reduce the computational burden and generate low-cost but accurate models that mimic those full order models at different values of the design variables, Recent progresses have witnessed the introduction, in real-time and many-query analyses, of surrogate-based approaches as rapid and cheaper to simulate models. In this paper, a comprehensive and state-of-the art survey on common surrogate modeling techniques and surrogate-based optimization methods is given, with an emphasis on models selection and validation, dimensionality reduction, sensitivity analyses, constraints handling or infill and stopping criteria. Benefits, drawbacks and comparative discussions in applying those methods are described. Furthermore, the paper familiarizes the readers with surrogate models that have been successfully applied to the general field of fluid dynamics, but not yet in the aerospace industry. Additionally, the review revisits the most popular sampling strategies used in conducting physical and simulation-based experiments in aircraft aerodynamic design. Attractive or smart designs infrequently used in the field and discussions on advanced sampling methodologies are presented, to give a glance on the various efficient possibilities to a priori sample the parameter space. Closing remarks foster on future perspectives, challenges and shortcomings associated with the use of surrogate models by aircraft industrial aerodynamicists, despite their increased interest among the research communities.

Evaluation of two new surrogate indices including parameters not using insulin to assess insulin sensitivity/resistance in non-diabetic postmenopausal women: a MONET group study.

PubMed

Bastard, J-P; Lavoie, M-E; Messier, V; Prud'homme, D; Rabasa-Lhoret, R

2012-06-01

The study evaluated and compared, with other surrogate indices of insulin sensitivity/resistance (IS/R), the relevance of the TyG index, a product of fasting glucose and triglyceride (TG) levels, and the EGIR index, which includes TG, high-density lipoprotein cholesterol (HDL-c) and waist circumference in its formula to estimate IS/R, in non-diabetic postmenopausal women. A secondary analysis was performed using the baseline data for 163 non-diabetic postmenopausal women from the Montreal-Ottawa New Emerging Team (MONET) population database. The subjects participated in hyperinsulinaemic-euglycaemic (HIEG) clamp and oral glucose tolerance (OGTT) tests. Correlations and comparisons between surrogate indices were performed in addition to inter-rater agreement tests. The optimal value of surrogate indices for diagnosis of IS/R was established on a receiver operating characteristic (ROC) scatter plot. A significant correlation was found between the HIEG clamp and all IS/R surrogate indices tested [r=-0.370 (TyG index) to 0.608 (SIisOGTT index); P<0.001]. On ROC curve analysis, a higher AUROC was found for SIisOGTT (0.791) than for TyG and EGIR (0.706 and 0.675, respectively; P=0.07 and P<0.05, respectively). The TyG and EGIR IS/R indices were only relatively modestly related to the HIEG clamp. In contrast, both fasting- and OGTT-derived IS/R surrogate indices, which include insulin values in their formulae, appeared to be more accurate in estimating IS/R in our study population. Thus, the TyG and EGIR IS/R indices need to be tested and validated more extensively in different populations before being put to large-scale clinical use. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Annual sediment flux estimates in a tidal strait using surrogate measurements

USGS Publications Warehouse

Ganju, N.K.; Schoellhamer, D.H.

2006-01-01

Annual suspended-sediment flux estimates through Carquinez Strait (the seaward boundary of Suisun Bay, California) are provided based on surrogate measurements for advective, dispersive, and Stokes drift flux. The surrogates are landward watershed discharge, suspended-sediment concentration at one location in the Strait, and the longitudinal salinity gradient. The first two surrogates substitute for tidally averaged discharge and velocity-weighted suspended-sediment concentration in the Strait, thereby providing advective flux estimates, while Stokes drift is estimated with suspended-sediment concentration alone. Dispersive flux is estimated using the product of longitudinal salinity gradient and the root-mean-square value of velocity-weighted suspended-sediment concentration as an added surrogate variable. Cross-sectional measurements validated the use of surrogates during the monitoring period. During high freshwater flow advective and dispersive flux were in the seaward direction, while landward dispersive flux dominated and advective flux approached zero during low freshwater flow. Stokes drift flux was consistently in the landward direction. Wetter than average years led to net export from Suisun Bay, while dry years led to net sediment import. Relatively low watershed sediment fluxes to Suisun Bay contribute to net export during the wet season, while gravitational circulation in Carquinez Strait and higher suspended-sediment concentrations in San Pablo Bay (seaward end of Carquinez Strait) are responsible for the net import of sediment during the dry season. Annual predictions of suspended-sediment fluxes, using these methods, will allow for a sediment budget for Suisun Bay, which has implications for marsh restoration and nutrient/contaminant transport. These methods also provide a general framework for estimating sediment fluxes in estuarine environments, where temporal and spatial variability of transport are large. ?? 2006 Elsevier Ltd. All rights reserved.

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

Zawisza, I; Yan, H; Yin, F

Purpose: To assure that tumor motion is within the radiation field during high-dose and high-precision radiosurgery, real-time imaging and surrogate monitoring are employed. These methods are useful in providing real-time tumor/surrogate motion but no future information is available. In order to anticipate future tumor/surrogate motion and track target location precisely, an algorithm is developed and investigated for estimating surrogate motion multiple-steps ahead. Methods: The study utilized a one-dimensional surrogate motion signal divided into three components: (a) training component containing the primary data including the first frame to the beginning of the input subsequence; (b) input subsequence component of the surrogatemore » signal used as input to the prediction algorithm: (c) output subsequence component is the remaining signal used as the known output of the prediction algorithm for validation. The prediction algorithm consists of three major steps: (1) extracting subsequences from training component which best-match the input subsequence according to given criterion; (2) calculating weighting factors from these best-matched subsequence; (3) collecting the proceeding parts of the subsequences and combining them together with assigned weighting factors to form output. The prediction algorithm was examined for several patients, and its performance is assessed based on the correlation between prediction and known output. Results: Respiratory motion data was collected for 20 patients using the RPM system. The output subsequence is the last 50 samples (∼2 seconds) of a surrogate signal, and the input subsequence was 100 (∼3 seconds) frames prior to the output subsequence. Based on the analysis of correlation coefficient between predicted and known output subsequence, the average correlation is 0.9644±0.0394 and 0.9789±0.0239 for equal-weighting and relative-weighting strategies, respectively. Conclusion: Preliminary results indicate that the prediction algorithm is effective in estimating surrogate motion multiple-steps in advance. Relative-weighting method shows better prediction accuracy than equal-weighting method. More parameters of this algorithm are under investigation.« less

Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer: Early Results from the COMPASS Trial.

PubMed

Aung, Kyaw L; Fischer, Sandra E; Denroche, Robert E; Jang, Gun-Ho; Dodd, Anna; Creighton, Sean; Southwood, Bernadette; Liang, Sheng-Ben; Chadwick, Dianne; Zhang, Amy; O'Kane, Grainne M; Albaba, Hamzeh; Moura, Shari; Grant, Robert C; Miller, Jessica K; Mbabaali, Faridah; Pasternack, Danielle; Lungu, Ilinca M; Bartlett, John M S; Ghai, Sangeet; Lemire, Mathieu; Holter, Spring; Connor, Ashton A; Moffitt, Richard A; Yeh, Jen Jen; Timms, Lee; Krzyzanowski, Paul M; Dhani, Neesha; Hedley, David; Notta, Faiyaz; Wilson, Julie M; Moore, Malcolm J; Gallinger, Steven; Knox, Jennifer J

2018-03-15

Purpose: To perform real-time whole genome sequencing (WGS) and RNA sequencing (RNASeq) of advanced pancreatic ductal adenocarcinoma (PDAC) to identify predictive mutational and transcriptional features for better treatment selection. Experimental Design: Patients with advanced PDAC were prospectively recruited prior to first-line combination chemotherapy. Fresh tumor tissue was acquired by image-guided percutaneous core biopsy for WGS and RNASeq. Laser capture microdissection was performed for all cases. Primary endpoint was feasibility to report WGS results prior to first disease assessment CT scan at 8 weeks. The main secondary endpoint was discovery of patient subsets with predictive mutational and transcriptional signatures. Results: Sixty-three patients underwent a tumor biopsy between December 2015 and June 2017. WGS and RNASeq were successful in 62 (98%) and 60 (95%), respectively. Genomic results were reported at a median of 35 days (range, 19-52 days) from biopsy, meeting the primary feasibility endpoint. Objective responses to first-line chemotherapy were significantly better in patients with the classical PDAC RNA subtype compared with those with the basal-like subtype ( P = 0.004). The best progression-free survival was observed in those with classical subtype treated with m-FOLFIRINOX. GATA6 expression in tumor measured by RNA in situ hybridization was found to be a robust surrogate biomarker for differentiating classical and basal-like PDAC subtypes. Potentially actionable genetic alterations were found in 30% of patients. Conclusions: Prospective genomic profiling of advanced PDAC is feasible, and our early data indicate that chemotherapy response differs among patients with different genomic/transcriptomic subtypes. Clin Cancer Res; 24(6); 1344-54. ©2017 AACR . ©2017 American Association for Cancer Research.

Diagnostic and prognostic value of right ventricular strain in patients with pulmonary arterial hypertension and relatively preserved functional capacity studied with echocardiography and magnetic resonance.

PubMed

da Costa Junior, Augusto Alberto; Ota-Arakaki, Jaquelina Sonoe; Ramos, Roberta Pulcheri; Uellendahl, Marly; Mancuso, Frederico José Neves; Gil, Manuel Adan; Fischer, Cláudio Henrique; Moises, Valdir Ambrosio; de Camargo Carvalho, Antonio Carlos; Campos, Orlando

2017-01-01

Right ventricular (RV) dysfunction harbingers adverse prognosis in pulmonary arterial hypertension (PAH). Although conventional two-dimensional echocardiography (2DE) is limited for RV systolic function quantitation, RV strain can be a useful tool. The diagnostic and prognostic impact of 2DE speckle-tracking RV longitudinal strain was evaluated, including other 2DE systolic indexes, in a group of PAH patients without severe impairment of functional capacity, chronic pulmonary thromboembolism or left ventricular dysfunction. Sixty-six group I PAH patients, 67 % NYHA functional class I or II (none in IV) were studied by 2DE to obtain: RV fractional area change, tricuspid annular plane systolic excursion, RV myocardial performance index, tissue Doppler tricuspid annulus systolic velocity. Global, free wall (RVFreeWSt) and septal RV longitudinal systolic strain were obtained. RV ejection fraction by cardiac magnetic resonance (CMR-RVEF) was also assessed. All patients were followed up to 3.9 years (mean 3.3 years). Combined endpoints were hospitalization for worsening PAH or cardiovascular death. Among all the 2DE indexes of RV systolic function, RVFreeWSt exhibited the best correlation with CMR-RVEF (r = 0.83; p < 0.005). Combined endpoints occurred in 15 (22.7 %) patients (6 hospitalizations and 9 deaths). Multivariate analysis identified RVFreeWSt ≤-14 % as the only 2DE independent variable associated with combined endpoints [HR 4.66 (1.25-17.37); p < 0.05]. We conclude that RVFreeWSt may be a suitable non-geometric 2DE surrogate of CMR-RVEF in PAH patients, constituting a powerful independent predictor of long-term outcome in this cohort with relatively preserved functional capacity.

Surrogate-based optimization of hydraulic fracturing in pre-existing fracture networks

NASA Astrophysics Data System (ADS)

Chen, Mingjie; Sun, Yunwei; Fu, Pengcheng; Carrigan, Charles R.; Lu, Zhiming; Tong, Charles H.; Buscheck, Thomas A.

2013-08-01

Hydraulic fracturing has been used widely to stimulate production of oil, natural gas, and geothermal energy in formations with low natural permeability. Numerical optimization of fracture stimulation often requires a large number of evaluations of objective functions and constraints from forward hydraulic fracturing models, which are computationally expensive and even prohibitive in some situations. Moreover, there are a variety of uncertainties associated with the pre-existing fracture distributions and rock mechanical properties, which affect the optimized decisions for hydraulic fracturing. In this study, a surrogate-based approach is developed for efficient optimization of hydraulic fracturing well design in the presence of natural-system uncertainties. The fractal dimension is derived from the simulated fracturing network as the objective for maximizing energy recovery sweep efficiency. The surrogate model, which is constructed using training data from high-fidelity fracturing models for mapping the relationship between uncertain input parameters and the fractal dimension, provides fast approximation of the objective functions and constraints. A suite of surrogate models constructed using different fitting methods is evaluated and validated for fast predictions. Global sensitivity analysis is conducted to gain insights into the impact of the input variables on the output of interest, and further used for parameter screening. The high efficiency of the surrogate-based approach is demonstrated for three optimization scenarios with different and uncertain ambient conditions. Our results suggest the critical importance of considering uncertain pre-existing fracture networks in optimization studies of hydraulic fracturing.

Evaluation of bone surrogates for indirect and direct ballistic fractures.

PubMed

Bir, Cynthia; Andrecovich, Chris; DeMaio, Marlene; Dougherty, Paul J

2016-04-01

The mechanism of injury for fractures to long bones has been studied for both direct ballistic loading as well as indirect. However, the majority of these studies have been conducted on both post-mortem human subjects (PMHS) and animal surrogates which have constraints in terms of storage, preparation and testing. The identification of a validated bone surrogate for use in forensic, medical and engineering testing would provide the ability to investigate ballistic loading without these constraints. Two specific bone surrogates, Sawbones and Synbone, were evaluated in comparison to PMHS for both direct and indirect ballistic loading. For the direct loading, the mean velocity to produce fracture was 121 ± 19 m/s for the PMHS, which was statistically different from the Sawbones (140 ± 7 m/s) and Synbone (146 ± 3 m/s). The average distance to fracture in the indirect loading was .70 cm for the PMHS. The Synbone had a statistically similar average distance to fracture (.61 cm, p=0.54) however the Sawbones average distance to fracture was statistically different (.41 cm, p<0.05). Fractures patterns were found to be comparable to the PMHS for tests conducted with Synbones, however the input parameters were slightly varied to produce similar results. The fractures patterns with the Sawbones were not found to be as comparable to the PMHS. An ideal bone surrogate for ballistic testing was not identified and future work is warranted. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

An efficient surrogate-based simulation-optimization method for calibrating a regional MODFLOW model

NASA Astrophysics Data System (ADS)

Chen, Mingjie; Izady, Azizallah; Abdalla, Osman A.

2017-01-01

Simulation-optimization method entails a large number of model simulations, which is computationally intensive or even prohibitive if the model simulation is extremely time-consuming. Statistical models have been examined as a surrogate of the high-fidelity physical model during simulation-optimization process to tackle this problem. Among them, Multivariate Adaptive Regression Splines (MARS), a non-parametric adaptive regression method, is superior in overcoming problems of high-dimensions and discontinuities of the data. Furthermore, the stability and accuracy of MARS model can be improved by bootstrap aggregating methods, namely, bagging. In this paper, Bagging MARS (BMARS) method is integrated to a surrogate-based simulation-optimization framework to calibrate a three-dimensional MODFLOW model, which is developed to simulate the groundwater flow in an arid hardrock-alluvium region in northwestern Oman. The physical MODFLOW model is surrogated by the statistical model developed using BMARS algorithm. The surrogate model, which is fitted and validated using training dataset generated by the physical model, can approximate solutions rapidly. An efficient Sobol' method is employed to calculate global sensitivities of head outputs to input parameters, which are used to analyze their importance for the model outputs spatiotemporally. Only sensitive parameters are included in the calibration process to further improve the computational efficiency. Normalized root mean square error (NRMSE) between measured and simulated heads at observation wells is used as the objective function to be minimized during optimization. The reasonable history match between the simulated and observed heads demonstrated feasibility of this high-efficient calibration framework.

Characterization of Non-Infectious Virus-Like Particle Surrogates for Viral Clearance Applications.

PubMed

Johnson, Sarah; Brorson, Kurt A; Frey, Douglas D; Dhar, Arun K; Cetlin, David A

2017-09-01

Viral clearance is a critical aspect of biopharmaceutical manufacturing process validation. To determine the viral clearance efficacy of downstream chromatography and filtration steps, live viral "spiking" studies are conducted with model mammalian viruses such as minute virus of mice (MVM). However, due to biosafety considerations, spiking studies are costly and typically conducted in specialized facilities. In this work, we introduce the concept of utilizing a non-infectious MVM virus-like particle (MVM-VLP) as an economical surrogate for live MVM during process development and characterization. Through transmission electron microscopy, size exclusion chromatography with multi-angle light scattering, chromatofocusing, and a novel solute surface hydrophobicity assay, we examined and compared the size, surface charge, and hydrophobic properties of MVM and MVM-VLP. The results revealed that MVM and MVM-VLP exhibited nearly identical physicochemical properties, indicating the potential utility of MVM-VLP as an accurate and economical surrogate to live MVM during chromatography and filtration process development and characterization studies.

Fair trade international surrogacy.

PubMed

Humbyrd, Casey

2009-12-01

Since the development of assisted reproductive technologies, infertile individuals have crossed borders to obtain treatments unavailable or unaffordable in their own country. Recent media coverage has focused on the outsourcing of surrogacy to developing countries, where the cost for surrogacy is significantly less than the equivalent cost in a more developed country. This paper discusses the ethical arguments against international surrogacy. The major opposition viewpoints can be broadly divided into arguments about welfare, commodification and exploitation. It is argued that the only valid objection to international surrogacy is that surrogate mothers may be exploited by being given too little compensation. However, the possibility of exploitation is a weak argument for prohibition, as employment alternatives for potential surrogate mothers may be more exploitative or more harmful than surrogacy. It is concluded that international surrogacy must be regulated, and the proposed regulatory mechanism is termed Fair Trade Surrogacy. The guidelines of Fair Trade Surrogacy focus on minimizing potential harms to all parties and ensuring fair compensation for surrogate mothers.

Field Validation of Molybdenum Accumulation as an Indicator of Hypoxic Water Conditions

EPA Science Inventory

Laboratory experiments have shown that the accumulation rate of authigenic molybdenum (Mo) in marine sediments may serve as a quantitative surrogate for direct measurement of hypoxic conditions in overlying waters: Mo accumulation in the top 1 cm of sediment is linearly related t...

Validation of the ENSCO surrogate bogie vehicle, FOIL test numbers 92F028 through 92F031

DOT National Transportation Integrated Search

1994-11-01

This document contains the results from four crash tests conducted at the Federal Outdoor Impact Laboratory (FOIL) located at the Turner-Fairbank Highway Research Center in McLean, Virginia. The crash tests involved two reusable bogie vehicles impact...

The inhibition, reactivation and mechanism of VX-, sarin-, fluoro-VX and fluoro-sarin surrogates following their interaction with HuAChE and HuBuChE.

PubMed

Chao, Chih-Kai; Balasubramanian, Narayanaganesh; Gerdes, John M; Thompson, Charles M

2018-06-16

In this study, the mechanisms of HuAChE and HuBChE inhibition by Me-P(O) (OPNP) (OR) [PNP = p-nitrophenyl; R = CH 2 CH 3 , CH 2 CH 2 F, OCH(CH 3 ) 2 , OCH(CH 3 ) (CH 2 F)] representing surrogates and fluoro-surrogates of VX and sarin were studied by in vitro kinetics and mass spectrometry. The in vitro measures showed that the VX- and fluoro-VX surrogates were relatively strong inhibitors of HuAChE and HuBChE (k i  ∼ 10 5 -10 6  M -1 min -1 ) and underwent spontaneous and 2-PAM-mediated reactivation within 30 min. The sarin surrogates were weaker inhibitors of HuAChE and HuBChE (k i  ∼ 10 4 -10 5  M -1 min -1 ), and in general did not undergo spontaneous reactivation, although HuAChE adducts were partially reactivatable at 18 h using 2-PAM. The mechanism of HuAChE and HuBChE inhibition by the surrogates was determined by Q-TOF and MALDI-TOF mass spectral analyses. The surrogate-adducted proteins were trypsin digested and the active site-containing peptide bearing the OP-modified serine identified by Q-TOF as triply- and quadruply-charged ions representing the respective increase in mass of the attached OP moiety. Correspondingly, monoisotopic ions of the tryptic peptides representing the mass increase of the OP-adducted peptide was identified by MALDI-TOF. The mass spectrometry analyses validated the identity of the OP moiety attached to HuAChE or HuBChE as MeP(O) (OR)-O-serine peptides (loss of the PNP leaving group) via mechanisms consistent with those found with chemical warfare agents. MALDI-TOF MS analyses of the VX-modified peptides versus time showed a steady reduction in adduct versus parent peptide (reactivation), whereas the sarin-surrogate-modified peptides remained largely intact over the course of the experiment (24 h). Overall, the presence of a fluorine atom on the surrogate modestly altered the rate constants of inhibition and reactivation, however, the mechanism of inhibition (ejection of PNP group) did not change. Copyright © 2018. Published by Elsevier B.V.

Multiple scaling behaviour and nonlinear traits in music scores

PubMed Central

Larralde, Hernán; Martínez-Mekler, Gustavo; Müller, Markus

2017-01-01

We present a statistical analysis of music scores from different composers using detrended fluctuation analysis (DFA). We find different fluctuation profiles that correspond to distinct autocorrelation structures of the musical pieces. Further, we reveal evidence for the presence of nonlinear autocorrelations by estimating the DFA of the magnitude series, a result validated by a corresponding study of appropriate surrogate data. The amount and the character of nonlinear correlations vary from one composer to another. Finally, we performed a simple experiment in order to evaluate the pleasantness of the musical surrogate pieces in comparison with the original music and find that nonlinear correlations could play an important role in the aesthetic perception of a musical piece. PMID:29308256

Neoadjuvant trials in ER+ breast cancer: A tool for acceleration of drug development and discovery

PubMed Central

Guerrero-Zotano, Angel L.; Arteaga, Carlos L.

2017-01-01

Neoadjuvant therapy trials offer an excellent strategy for drug development and discovery in breast cancer, particularly in triple negative and HER2-overexpressing subtypes, where pathologic complete response is a good surrogate of long term patient benefit. For estrogen receptor (ER)-positive breast cancers, however, use of this strategy has been challenging because of the lack of validated surrogates of long term efficacy and the overall good prognosis of the majority of patients with this cancer subtype. We review below the clinical benefits of neodjuvant endocrine therapy for ER+/HER2-negative breast cancer, its use and limitations for drug development, prioritization of adjuvant and metastatic trials, and biomarker discovery. PMID:28495849

Multiple scaling behaviour and nonlinear traits in music scores

NASA Astrophysics Data System (ADS)

González-Espinoza, Alfredo; Larralde, Hernán; Martínez-Mekler, Gustavo; Müller, Markus

2017-12-01

We present a statistical analysis of music scores from different composers using detrended fluctuation analysis (DFA). We find different fluctuation profiles that correspond to distinct autocorrelation structures of the musical pieces. Further, we reveal evidence for the presence of nonlinear autocorrelations by estimating the DFA of the magnitude series, a result validated by a corresponding study of appropriate surrogate data. The amount and the character of nonlinear correlations vary from one composer to another. Finally, we performed a simple experiment in order to evaluate the pleasantness of the musical surrogate pieces in comparison with the original music and find that nonlinear correlations could play an important role in the aesthetic perception of a musical piece.

Development and Validation of a Path Length Calculation for Carotid-Femoral Pulse Wave Velocity Measurement: A TASCFORCE, SUMMIT, and Caerphilly Collaborative Venture.

PubMed

Weir-McCall, Jonathan R; Brown, Liam; Summersgill, Jennifer; Talarczyk, Piotr; Bonnici-Mallia, Michael; Chin, Sook C; Khan, Faisel; Struthers, Allan D; Sullivan, Frank; Colhoun, Helen M; Shore, Angela C; Aizawa, Kunihiko; Groop, Leif; Nilsson, Jan; Cockcroft, John R; McEniery, Carmel M; Wilkinson, Ian B; Ben-Shlomo, Yoav; Houston, J Graeme

2018-05-01

Current distance measurement techniques for pulse wave velocity (PWV) calculation are susceptible to intercenter variability. The aim of this study was to derive and validate a formula for this distance measurement. Based on carotid femoral distance in 1183 whole-body magnetic resonance angiograms, a formula was derived for calculating distance. This was compared with distance measurements in 128 whole-body magnetic resonance angiograms from a second study. The effects of recalculation of PWV using the new formula on association with risk factors, disease discrimination, and prediction of major adverse cardiovascular events were examined within 1242 participants from the multicenter SUMMIT study (Surrogate Markers of Micro- and Macrovascular Hard End-Points for Innovative Diabetes Tools) and 825 participants from the Caerphilly Prospective Study. The distance formula yielded a mean error of 7.8 mm (limits of agreement =-41.1 to 56.7 mm; P <0.001) compared with the second whole-body magnetic resonance angiogram group. Compared with an external distance measurement, the distance formula did not change associations between PWV and age, blood pressure, or creatinine ( P <0.01) but did remove significant associations between PWV and body mass index (BMI). After accounting for differences in age, sex, and mean arterial pressure, intercenter differences in PWV persisted using the external distance measurement ( F =4.6; P =0.004), whereas there was a loss of between center difference using the distance formula ( F =1.4; P =0.24). PWV odds ratios for cardiovascular mortality remained the same using both the external distance measurement (1.14; 95% confidence interval, 1.06-1.24; P =0.001) and the distance formula (1.17; 95% confidence interval, 1.08-1.28; P <0.001). A population-derived automatic distance calculation for PWV obtained from routinely collected clinical information is accurate and removes intercenter measurement variability without impacting the diagnostic utility of carotid-femoral PWV. © 2018 The Authors.

The value of enduring environmental surrogates as predictors of estuarine benthic macroinvertebrate assemblages

NASA Astrophysics Data System (ADS)

Wildsmith, Michelle D.; Valesini, Fiona J.; Robinson, Samuel F.

2017-10-01

This study tested the extent to which spatial differences in the benthic macroinvertebrate assemblages of a temperate microtidal estuary were 'explained' by the enduring (biophysical) vs non-enduring (water and sediment quality) environmental attributes of a diverse range of habitats, and thus the potential of those environmental surrogates to support faunal prediction. Species composition differed significantly among habitats in each season, with the greatest differences occurring in winter and spring and the least in summer. The pattern of habitat differences, as defined by their enduring environmental characteristics, was significantly and well matched with that in the fauna in each season. In contrast, significant matches between the non-enduring environmental and faunal data were only detected in winter and/or spring, and to a lesser extent. Field validation of the faunal prediction capacity of the biophysical surrogate framework at various 'test' sites throughout the estuary showed good agreement between the actual vs predicted key species. These findings demonstrate that enduring environmental criteria, which can be readily measured from mapped data, provide a better and more cost-effective surrogate for explaining spatial differences in the invertebrate fauna of this system than non-enduring criteria, and are thus a promising basis for faunal prediction. The approaches developed in this study are also readily adapted to any estuary worldwide.

Characterizing Variability in Ohio River NOM and Validating Reconstituted Freeze-Dried NOM as a Surrogate for its Aqueous Source

EPA Science Inventory

Surface water contains natural organic matter (NOM) which reacts with disinfectants creating disinfection byproducts (DBPs), some of which are USEPA regulated contaminants. Characterizing NOM can provide important insight on DBP formation and water treatment process adaptation t...

Effects of telmisartan and losartan on cardiovascular protection in Japanese hypertensive patients.

PubMed

Hasegawa, Hiroshi; Takano, Hiroyuki; Narumi, Hiroya; Ohtsuka, Masashi; Mizuguchi, Tadahiko; Namiki, Takao; Kobayashi, Yoshio; Komuro, Issei

2011-11-01

The Telmisartan and Losartan Cardiac Evaluation Trial, a multicenter, prospective, randomized, open-labeled, blinded-endpoint trial, was designed to compare the effects of two angiotensin II receptor blockers (ARBs), telmisartan and losartan, on cardiovascular protection in Japanese patients with mild to moderate essential hypertension. We compared the effects of telmisartan and losartan on left ventricular (LV) hypertrophy, cardiac function, atherosclerosis of carotid arteries and surrogate markers related to the actions of peroxisome proliferator-activated receptor-γ. A total of 58 patients were enrolled in the present trial and the follow-up period was 1 year. There were no significant differences in blood pressure (BP) levels between the telmisartan group and the losartan group throughout the trial. The percentage of the patients treated with ARB monotherapy was significantly higher in the telmisartan group compared with the losartan group. In addition, the progression of intima-media thickness of common carotid artery was significantly inhibited in the telmisartan group compared with the losartan group. Neither group experienced significant changes in cardiac function and LV mass index. There were no differences between the groups with respect to changes in surrogate markers such as serum adiponectin, creatinine, homeostasis model assessment index, plasminogen activator inhibitor-1 and high sensitivity C-reactive protein. Although BP levels were equal and well controlled in both groups, telmisartan showed more protective vascular effects than losartan.

Cardiovascular actions of mineralocorticoid receptor antagonists in patients with chronic kidney disease: A systematic review and meta-analysis of randomized trials.

PubMed

Ng, Khai P; Arnold, Julia; Sharif, Adnan; Gill, Paramjit; Townend, Jonathan N; Ferro, Charles J

2015-09-01

The safety and actions of mineralocorticoid receptor antagonists on surrogate markers of cardiovascular disease as well as major patient level cardiovascular end-points in patients with chronic kidney disease are unclear. MEDLINE, EMBASE, Trip Database, Cochrane Central Register of Controlled Trials, Cochrane Renal Group specialized register, Current Controlled Trials and clinicaltrials.gov were searched for relevant trials. Twenty-nine trials (1581 patients) were included. Overall, mineralocorticoid receptor antagonists lowered both systolic and diastolic blood pressure (-5.24, 95% confidence interval (CI) -8.65, -1.82 mmHg; p=0.003 and -1.96, 95% CI -3.22, -0.69 mmHg; p=0.002 respectively). There were insufficient data to perform a meta-analysis of other cardiovascular effects. However, a systematic review of the studies included suggested a consistent improvement in surrogate markers of cardiovascular disease. Overall, the use of mineralocorticoid receptor antagonists was associated with an increased serum potassium (0.23, 95% CI 0.13, 0.33 mmol/l; p<0.0001) and higher risk ratio (1.76, 95% CI 1.20, 2.57; p=0.001) of hyperkalemia. Data on long-term cardiovascular outcomes and mortality were not available in any of the trials. The long-term effects of mineralocorticoid receptor antagonists on cardiovascular events, mortality and safety need to be established. © The Author(s) 2015.

A comprehensive pathophysiology of dandruff and seborrheic dermatitis - towards a more precise definition of scalp health.

PubMed

Schwartz, James R; Messenger, Andrew G; Tosti, Antonella; Todd, Gail; Hordinsky, Maria; Hay, Roderick J; Wang, Xuemin; Zachariae, Claus; Kerr, Kathy M; Henry, James P; Rust, Rene C; Robinson, Michael K

2013-03-27

Despite an increasing knowledge of dandruff and seborrheic dermatitis (D/SD), the pathophysiological understanding is still incomplete but suggests a role of Malassezia yeasts in triggering inflammatory and hyper-proliferative epidermal responses. The objective of this report is to review published literature from in vivo studies of D/SD populations to provide a more complete description of overall scalp health. New biomolecular capabilities establish a depth of pathophysiological understanding not previously achievable with traditional means of investigation. Biomarkers representing inflammation, hyper-proliferation and barrier function are all perturbed by the D/SD condition and robustly respond to therapeutic resolution. These biomarkers can be sampled noninvasively, enabling their use in routine clinical evaluations as either surrogate endpoints or complementary ones to classical signs/symptoms to broaden the etiological learning.

Aspects of Cardiometabolic Risk in Women with Polycystic Ovary Syndrome.

PubMed

Paterakis, Thomas S; Diamanti-Kandarakis, Evanthia

2014-12-01

Women with polycystic ovary syndrome (PCOS), the most common endocrine disorder among women of reproductive age, exhibit an adverse cardiovascular risk profile characteristic of the cardiometabolic syndrome. These women, compared with age- and body mass index-matched women without PCOS, appear to present a higher risk of insulin resistance, glucose intolerance, and dyslipidemia, and possibly a higher rate of type 2 diabetes mellitus and cardiovascular disease. However, despite the presence of cardiovascular risk factors and increased surrogate markers of cardiovascular disease, it is unclear whether they have accelerated atherosclerosis and greater mortality, the latter mainly because of a lack of endpoint studies. This article addresses, summarizes, and discusses salient data from the existing literature, including gaps and uncertainties, aspects, and mechanisms related to the spectrum of adverse cardiometabolic profile factors in women with PCOS.

Evaluation of safety effect of turbo-roundabout lane dividers using floating car data and video observation.

PubMed

Kieć, Mariusz; Ambros, Jiří; Bąk, Radosław; Gogolín, Ondřej

2018-06-01

Roundabouts are one of the safest types of intersections. However, the needs to meet the requirements of operation, capacity, traffic organization and surrounding development lead to a variety of design solutions. One of such alternatives are turbo-roundabouts, which simplify drivers' decision making, limit lane changing in the roundabout, and induce low driving speed thanks to raised lane dividers. However, in spite of their generally positive reception, the safety impact of turbo-roundabouts has not been sufficiently studied. Given the low number of existing turbo-roundabouts and the statistical rarity of accident occurrence, the prevalent previously conducted studies applied only simple before-after designs or relied on traffic conflicts in micro-simulations. Nevertheless, the presence of raised lane dividers is acknowledged as an important feature of well performing and safe turbo-roundabouts. Following the previous Polish studies, the primary objective of the present study was assessment of influence of presence of lane dividers on road safety and developing a reliable and valid surrogate safety measure based on field data, which will circumvent the limitations of accident data or micro-simulations. The secondary objective was using the developed surrogate safety measure to assess and compare the safety levels of Polish turbo-roundabout samples with and without raised lane dividers. The surrogate safety measure was based on speed and lane behaviour. Speed was obtained from video observations and floating car data, which enabled the construction of representative speed profiles. Lane behaviour data was gathered from video observations. The collection of the data allowed for a relative validation of the method by comparing the safety performance of turbo-roundabouts with and without raised lane dividers. In the end, the surrogate measure was applied for evaluation of safety levels and enhancement of the existing safety performance functions, which combine traffic volumes, and speeds as a function of radii). The final models may help quantify the safety impact of different turbo-roundabout solutions. Copyright © 2018 Elsevier Ltd. All rights reserved.

Lost in Translation: The Unintended Consequences of Advance Directive Law on Clinical Care

PubMed Central

Castillo, Lesley S.; Williams, Brie A.; Hooper, Sarah M.; Sabatino, Charles P.; Weithorn, Lois A.; Sudore, Rebecca L.

2011-01-01

Background Advance directive law may compromise the clinical effectiveness of advance directives. Purpose To identify unintended legal consequences of advance directive law that may prevent patients from communicating end-of-life preferences. Data Sources Advance directive legal statutes for all 50 U.S. states and the District of Columbia and English-language searches of LexisNexis, Westlaw, and MEDLINE from 1966 to August 2010. Study Selection Two independent reviewers selected 51 advance directive statutes and 20 articles. Three independent legal reviewers selected 105 legal proceedings. Data Extraction Two reviewers independently assessed data sources and used critical content analysis to determine legal barriers to the clinical effectiveness of advance directives. Disagreements were resolved by consensus. Data Synthesis Legal and content-related barriers included poor readability (that is, laws in all states were written above a 12th-grade reading level), health care agent or surrogate restrictions (for example, 40 states did not include same-sex or domestic partners as default surrogates), and execution requirements needed to make forms legally valid (for example, 35 states did not allow oral advance directives, and 48 states required witness signatures, a notary public, or both). Vulnerable populations most likely to be affected by these barriers included patients with limited literacy, limited English proficiency, or both who cannot read or execute advance directives; same-sex or domestic partners who may be without legally valid and trusted surrogates; and unbefriended, institutionalized, or homeless patients who may be without witnesses and suitable surrogates. Limitation Only appellate-level legal cases were available, which may have excluded relevant cases. Conclusion Unintended negative consequences of advance directive legal restrictions may prevent all patients, and particularly vulnerable patients, from making and communicating their end-of-life wishes and having them honored. These restrictions have rendered advance directives less clinically useful. Recommendations include improving readability, allowing oral advance directives, and eliminating witness or notary requirements. Primary Funding Source U.S. Department of Veterans Affairs and the Pfizer Foundation. PMID:21242368

Validation of a HLA-A2 tetramer flow cytometric method, IFNgamma real time RT-PCR, and IFNgamma ELISPOT for detection of immunologic response to gp100 and MelanA/MART-1 in melanoma patients

PubMed Central

Xu, Yuanxin; Theobald, Valerie; Sung, Crystal; DePalma, Kathleen; Atwater, Laura; Seiger, Keirsten; Perricone, Michael A; Richards, Susan M

2008-01-01

Background HLA-A2 tetramer flow cytometry, IFNγ real time RT-PCR and IFNγ ELISPOT assays are commonly used as surrogate immunological endpoints for cancer immunotherapy. While these are often used as research assays to assess patient's immunologic response, assay validation is necessary to ensure reliable and reproducible results and enable more accurate data interpretation. Here we describe a rigorous validation approach for each of these assays prior to their use for clinical sample analysis. Methods Standard operating procedures for each assay were established. HLA-A2 (A*0201) tetramer assay specific for gp100209(210M) and MART-126–35(27L), IFNγ real time RT-PCR and ELISPOT methods were validated using tumor infiltrating lymphocyte cell lines (TIL) isolated from HLA-A2 melanoma patients. TIL cells, specific for gp100 (TIL 1520) or MART-1 (TIL 1143 and TIL1235), were used alone or spiked into cryopreserved HLA-A2 PBMC from healthy subjects. TIL/PBMC were stimulated with peptides (gp100209, gp100pool, MART-127–35, or influenza-M1 and negative control peptide HIV) to further assess assay performance characteristics for real time RT-PCR and ELISPOT methods. Validation parameters included specificity, accuracy, precision, linearity of dilution, limit of detection (LOD) and limit of quantification (LOQ). In addition, distribution was established in normal HLA-A2 PBMC samples. Reference ranges for assay controls were established. Results The validation process demonstrated that the HLA-A2 tetramer, IFNγ real time RT-PCR, and IFNγ ELISPOT were highly specific for each antigen, with minimal cross-reactivity between gp100 and MelanA/MART-1. The assays were sensitive; detection could be achieved at as few as 1/4545–1/6667 cells by tetramer analysis, 1/50,000 cells by real time RT-PCR, and 1/10,000–1/20,000 by ELISPOT. The assays met criteria for precision with %CV < 20% (except ELISPOT using high PBMC numbers with %CV < 25%) although flow cytometric assays and cell based functional assays are known to have high assay variability. Most importantly, assays were demonstrated to be effective for their intended use. A positive IFNγ response (by RT-PCR and ELISPOT) to gp100 was demonstrated in PBMC from 3 melanoma patients. Another patient showed a positive MART-1 response measured by all 3 validated methods. Conclusion Our results demonstrated the tetramer flow cytometry assay, IFNγ real-time RT-PCR, and INFγ ELISPOT met validation criteria. Validation approaches provide a guide for others in the field to validate these and other similar assays for assessment of patient T cell response. These methods can be applied not only to cancer vaccines but to other therapeutic proteins as part of immunogenicity and safety analyses. PMID:18945350

A Bayesian prediction model between a biomarker and the clinical endpoint for dichotomous variables.

PubMed

Jiang, Zhiwei; Song, Yang; Shou, Qiong; Xia, Jielai; Wang, William

2014-12-20

Early biomarkers are helpful for predicting clinical endpoints and for evaluating efficacy in clinical trials even if the biomarker cannot replace clinical outcome as a surrogate. The building and evaluation of an association model between biomarkers and clinical outcomes are two equally important concerns regarding the prediction of clinical outcome. This paper is to address both issues in a Bayesian framework. A Bayesian meta-analytic approach is proposed to build a prediction model between the biomarker and clinical endpoint for dichotomous variables. Compared with other Bayesian methods, the proposed model only requires trial-level summary data of historical trials in model building. By using extensive simulations, we evaluate the link function and the application condition of the proposed Bayesian model under scenario (i) equal positive predictive value (PPV) and negative predictive value (NPV) and (ii) higher NPV and lower PPV. In the simulations, the patient-level data is generated to evaluate the meta-analytic model. PPV and NPV are employed to describe the patient-level relationship between the biomarker and the clinical outcome. The minimum number of historical trials to be included in building the model is also considered. It is seen from the simulations that the logit link function performs better than the odds and cloglog functions under both scenarios. PPV/NPV ≥0.5 for equal PPV and NPV, and PPV + NPV ≥1 for higher NPV and lower PPV are proposed in order to predict clinical outcome accurately and precisely when the proposed model is considered. Twenty historical trials are required to be included in model building when PPV and NPV are equal. For unequal PPV and NPV, the minimum number of historical trials for model building is proposed to be five. A hypothetical example shows an application of the proposed model in global drug development. The proposed Bayesian model is able to predict well the clinical endpoint from the observed biomarker data for dichotomous variables as long as the conditions are satisfied. It could be applied in drug development. But the practical problems in applications have to be studied in further research.

Handling missing values in the MDS-UPDRS.

PubMed

Goetz, Christopher G; Luo, Sheng; Wang, Lu; Tilley, Barbara C; LaPelle, Nancy R; Stebbins, Glenn T

2015-10-01

This study was undertaken to define the number of missing values permissible to render valid total scores for each Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part. To handle missing values, imputation strategies serve as guidelines to reject an incomplete rating or create a surrogate score. We tested a rigorous, scale-specific, data-based approach to handling missing values for the MDS-UPDRS. From two large MDS-UPDRS datasets, we sequentially deleted item scores, either consistently (same items) or randomly (different items) across all subjects. Lin's Concordance Correlation Coefficient (CCC) compared scores calculated without missing values with prorated scores based on sequentially increasing missing values. The maximal number of missing values retaining a CCC greater than 0.95 determined the threshold for rendering a valid prorated score. A second confirmatory sample was selected from the MDS-UPDRS international translation program. To provide valid part scores applicable across all Hoehn and Yahr (H&Y) stages when the same items are consistently missing, one missing item from Part I, one from Part II, three from Part III, but none from Part IV can be allowed. To provide valid part scores applicable across all H&Y stages when random item entries are missing, one missing item from Part I, two from Part II, seven from Part III, but none from Part IV can be allowed. All cutoff values were confirmed in the validation sample. These analyses are useful for constructing valid surrogate part scores for MDS-UPDRS when missing items fall within the identified threshold and give scientific justification for rejecting partially completed ratings that fall below the threshold. © 2015 International Parkinson and Movement Disorder Society.

Linking simulation-based educational assessments and patient-related outcomes: a systematic review and meta-analysis.

PubMed

Brydges, Ryan; Hatala, Rose; Zendejas, Benjamin; Erwin, Patricia J; Cook, David A

2015-02-01

To examine the evidence supporting the use of simulation-based assessments as surrogates for patient-related outcomes assessed in the workplace. The authors systematically searched MEDLINE, EMBASE, Scopus, and key journals through February 26, 2013. They included original studies that assessed health professionals and trainees using simulation and then linked those scores with patient-related outcomes assessed in the workplace. Two reviewers independently extracted information on participants, tasks, validity evidence, study quality, patient-related and simulation-based outcomes, and magnitude of correlation. All correlations were pooled using random-effects meta-analysis. Of 11,628 potentially relevant articles, the 33 included studies enrolled 1,203 participants, including postgraduate physicians (n = 24 studies), practicing physicians (n = 8), medical students (n = 6), dentists (n = 2), and nurses (n = 1). The pooled correlation for provider behaviors was 0.51 (95% confidence interval [CI], 0.38 to 0.62; n = 27 studies); for time behaviors, 0.44 (95% CI, 0.15 to 0.66; n = 7); and for patient outcomes, 0.24 (95% CI, -0.02 to 0.47; n = 5). Most reported validity evidence was favorable, though studies often included only correlational evidence. Validity evidence of internal structure (n = 13 studies), content (n = 12), response process (n = 2), and consequences (n = 1) were reported less often. Three tools showed large pooled correlations and favorable (albeit incomplete) validity evidence. Simulation-based assessments often correlate positively with patient-related outcomes. Although these surrogates are imperfect, tools with established validity evidence may replace workplace-based assessments for evaluating select procedural skills.

Sensitivity of regression calibration to non-perfect validation data with application to the Norwegian Women and Cancer Study.

PubMed

Buonaccorsi, John P; Dalen, Ingvild; Laake, Petter; Hjartåker, Anette; Engeset, Dagrun; Thoresen, Magne

2015-04-15

Measurement error occurs when we observe error-prone surrogates, rather than true values. It is common in observational studies and especially so in epidemiology, in nutritional epidemiology in particular. Correcting for measurement error has become common, and regression calibration is the most popular way to account for measurement error in continuous covariates. We consider its use in the context where there are validation data, which are used to calibrate the true values given the observed covariates. We allow for the case that the true value itself may not be observed in the validation data, but instead, a so-called reference measure is observed. The regression calibration method relies on certain assumptions.This paper examines possible biases in regression calibration estimators when some of these assumptions are violated. More specifically, we allow for the fact that (i) the reference measure may not necessarily be an 'alloyed gold standard' (i.e., unbiased) for the true value; (ii) there may be correlated random subject effects contributing to the surrogate and reference measures in the validation data; and (iii) the calibration model itself may not be the same in the validation study as in the main study; that is, it is not transportable. We expand on previous work to provide a general result, which characterizes potential bias in the regression calibration estimators as a result of any combination of the violations aforementioned. We then illustrate some of the general results with data from the Norwegian Women and Cancer Study. Copyright © 2015 John Wiley & Sons, Ltd.

Concentration determination of methyl magnesium chloride and other Grignard reagents by potentiometric titration with in-line characterization of reaction species by FTIR spectroscopy.

PubMed

Chen, Yadan; Wang, Tao; Helmy, Roy; Zhou, George X; LoBrutto, Rosario

2002-07-01

A potentiometric titration method for methyl magnesium chloride and other Grignard reagents based on the reaction with 2-butanol in THF has been developed and validated. The method employs a commercially available platinum electrode, using an electrolyte compatible with non-aqueous solvents. Well-defined titration curves were obtained, along with excellent method precision. The endpoint was precisely determined based on the first derivative of the titration curve. Different solvents such as THF, diethyl ether and methylene chloride provided similar results with regard to sharpness of the endpoint and method precision. The method was applied to a wide array of Grignard reagents including methyl magnesium bromide, ethyl magnesium chloride, propyl magnesium chloride, vinyl magnesium chloride, phenyl magnesium chloride, and benzyl magnesium chloride with similar precision and accuracy. Application of in-line FTIR was demonstrated for in situ monitoring of the titration reaction, allowing characterization of the reaction species. An authentic spectrum of the MeMgCl-THF complex was obtained using spectral subtraction and the vibrational absorbance bands were identified. FTIR also provided an alternative for detecting the titration endpoint, and the titration results so obtained, provided a cross-validation of the accuracy of the potentiometric titration.

Application of chemical reaction mechanistic domains to an ecotoxicity QSAR model, the KAshinhou Tool for Ecotoxicity (KATE).

PubMed

Furuhama, A; Hasunuma, K; Aoki, Y; Yoshioka, Y; Shiraishi, H

2011-01-01

The validity of chemical reaction mechanistic domains defined by skin sensitisation in the Quantitative Structure-Activity Relationship (QSAR) ecotoxicity system, KAshinhou Tools for Ecotoxicity (KATE), March 2009 version, has been assessed and an external validation of the current KATE system carried out. In the case of the fish end-point, the group of chemicals with substructures reactive to skin sensitisation always exhibited higher root mean square errors (RMSEs) than chemicals without reactive substructures under identical C- or log P-judgements in KATE. However, in the case of the Daphnia end-point this was not so, and the group of chemicals with reactive substructures did not always have higher RMSEs: the Schiff base mechanism did not function as a high error detector. In addition to the RMSE findings, the presence of outliers suggested that the KATE classification rules needs to be reconsidered, particularly for the amine group. Examination of the dependency of the organism on the toxic action of chemicals in fish and Daphnia revealed that some of the reactive substructures could be applied to the improvement of the KATE system. It was concluded that the reaction mechanistic domains of toxic action for skin sensitisation could provide useful complementary information in predicting acute aquatic ecotoxicity, especially at the fish end-point.

Rationale and design of the East-West late lumen loss study: Comparison of late lumen loss between Eastern and Western drug-eluting stent study cohorts.

PubMed

Harrison, Robert W; Radhakrishnan, Vaishnavi; Lam, Peter S; Allocco, Dominic J; Brar, Sandeep; Fahy, Martin; Fisher, Rebecca; Ikeno, Fumiaki; Généreux, Philippe; Kimura, Takeshi; Liu, Minglei; Lye, Weng Kit; Mintz, Gary S; Nagai, Hirofumi; Suzuki, Yuka; White, Roseann; Allen, John C; Krucoff, Mitchell W

2016-12-01

The contemporary evaluation of novel drug-eluting stents (DES) includes mechanistic observations that characterize postdeployment stent behavior. Quantification of late lumen loss due to neointimal hyperplasia 8-13 months after stent implantation, via quantitative coronary angiography (QCA), constitutes such an observation and is required by most regulatory authorities. Late lumen loss, as determined by QCA, has been validated as a surrogate for clinical endpoints such as target vessel revascularization. The mechanistic response to DES has not been directly compared across predominantly Asian or Western populations, whereas understanding their comparability across geographic populations could enhance global DES evaluation. The East-West late lumen loss study is designed to demonstrate whether the residual differences in late lumen loss, as assessed by QCA, is different between Eastern and Western DES recipients from studies with protocol angiography at 8-13 months of follow-up. Data from independent core laboratories that have characterized angiographic late lumen loss in DES clinical trials with protocol follow-up angiography will be compiled and dichotomized into Eastern and Western populations. A prospectively developed propensity score model incorporating clinical and anatomic variables affecting late lumen loss will be used to adjust comparisons of QCA measurements. Documentation of whether there are clinically meaningful differences in mechanistic response to DES implantation across genetically unique geographies could facilitate both the quality and efficiency of global device evaluation requiring invasive follow-up for novel stent designs. Copyright © 2016 Elsevier Inc. All rights reserved.

Revisiting the NIH Taskforce on the Research needs of Eosinophil-Associated Diseases (RE-TREAD).

PubMed

Khoury, Paneez; Akuthota, Praveen; Ackerman, Steven J; Arron, Joseph R; Bochner, Bruce S; Collins, Margaret H; Kahn, Jean-Emmanuel; Fulkerson, Patricia C; Gleich, Gerald J; Gopal-Srivastava, Rashmi; Jacobsen, Elizabeth A; Leiferman, Kristen M; Francesca, Levi-Schaffer; Mathur, Sameer K; Minnicozzi, Michael; Prussin, Calman; Rothenberg, Marc E; Roufosse, Florence; Sable, Kathleen; Simon, Dagmar; Simon, Hans-Uwe; Spencer, Lisa A; Steinfeld, Jonathan; Wardlaw, Andrew J; Wechsler, Michael E; Weller, Peter F; Klion, Amy D

2018-04-19

Eosinophil-associated diseases (EADs) are rare, heterogeneous disorders characterized by the presence of eosinophils in tissues and/or peripheral blood resulting in immunopathology. The heterogeneity of tissue involvement, lack of sufficient animal models, technical challenges in working with eosinophils, and lack of standardized histopathologic approaches have hampered progress in basic research. Additionally, clinical trials and drug development for rare EADs are limited by the lack of primary and surrogate endpoints, biomarkers, and validated patient-reported outcomes. Researchers with expertise in eosinophil biology and eosinophil-related diseases reviewed the state of current eosinophil research, resources, progress, and unmet needs in the field since the 2012 meeting of the NIH Taskforce on the Research of Eosinophil-Associated Diseases (TREAD). RE-TREAD focused on gaps in basic science, translational, and clinical research on eosinophils and eosinophil-related pathogenesis. Improved recapitulation of human eosinophil biology and pathogenesis in murine models was felt to be of importance. Characterization of eosinophil phenotypes, the role of eosinophil subsets in tissues, identification of biomarkers of eosinophil activation and tissue load, and a better understanding of the role of eosinophils in human disease were prioritized. Finally, an unmet need for tools for use in clinical trials was emphasized. Histopathologic scoring, patient- and clinician-reported outcomes, and appropriate coding were deemed of paramount importance for research collaborations, drug development, and approval by regulatory agencies. Further exploration of the eosinophil genome, epigenome, and proteome was also encouraged. Although progress has been made since 2012, unmet needs in eosinophil research remain a priority. ©2018 Society for Leukocyte Biology.

Dosimetric Factors Associated With Long-Term Dysphagia After Definitive Radiotherapy for Squamous Cell Carcinoma of the Head and Neck

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

Caudell, Jimmy J.; Schaner, Philip E.; Desmond, Renee A.

2010-02-01

Purpose: Intensification of radiotherapy and chemotherapy for head-and-neck cancer may lead to increased rates of dysphagia. Dosimetric predictors of objective findings of long-term dysphagia were sought. Methods and Materials: From an institutional database, 83 patients were identified who underwent definitive intensity-modulated radiotherapy for squamous cell carcinoma of the head and neck, after exclusion of those who were treated for a second or recurrent head-and-neck primary lesion, had locoregional recurrence at any time, had less than 12 months of follow-up, or had postoperative radiotherapy. Dosimetric parameters were analyzed relative to three objective endpoints as a surrogate for severe long-term dysphagia: percutaneousmore » endoscopic gastrostomy (PEG) tube dependence at 12 months, aspiration on modified barium swallow, or pharyngoesophageal stricture requiring dilation. Results: Mean dose greater than 41 Gy and volume receiving 60 Gy (V{sub 60}) greater than 24% to the larynx were significantly associated with PEG tube dependence and aspiration. V{sub 60} greater than 12% to the inferior pharyngeal constrictor was also significantly associated with increased PEG tube dependence and aspiration. V{sub 65} greater than 33% to the superior pharyngeal constrictor or greater than 75% to the middle pharyngeal constrictor was associated with pharyngoesophageal stricture requiring dilation. Conclusions: Doses to the larynx and pharyngeal constrictors predicted long-term swallowing complications, even when controlled for other clinical factors. The addition of these structures to intensity-modulated radiotherapy optimization may reduce the incidence of dysphagia, although cautious clinical validation is necessary.« less

Effects of Exercise on Select Biomarkers and Associated Outcomes in Chronic Pain Conditions: Systematic Review.

PubMed

Kawi, Jennifer; Lukkahatai, Nada; Inouye, Jillian; Thomason, Diane; Connelly, Kirsten

2016-03-01

Chronic pain is highly prevalent. Current management is challenged by lack of validated objective measures like biological markers. Clinical pain studies employing exercise interventions have evaluated biomarkers; however, it is unclear how exercise impacts biomarkers involved in pain pathways and whether these markers are associated with relevant pain-related outcomes. This systematic review evaluates data from clinical studies employing exercise interventions in chronic musculoskeletal nonmalignant pain conditions in which biomarkers in pain pathways were measured. Published research studies from several databases were examined using the Jadad Scale for assessing the quality of clinical studies. Twelve research studies were reviewed. Jadad scores ranged from 5 to 11 out of 13 points. Inflammatory markers were most commonly measured followed by neurotransmitter-related genes and metabolite-detecting genes. After exercise interventions, changes in biomarkers involved in neurotransmission and inflammation suggest a hypoalgesic exercise effect. Significant biomarker associations were found with pain intensity, fatigue, depression, anxiety, and quality of life. However, there were varying methodologies in the studies reviewed. It remains a question whether biomarkers can be used as objective measures for risk assessment, diagnosis, or evaluation or as surrogate endpoints in chronic pain. Adequate sample sizes, optimal exercise dose determination, study replications, and longitudinal research studies with consistent methodologies are warranted. Regardless, the potential translational value of biomarkers in chronic pain is evident. Advancing nursing research in biomarkers is vital for moving the nursing discipline and clinical chronic pain practice forward. Developing a biobehavioral perspective in chronic pain is also necessary for comprehensive management. © The Author(s) 2015.

Fatigue as a Driver of Overall Quality of Life in Cancer Patients.

PubMed

McCabe, Ryan M; Grutsch, James F; Braun, Donald P; Nutakki, Swetha B

2015-01-01

This manuscript describes an approach for analyzing large amounts of disparate clinical data to elucidate the most impactful factor(s) that relate to a meaningful clinical outcome, in this case, the quality of life of cancer patients. The relationships between clinical and quality of life variables were evaluated using the EORTC QLQ-C30 global health domain--a validated surrogate variable for overall cancer patient well-being. A cross-sectional study design was used to evaluate the determinants of global health in cancer patients who initiated treatment at two regional medical centers between January 2001 and December 2009. Variables analyzed included 15 EORTC QLQ-C30 scales, age at diagnosis, gender, newly diagnosed/ recurrent disease status, and stage. The decision tree algorithm, perhaps unfamiliar to practicing clinicians, evaluates the relative contribution of individual parameters in classifying a clinically meaningful functional endpoint, such as the global health of a patient. Multiple patient characteristics were identified as important contributors. Fatigue, in particular, emerged as the most prevalent indicator of cancer patients' quality of life in 16/23 clinically relevant subsets. This analysis allowed results to be stated in a clinically-intuitive, rule set format using the language and quantities of the Quality of Life (QoL) tool itself. By applying the classification algorithms to a large data set, identification of fatigue as a root factor in driving global health and overall QoL was revealed. The ability to practice mining of clinical data sets to uncover critical clinical insights that are immediately applicable to patient care practices is illustrated.

Fatigue as a Driver of Overall Quality of Life in Cancer Patients

PubMed Central

McCabe, Ryan M.; Grutsch, James F.; Braun, Donald P.; Nutakki, Swetha B.

2015-01-01

Background This manuscript describes an approach for analyzing large amounts of disparate clinical data to elucidate the most impactful factor(s) that relate to a meaningful clinical outcome, in this case, the quality of life of cancer patients. The relationships between clinical and quality of life variables were evaluated using the EORTC QLQ-C30 global health domain—a validated surrogate variable for overall cancer patient well-being. Methods A cross-sectional study design was used to evaluate the determinants of global health in cancer patients who initiated treatment at two regional medical centers between January 2001 and December 2009. Variables analyzed included 15 EORTC QLQ-C30 scales, age at diagnosis, gender, newly diagnosed/ recurrent disease status, and stage. The decision tree algorithm, perhaps unfamiliar to practicing clinicians, evaluates the relative contribution of individual parameters in classifying a clinically meaningful functional endpoint, such as the global health of a patient. Findings Multiple patient characteristics were identified as important contributors. Fatigue, in particular, emerged as the most prevalent indicator of cancer patients’ quality of life in 16/23 clinically relevant subsets. This analysis allowed results to be stated in a clinically-intuitive, rule set format using the language and quantities of the Quality of Life (QoL) tool itself. Interpretation By applying the classification algorithms to a large data set, identification of fatigue as a root factor in driving global health and overall QoL was revealed. The ability to practice mining of clinical data sets to uncover critical clinical insights that are immediately applicable to patient care practices is illustrated. PMID:26070133

Surrogacy litigation in China and beyond.

PubMed

Ding, Chunyan

2015-02-01

Chinese law neither generally prohibits nor expressly permits surrogacy. As there has been a massive underground surrogacy market in the country, surrogacy lawsuits have occurred from time to time. Chinese courts are called to decide a number of disputed issues regarding validity of surrogacy contract, parenthood of the surrogate child, and sole care and control of the surrogate child. This article examines the judicial solutions to these disputes through a case study, and analyses whether Chinese courts have adopted appropriate approaches in applying the existing law to surrogacy lawsuits. The article further discusses the inadequacies of Chinese law in solving surrogacy disputes and regulating surrogacy, and recommends a set of suggestions for improvement so that Chinese law may better adapt to the social demand of surrogacy.

Surrogacy litigation in China and beyond

PubMed Central

Ding, Chunyan

2015-01-01

Chinese law neither generally prohibits nor expressly permits surrogacy. As there has been a massive underground surrogacy market in the country, surrogacy lawsuits have occurred from time to time. Chinese courts are called to decide a number of disputed issues regarding validity of surrogacy contract, parenthood of the surrogate child, and sole care and control of the surrogate child. This article examines the judicial solutions to these disputes through a case study, and analyses whether Chinese courts have adopted appropriate approaches in applying the existing law to surrogacy lawsuits. The article further discusses the inadequacies of Chinese law in solving surrogacy disputes and regulating surrogacy, and recommends a set of suggestions for improvement so that Chinese law may better adapt to the social demand of surrogacy. PMID:27774179

Survey of international regulatory bioequivalence recommendations for approval of generic topical dermatological drug products.

PubMed

Braddy, April C; Davit, Barbara M; Stier, Ethan M; Conner, Dale P

2015-01-01

The objective of this article is to discuss the similarities and differences in accepted bioequivalence (BE) approaches for generic topical dermatological drug products between international regulatory authorities and organizations. These drug products are locally applied and not intended for systemic absorption. Therefore, the BE approaches which serve as surrogates to establish safety and efficacy for topical dosage forms tend to differ from the traditional solid oral dosage forms. We focused on 15 different international jurisdictions and organizations that currently participate in the International Generic Drug Regulators Pilot Project. These are Australia, Brazil, Canada, China, Chinese Taipei, the European Medicines Association (EMA), Japan, Mexico, New Zealand, Singapore (a member of the Association of Southeast Asian Nations), South Africa, South Korea, Switzerland, the USA and the World Health Organization (WHO). Upon evaluation, we observed that currently only Canada, the EMA, Japan, and the USA have specific guidance documents for topical drug products. Across all jurisdictions and organizations, the three approaches consistently required are (1) BE studies with clinical endpoints for most topical drug products; (2) in vivo pharmacodynamic studies, in particular the vasoconstrictor assay for topical corticosteroids; and (3) waivers from BE study requirements for topical solutions. Japan, South Africa, the USA, and the WHO are also making strides to accept other BE approaches such as in vivo pharmacokinetic studies for BE assessment, in vivo dermatopharmacokinetic studies and/or BE studies with in vitro endpoints.

A critical evaluation of the clinical evidence for pomegranate preparations in the prevention and treatment of cardiovascular diseases.

PubMed

Vlachojannis, Christian; Erne, Paul; Schoenenberger, Andreas W; Chrubasik-Hausmann, Sigrun

2015-04-01

This study attempts a critical evaluation of the clinical evidence behind the use of dietary pomegranate preparations in the prevention and treatment of cardiovascular diseases. A search of PubMed on August 10, 2014 identified 228 references, which yielded extractable data from 24 clinical studies of pomegranate preparations. Hand searching identified two further studies. The quality of the studies and evidence of effectiveness of pomegranate were assessed by an established set of conventional criteria. Overall, the study quality was poor. Even in the best studies, indications of benefit did not reach the conventional levels of statistical significance. The only study with a definitive design had a biochemical rather than a clinical endpoint: it showed the expected difference in blood concentrations of myeloperoxidase after a single dose of either pomegranate or placebo. Only 10 of the 26 studies provided HPLC data on the amounts of co-active ingredients in the preparations that were consumed by the subjects. If pomegranate has a role in the prevention and treatment of cardiovascular diseases, there is a pressing need for dose-finding and long-term confirmatory studies. The ultimate endpoint for definitive studies would be mortality, but reductions in blood pressure or demonstrable decreases in atherosclerotic plaques would be useful surrogates. Sample sizes for various assumptions are provided. Future studies need to prove the clinical benefit. Copyright © 2015 John Wiley & Sons, Ltd.

Evaluation of habitat suitability models for forest passerines using demographic data

Treesearch

Chadwick D. Rittenhouse; Frank R., III Thompson; William D. Dijak; Joshua J. Millspaugh; Richard L. Clawson

2010-01-01

Habitat suitability is often used as a surrogate for demographic responses (i.e., abundance, survival, fecundity, or population viability) in the application of habitat suitability index (HSI) models. Whether habitat suitability actually relates to demographics, however, has rarely been evaluated. We validated HSI models of breeding habitat suitability for wood thrush...

Mechanism reduction for multicomponent surrogates: A case study using toluene reference fuels

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

Niemeyer, Kyle E.; Sung, Chih-Jen

Strategies and recommendations for performing skeletal reductions of multicomponent surrogate fuels are presented, through the generation and validation of skeletal mechanisms for a three-component toluene reference fuel. Using the directed relation graph with error propagation and sensitivity analysis method followed by a further unimportant reaction elimination stage, skeletal mechanisms valid over comprehensive and high-temperature ranges of conditions were developed at varying levels of detail. These skeletal mechanisms were generated based on autoignition simulations, and validation using ignition delay predictions showed good agreement with the detailed mechanism in the target range of conditions. When validated using phenomena other than autoignition, suchmore » as perfectly stirred reactor and laminar flame propagation, tight error control or more restrictions on the reduction during the sensitivity analysis stage were needed to ensure good agreement. In addition, tight error limits were needed for close prediction of ignition delay when varying the mixture composition away from that used for the reduction. In homogeneous compression-ignition engine simulations, the skeletal mechanisms closely matched the point of ignition and accurately predicted species profiles for lean to stoichiometric conditions. Furthermore, the efficacy of generating a multicomponent skeletal mechanism was compared to combining skeletal mechanisms produced separately for neat fuel components; using the same error limits, the latter resulted in a larger skeletal mechanism size that also lacked important cross reactions between fuel components. Based on the present results, general guidelines for reducing detailed mechanisms for multicomponent fuels are discussed.« less

Mechanism reduction for multicomponent surrogates: A case study using toluene reference fuels

DOE PAGES

Niemeyer, Kyle E.; Sung, Chih-Jen

2014-11-01

Strategies and recommendations for performing skeletal reductions of multicomponent surrogate fuels are presented, through the generation and validation of skeletal mechanisms for a three-component toluene reference fuel. Using the directed relation graph with error propagation and sensitivity analysis method followed by a further unimportant reaction elimination stage, skeletal mechanisms valid over comprehensive and high-temperature ranges of conditions were developed at varying levels of detail. These skeletal mechanisms were generated based on autoignition simulations, and validation using ignition delay predictions showed good agreement with the detailed mechanism in the target range of conditions. When validated using phenomena other than autoignition, suchmore » as perfectly stirred reactor and laminar flame propagation, tight error control or more restrictions on the reduction during the sensitivity analysis stage were needed to ensure good agreement. In addition, tight error limits were needed for close prediction of ignition delay when varying the mixture composition away from that used for the reduction. In homogeneous compression-ignition engine simulations, the skeletal mechanisms closely matched the point of ignition and accurately predicted species profiles for lean to stoichiometric conditions. Furthermore, the efficacy of generating a multicomponent skeletal mechanism was compared to combining skeletal mechanisms produced separately for neat fuel components; using the same error limits, the latter resulted in a larger skeletal mechanism size that also lacked important cross reactions between fuel components. Based on the present results, general guidelines for reducing detailed mechanisms for multicomponent fuels are discussed.« less

WE-AB-303-11: Verification of a Deformable 4DCT Motion Model for Lung Tumor Tracking Using Different Driving Surrogates

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

Woelfelschneider, J; Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, DE; Seregni, M

2015-06-15

Purpose: Tumor tracking is an advanced technique to treat intra-fractionally moving tumors. The aim of this study is to validate a surrogate-driven model based on four-dimensional computed tomography (4DCT) that is able to predict CT volumes corresponding to arbitrary respiratory states. Further, the comparison of three different driving surrogates is evaluated. Methods: This study is based on multiple 4DCTs of two patients treated for bronchial carcinoma and metastasis. Analyses for 18 additional patients are currently ongoing. The motion model was estimated from the planning 4DCT through deformable image registration. To predict a certain phase of a follow-up 4DCT, the modelmore » considers for inter-fractional variations (baseline correction) and intra-fractional respiratory parameters (amplitude and phase) derived from surrogates. In this evaluation, three different approaches were used to extract the motion surrogate: for each 4DCT phase, the 3D thoraco-abdominal surface motion, the body volume and the anterior-posterior motion of a virtual single external marker defined on the sternum were investigated. The estimated volumes resulting from the model were compared to the ground-truth clinical 4DCTs using absolute HU differences in the lung volume and landmarks localized using the Scale Invariant Feature Transform (SIFT). Results: The results show absolute HU differences between estimated and ground-truth images with median values limited to 55 HU and inter-quartile ranges (IQR) lower than 100 HU. Median 3D distances between about 1500 matching landmarks are below 2 mm for 3D surface motion and body volume methods. The single marker surrogates Result in increased median distances up to 0.6 mm. Analyses for the extended database incl. 20 patients are currently in progress. Conclusion: The results depend mainly on the image quality of the initial 4DCTs and the deformable image registration. All investigated surrogates can be used to estimate follow-up 4DCT phases, however uncertainties decrease for three-dimensional approaches. This work was funded in parts by the German Research Council (DFG) - KFO 214/2.« less

Developing the (d,p γ) reaction as a surrogate for (n, γ) in inverse kinematics

NASA Astrophysics Data System (ADS)

Lepailleur, Alexandre; Baugher, Travis; Cizewski, Jolie; Ratkiewicz, Andrew; Walter, David; Pain, Steven; Smith, Karl; Garland, Heather; Goddess Collaboration

2016-09-01

The r-process that proceeds via (n, γ) reactions on neutron-rich nuclei is responsible for the synthesis of about half of the elements heavier than iron. Because (n, γ) measurements on short-lived isotopes are not possible, the (d,p γ) reaction is being investigated as a surrogate for (n, γ). Of particular importance is validating a surrogate in inverse kinematics. Therefore, the 95Mo(d,p γ) reaction was measured in inverse kinematics with stable beams from ATLAS and CD2 targets. Reaction protons were measured in coincidence with gamma rays with GODDESS - Gammasphere ORRUBA: Dual Detectors for Experimental Structure Studies. The Oak Ridge Rutgers University Barrel Array (ORRUBA) of position-sensitive silicon strip detectors was augmented with annular arrays of segmented strip detectors at backward and forward angles, resulting in a high-angular coverage for light ejectiles. Preliminary results from the 95Mo(d,p γ) study will be presented. This work was supported in part by the U.S. Department of Energy and National Science Foundation.

Habitats as Surrogates of Taxonomic and Functional Fish Assemblages in Coral Reef Ecosystems: A Critical Analysis of Factors Driving Effectiveness

PubMed Central

Van Wynsberge, Simon; Andréfouët, Serge; Hamel, Mélanie A.; Kulbicki, Michel

2012-01-01

Species check-lists are helpful to establish Marine Protected Areas (MPAs) and protect local richness, endemicity, rarity, and biodiversity in general. However, such exhaustive taxonomic lists (i.e., true surrogate of biodiversity) require extensive and expensive censuses, and the use of estimator surrogates (e.g., habitats) is an appealing alternative. In truth, surrogate effectiveness appears from the literature highly variable both in marine and terrestrial ecosystems, making it difficult to provide practical recommendations for managers. Here, we evaluate how the biodiversity reference data set and its inherent bias can influence effectiveness. Specifically, we defined habitats by geomorphology, rugosity, and benthic cover and architecture criteria, and mapped them with satellite images for a New-Caledonian site. Fish taxonomic and functional lists were elaborated from Underwater Visual Censuses, stratified according to geomorphology and exposure. We then tested if MPA networks designed to maximize habitat richness, diversity and rarity could also effectively maximize fish richness, diversity, and rarity. Effectiveness appeared highly sensitive to the fish census design itself, in relation to the type of habitat map used and the scale of analysis. Spatial distribution of habitats (estimator surrogate’s distribution), quantity and location of fish census stations (target surrogate’s sampling), and random processes in the MPA design all affected effectiveness to the point that one small change in the data set could lead to opposite conclusions. We suggest that previous conclusions on surrogacy effectiveness, either positive or negative, marine or terrestrial, should be considered with caution, except in instances where very dense data sets were used without pseudo-replication. Although this does not rule out the validity of using surrogates of species lists for conservation planning, the critical joint examination of both target and estimator surrogates is needed for every case study. PMID:22815891

Quantitation of a PEGylated protein in monkey serum by UHPLC-HRMS using a surrogate disulfide-containing peptide: A new approach to bioanalysis and in vivo stability evaluation of disulfide-rich protein therapeutics.

PubMed

Zheng, Naiyu; Zeng, Jianing; Manney, Amy; Williams, Lakenya; Aubry, Anne-Françoise; Voronin, Kimberly; Buzescu, Adela; Zhang, Yan J; Allentoff, Alban; Xu, Carrie; Shen, Hongwu; Warner, William; Arnold, Mark E

2016-04-15

To quantify a therapeutic PEGylated protein in monkey serum as well as to monitor its potential in vivo instability and methionine oxidation, a novel ultra high performance liquid chromatography-high resolution mass spectrometric (UHPLC-HRMS) assay was developed using a surrogate disulfide-containing peptide, DCP(SS), and a confirmatory peptide, CP, a disulfide-free peptide. DCP(SS) was obtained by eliminating the step of reduction/alkylation before trypsin digestion. It contains an intact disulfide linkage between two peptide sequences that are essential for drug function but susceptible to potential in vivo cleavages. HRMS-based single ion monitoring (SIM) on a Q Exactive™ mass spectrometer was employed to improve assay specificity and sensitivity for DCP(SS) due to its poor fragmentation and low sensitivity with SRM detection. The assay has been validated for the protein drug in monkey serum using both surrogate peptides with excellent accuracy (within ±4.4%Dev) and precision (within 7.5%CV) with a lower limit of quantitation (LLOQ) at 10 ng mL(-1). The protein concentrations in monkey serum obtained from the DCP(SS)-based assay not only provided important pharmacokinetic parameters, but also confirmed in vivo stability of the peptide regions of interest by comparing drug concentrations with those obtained from the CP-based assay or from a ligand-binding assay (LBA). Furthermore, UHPLC-HRMS allowed simultaneous monitoring of the oxidized forms of both surrogate peptides to evaluate potential ex vivo/in vivo oxidation of one methionine present in each of both surrogate peptides. To the best of our knowledge, this is the first report of using a surrogate disulfide-containing peptide for LC-MS bioanalysis of a therapeutic protein. Copyright © 2016 Elsevier B.V. All rights reserved.

SU-E-I-71: Quality Assessment of Surrogate Metrics in Multi-Atlas-Based Image Segmentation

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

Zhao, T; Ruan, D

Purpose: With the ever-growing data of heterogeneous quality, relevance assessment of atlases becomes increasingly critical for multi-atlas-based image segmentation. However, there is no universally recognized best relevance metric and even a standard to compare amongst candidates remains elusive. This study, for the first time, designs a quantification to assess relevance metrics’ quality, based on a novel perspective of the metric as surrogate for inferring the inaccessible oracle geometric agreement. Methods: We first develop an inference model to relate surrogate metrics in image space to the underlying oracle relevance metric in segmentation label space, with a monotonically non-decreasing function subject tomore » random perturbations. Subsequently, we investigate model parameters to reveal key contributing factors to surrogates’ ability in prognosticating the oracle relevance value, for the specific task of atlas selection. Finally, we design an effective contract-to-noise ratio (eCNR) to quantify surrogates’ quality based on insights from these analyses and empirical observations. Results: The inference model was specialized to a linear function with normally distributed perturbations, with surrogate metric exemplified by several widely-used image similarity metrics, i.e., MSD/NCC/(N)MI. Surrogates’ behaviors in selecting the most relevant atlases were assessed under varying eCNR, showing that surrogates with high eCNR dominated those with low eCNR in retaining the most relevant atlases. In an end-to-end validation, NCC/(N)MI with eCNR of 0.12 compared to MSD with eCNR of 0.10 resulted in statistically better segmentation with mean DSC of about 0.85 and the first and third quartiles of (0.83, 0.89), compared to MSD with mean DSC of 0.84 and the first and third quartiles of (0.81, 0.89). Conclusion: The designed eCNR is capable of characterizing surrogate metrics’ quality in prognosticating the oracle relevance value. It has been demonstrated to be correlated with the performance of relevant atlas selection and ultimate label fusion.« less

Blended shared control utilizing online identification : Regulating grasping forces of a surrogate surgical grasper.

PubMed

Stephens, Trevor K; Kong, Nathan J; Dockter, Rodney L; O'Neill, John J; Sweet, Robert M; Kowalewski, Timothy M

2018-06-01

Surgical robots are increasingly common, yet routine tasks such as tissue grasping remain potentially harmful with high occurrences of tissue crush injury due to the lack of force feedback from the grasper. This work aims to investigate whether a blended shared control framework which utilizes real-time identification of the object being grasped as part of the feedback may help address the prevalence of tissue crush injury in robotic surgeries. This work tests the proposed shared control framework and tissue identification algorithm on a custom surrogate surgical robotic grasping setup. This scheme utilizes identification of the object being grasped as part of the feedback to regulate to a desired force. The blended shared control is arbitrated between human and an implicit force controller based on a computed confidence in the identification of the grasped object. The online identification is performed using least squares based on a nonlinear tissue model. Testing was performed on five silicone tissue surrogates. Twenty grasps were conducted, with half of the grasps performed under manual control and half of the grasps performed with the proposed blended shared control, to test the efficacy of the control scheme. The identification method resulted in an average of 95% accuracy across all time samples of all tissue grasps using a full leave-grasp-out cross-validation. There was an average convergence time of [Formula: see text] ms across all training grasps for all tissue surrogates. Additionally, there was a reduction in peak forces induced during grasping for all tissue surrogates when applying blended shared control online. The blended shared control using online identification more successfully regulated grasping forces to the desired target force when compared with manual control. The preliminary work on this surrogate setup for surgical grasping merits further investigation on real surgical tools and with real human tissues.

Polycyclic aromatic hydrocarbons (PAHs), nitro-PAHs and related environmental compounds: biological markers of exposure and effects.

PubMed Central

Talaska, G; Underwood, P; Maier, A; Lewtas, J; Rothman, N; Jaeger, M

1996-01-01

Lung cancer caused by polycyclic aromatic hydrocarbons (PAHs), nitro-PAHs and related environmental agents is a major problem in industrialized nations. The high case-fatality rate of the disease, even with the best supportive treatment, underscores the importance of primary lung cancer prevention. Development of biomarkers of exposure and effects to PAHs and related compounds is now underway and includes measurement of urinary metabolites of specific PAHs as well as detection of protein and DNA adducts as indicators of effective dose. Validation of these markers in terms of total environmental dose requires that concurrent measures of air levels and potential dermal exposure be made. In addition, the interrelationships between PAH biomarkers must be determined, particularly when levels of the marker in surrogate molecules (e.g., protein) or markers from surrogate tissues (e.g., lymphocyte DNA) are used to assess the risk to the target organ, the lung. Two approaches to biomarker studies will be reviewed in this article: the progress made using blood lymphocytes as surrogates for lung tissues and the progress made developing noninvasive markers of carcinogen-DNA adduct levels in lung-derived cells available in bronchial-alveolar lavage and in sputum. Data are presented from studies in which exfoliated urothelial cells were used as a surrogate tissue to assess exposure to human urinary bladder carcinogens in occupational groups. PMID:8933032

Optimal descriptor as a translator of eclectic data into endpoint prediction: mutagenicity of fullerene as a mathematical function of conditions.

PubMed

Toropov, Andrey A; Toropova, Alla P

2014-06-01

The experimental data on the bacterial reverse mutation test on C60 nanoparticles (TA100) is examined as an endpoint. By means of the optimal descriptors calculated with the Monte Carlo method a mathematical model of the endpoint has been built up. The model is the mathematical function of (i) dose (g/plate); (ii) metabolic activation (i.e. with S9 mix or without S9 mix); and (iii) illumination (i.e. dark or irradiation). The statistical quality of the model is the following: n=10, r(2)=0.7549, q(2)=0.5709, s=7.67, F=25 (Training set); n=5, r(2)=0.8987, s=18.4 (Calibration set); and n=5, r(2)=0.6968, s=10.9 (Validation set). Copyright © 2013 Elsevier Ltd. All rights reserved.

Comparison of RNA-seq and microarray-based models for clinical endpoint prediction.

PubMed

Zhang, Wenqian; Yu, Ying; Hertwig, Falk; Thierry-Mieg, Jean; Zhang, Wenwei; Thierry-Mieg, Danielle; Wang, Jian; Furlanello, Cesare; Devanarayan, Viswanath; Cheng, Jie; Deng, Youping; Hero, Barbara; Hong, Huixiao; Jia, Meiwen; Li, Li; Lin, Simon M; Nikolsky, Yuri; Oberthuer, André; Qing, Tao; Su, Zhenqiang; Volland, Ruth; Wang, Charles; Wang, May D; Ai, Junmei; Albanese, Davide; Asgharzadeh, Shahab; Avigad, Smadar; Bao, Wenjun; Bessarabova, Marina; Brilliant, Murray H; Brors, Benedikt; Chierici, Marco; Chu, Tzu-Ming; Zhang, Jibin; Grundy, Richard G; He, Min Max; Hebbring, Scott; Kaufman, Howard L; Lababidi, Samir; Lancashire, Lee J; Li, Yan; Lu, Xin X; Luo, Heng; Ma, Xiwen; Ning, Baitang; Noguera, Rosa; Peifer, Martin; Phan, John H; Roels, Frederik; Rosswog, Carolina; Shao, Susan; Shen, Jie; Theissen, Jessica; Tonini, Gian Paolo; Vandesompele, Jo; Wu, Po-Yen; Xiao, Wenzhong; Xu, Joshua; Xu, Weihong; Xuan, Jiekun; Yang, Yong; Ye, Zhan; Dong, Zirui; Zhang, Ke K; Yin, Ye; Zhao, Chen; Zheng, Yuanting; Wolfinger, Russell D; Shi, Tieliu; Malkas, Linda H; Berthold, Frank; Wang, Jun; Tong, Weida; Shi, Leming; Peng, Zhiyu; Fischer, Matthias

2015-06-25

Gene expression profiling is being widely applied in cancer research to identify biomarkers for clinical endpoint prediction. Since RNA-seq provides a powerful tool for transcriptome-based applications beyond the limitations of microarrays, we sought to systematically evaluate the performance of RNA-seq-based and microarray-based classifiers in this MAQC-III/SEQC study for clinical endpoint prediction using neuroblastoma as a model. We generate gene expression profiles from 498 primary neuroblastomas using both RNA-seq and 44 k microarrays. Characterization of the neuroblastoma transcriptome by RNA-seq reveals that more than 48,000 genes and 200,000 transcripts are being expressed in this malignancy. We also find that RNA-seq provides much more detailed information on specific transcript expression patterns in clinico-genetic neuroblastoma subgroups than microarrays. To systematically compare the power of RNA-seq and microarray-based models in predicting clinical endpoints, we divide the cohort randomly into training and validation sets and develop 360 predictive models on six clinical endpoints of varying predictability. Evaluation of factors potentially affecting model performances reveals that prediction accuracies are most strongly influenced by the nature of the clinical endpoint, whereas technological platforms (RNA-seq vs. microarrays), RNA-seq data analysis pipelines, and feature levels (gene vs. transcript vs. exon-junction level) do not significantly affect performances of the models. We demonstrate that RNA-seq outperforms microarrays in determining the transcriptomic characteristics of cancer, while RNA-seq and microarray-based models perform similarly in clinical endpoint prediction. Our findings may be valuable to guide future studies on the development of gene expression-based predictive models and their implementation in clinical practice.

Optimization of training periods for the estimation model of three-dimensional target positions using an external respiratory surrogate.

PubMed

Iramina, Hiraku; Nakamura, Mitsuhiro; Iizuka, Yusuke; Mitsuyoshi, Takamasa; Matsuo, Yukinori; Mizowaki, Takashi; Kanno, Ikuo

2018-04-19

During therapeutic beam irradiation, an unvisualized three-dimensional (3D) target position should be estimated using an external surrogate with an estimation model. Training periods for the developed model with no additional imaging during beam irradiation were optimized using clinical data. Dual-source 4D-CBCT projection data for 20 lung cancer patients were used for validation. Each patient underwent one to three scans. The actual target positions of each scan were equally divided into two equal parts: one for the modeling and the other for the validating session. A quadratic target position estimation equation was constructed during the modeling session. Various training periods for the session-i.e., modeling periods (T M )-were employed: T M  ∈ {5,10,15,25,35} [s]. First, the equation was used to estimate target positions in the validating session of the same scan (intra-scan estimations). Second, the equation was then used to estimate target positions in the validating session of another temporally different scan (inter-scan estimations). The baseline drift of the surrogate and target between scans was corrected. Various training periods for the baseline drift correction-i.e., correction periods (T C s)-were employed: T C  ∈ {5,10,15; T C  ≤ T M } [s]. Evaluations were conducted with and without the correction. The difference between the actual and estimated target positions was evaluated by the root-mean-square error (RMSE). The range of mean respiratory period and 3D motion amplitude of the target was 2.4-13.0 s and 2.8-34.2 mm, respectively. On intra-scan estimation, the median 3D RMSE was within 1.5-2.1 mm, supported by previous studies. On inter-scan estimation, median elapsed time between scans was 10.1 min. All T M s exhibited 75th percentile 3D RMSEs of 5.0-6.4 mm due to baseline drift of the surrogate and the target. After the correction, those for each T M s fell by 1.4-2.3 mm. The median 3D RMSE for both the 10-s T M and the T C period was 2.4 mm, which plateaued when the two training periods exceeded 10 s. A widely-applicable estimation model for the 3D target positions during beam irradiation was developed. The optimal T M and T C for the model were both 10 s, to allow for more than one respiratory cycle. UMIN000014825 . Registered: 11 August 2014.

Validation of a Fish Short-term Reproduction Assay

EPA Science Inventory

The Fish Short-term Reproduction Assay is an in vivo assay conducted with fathead minnows and is designed to detect changes in spawning, gross morphology, histopathology, and specific biochemical endpoints that reflect disturbances in the hypothalamic-pituitary-gonadal (HPG) axis...

CheS-Mapper 2.0 for visual validation of (Q)SAR models

PubMed Central

2014-01-01

Background Sound statistical validation is important to evaluate and compare the overall performance of (Q)SAR models. However, classical validation does not support the user in better understanding the properties of the model or the underlying data. Even though, a number of visualization tools for analyzing (Q)SAR information in small molecule datasets exist, integrated visualization methods that allow the investigation of model validation results are still lacking. Results We propose visual validation, as an approach for the graphical inspection of (Q)SAR model validation results. The approach applies the 3D viewer CheS-Mapper, an open-source application for the exploration of small molecules in virtual 3D space. The present work describes the new functionalities in CheS-Mapper 2.0, that facilitate the analysis of (Q)SAR information and allows the visual validation of (Q)SAR models. The tool enables the comparison of model predictions to the actual activity in feature space. The approach is generic: It is model-independent and can handle physico-chemical and structural input features as well as quantitative and qualitative endpoints. Conclusions Visual validation with CheS-Mapper enables analyzing (Q)SAR information in the data and indicates how this information is employed by the (Q)SAR model. It reveals, if the endpoint is modeled too specific or too generic and highlights common properties of misclassified compounds. Moreover, the researcher can use CheS-Mapper to inspect how the (Q)SAR model predicts activity cliffs. The CheS-Mapper software is freely available at http://ches-mapper.org. Graphical abstract Comparing actual and predicted activity values with CheS-Mapper.

A pretest prognostic score to assess patients undergoing exercise or pharmacological stress testing

PubMed Central

Morise, Anthony; Evans, Matthew; Jalisi, Farrukh; Shetty, Rajendra; Stauffer, Marc

2007-01-01

Objective A previously developed pretest score was validated to stratify patients presenting for exercise testing with suspected coronary disease according to the presence of angiographic coronary disease. Our goal was to determine how well this pretest score risk stratified patients undergoing pharmacological and exercise stress tests concerning prognostic endpoints. Design Retrospective cohort analysis. Setting University hospital stress laboratory. Patients 7452 unselected ambulatory patients with symptoms of suspected coronary disease undergoing stress testing between 1995 and 2004. Main outcomes measures All‐cause death, cardiac death and non‐fatal myocardial infarction. Results The rate of all‐cause death was 5.5% (CI 5.0 to 6.1) with 4.3 (SD 2.4) years of follow‐up (Exercise 2.8% (CI 2.3 to 3.2) v Pharmacological group 11.9% (CI 10.5 to 13.3); p<0.001). The rate of cardiac death/myocardial infarction was 2.6% (CI 2.2 to 3.0) (Exercise 1.4% (CI 1.1 to 1.8) v Pharmacological group 5.3% (CI 4.3 to 6.2); p<0.001). In both groups, stratification by pretest score was significant for all‐cause death and the combined endpoint. However, stratification was more effective in the pharmacological group using the combined endpoint rather than all‐cause death. Pharmacological stress patients in intermediate and high risk groups were at higher risk than their respective exercise test cohorts. Referral for pharmacological stress testing was found to be an independent predictor of time to death (2.7 (CI 2.0 to 3.6); p<0.001). Conclusion A pretest score previously validated to stratify according to angiographic outcomes, effectively risk stratified pharmacological and exercise stress patients according to the combined endpoint of cardiac death/myocardial infarction. PMID:17228070

A pretest prognostic score to assess patients undergoing exercise or pharmacological stress testing.

PubMed

Morise, Anthony; Evans, Matthew; Jalisi, Farrukh; Shetty, Rajendra; Stauffer, Marc

2007-02-01

A previously developed pretest score was validated to stratify patients presenting for exercise testing with suspected coronary disease according to the presence of angiographic coronary disease. Our goal was to determine how well this pretest score risk stratified patients undergoing pharmacological and exercise stress tests concerning prognostic endpoints. Retrospective cohort analysis. University hospital stress laboratory. 7452 unselected ambulatory patients with symptoms of suspected coronary disease undergoing stress testing between 1995 and 2004. All-cause death, cardiac death and non-fatal myocardial infarction. The rate of all-cause death was 5.5% (CI 5.0 to 6.1) with 4.3 (SD 2.4) years of follow-up (Exercise 2.8% (CI 2.3 to 3.2) v Pharmacological group 11.9% (CI 10.5 to 13.3); p<0.001). The rate of cardiac death/myocardial infarction was 2.6% (CI 2.2 to 3.0) (Exercise 1.4% (CI 1.1 to 1.8) v Pharmacological group 5.3% (CI 4.3 to 6.2); p<0.001). In both groups, stratification by pretest score was significant for all-cause death and the combined endpoint. However, stratification was more effective in the pharmacological group using the combined endpoint rather than all-cause death. Pharmacological stress patients in intermediate and high risk groups were at higher risk than their respective exercise test cohorts. Referral for pharmacological stress testing was found to be an independent predictor of time to death (2.7 (CI 2.0 to 3.6); p<0.001). A pretest score previously validated to stratify according to angiographic outcomes, effectively risk stratified pharmacological and exercise stress patients according to the combined endpoint of cardiac death/myocardial infarction.

The AIMS65 score compared with the Glasgow-Blatchford score in predicting outcomes in upper GI bleeding.

PubMed

Hyett, Brian H; Abougergi, Marwan S; Charpentier, Joseph P; Kumar, Navin L; Brozovic, Suzana; Claggett, Brian L; Travis, Anne C; Saltzman, John R

2013-04-01

We previously derived and validated the AIMS65 score, a mortality prognostic scale for upper GI bleeding (UGIB). To validate the AIMS65 score in a different patient population and compare it with the Glasgow-Blatchford risk score (GBRS). Retrospective cohort study. Adults with a primary diagnosis of UGIB. inpatient mortality. composite clinical endpoint of inpatient mortality, rebleeding, and endoscopic, radiologic or surgical intervention; blood transfusion; intensive care unit admission; rebleeding; length of stay; timing of endoscopy. The area under the receiver-operating characteristic curve (AUROC) was calculated for each score. Of the 278 study patients, 6.5% died and 35% experienced the composite clinical endpoint. The AIMS65 score was superior in predicting inpatient mortality (AUROC, 0.93 vs 0.68; P < .001), whereas the GBRS was superior in predicting blood transfusions (AUROC, 0.85 vs 0.65; P < .01) The 2 scores were similar in predicting the composite clinical endpoint (AUROC, 0.62 vs 0.68; P = .13) as well as the secondary outcomes. A GBRS of 10 and 12 or more maximized the sum of the sensitivity and specificity for inpatient mortality and rebleeding, respectively. The cutoff was 2 or more for the AIMS65 score for both outcomes. Retrospective, single-center study. The AIMS65 score is superior to the GBRS in predicting inpatient mortality from UGIB, whereas the GBRS is superior for predicting blood transfusion. Both scores are similar in predicting the composite clinical endpoint and other outcomes in clinical care and resource use. Copyright © 2013 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.

A combined QSAR and partial order ranking approach to risk assessment.

PubMed

Carlsen, L

2006-04-01

QSAR generated data appear as an attractive alternative to experimental data as foreseen in the proposed new chemicals legislation REACH. A preliminary risk assessment for the aquatic environment can be based on few factors, i.e. the octanol-water partition coefficient (Kow), the vapour pressure (VP) and the potential biodegradability of the compound in combination with the predicted no-effect concentration (PNEC) and the actual tonnage in which the substance is produced. Application of partial order ranking, allowing simultaneous inclusion of several parameters leads to a mutual prioritisation of the investigated substances, the prioritisation possibly being further analysed through the concept of linear extensions and average ranks. The ranking uses endpoint values (log Kow and log VP) derived from strictly linear 'noise-deficient' QSAR models as input parameters. Biodegradation estimates were adopted from the BioWin module of the EPI Suite. The population growth impairment of Tetrahymena pyriformis was used as a surrogate for fish lethality.

Evaluating Periodontal Treatment to Prevent Cardiovascular Disease: Challenges and Possible Solutions.

PubMed

Merchant, Anwar T; Virani, Salim S

2017-01-01

Periodontal disease is correlated with cardiovascular disease (CVD) in observational studies, but a causal connection has not been established. The empirical evidence linking periodontal disease and CVD consists of a large body of observational and mechanistic studies, but a limited number of clinical trials evaluating the effects of periodontal treatment on surrogate CVD endpoints. No randomized controlled trial has been conducted to evaluate the effect of periodontal treatment on CVD risk. In this review, we have summarized these data, described possible biological mechanisms linking periodontal disease and CVD, discussed barriers to conducting a randomized controlled trial to evaluate this hypothesis, and provided an alternative analytical approach using causal inference methods to answer the question. The public health implications of addressing this question can be significant because periodontal disease is under-treated, and highly prevalent among adults at risk of CVD. Even a small beneficial effect of periodontal treatment on CVD risk can be important.

Post-traumatic Stress Disorder and Cardiovascular Disease.

PubMed

Burg, Matthew M; Soufer, Robert

2016-10-01

Post-traumatic stress disorder (PTSD) is a disabling condition that develops consequent to trauma exposure such as natural disasters, sexual assault, automobile accidents, and combat that independently increases risk for early incident cardiovascular disease (CVD) and cardiovascular (CV) mortality by over 50 % and incident hypertension risk by over 30 %. While the majority of research on PTSD and CVD has concerned initially healthy civilian and military veteran samples, emerging research is also demonstrating that PTSD consequent to the trauma of an acute cardiac event significantly increases risk for early recurrence and mortality and that patient experiences in the clinical pathway that are related to the emergency department environment may provide an opportunity to prevent PTSD onset and thus improve outcomes. Future directions for clinical and implementation science concern broad PTSD and trauma screening in the context of primary care medical environments and the testing of PTSD treatments with CVD-related surrogates and endpoints.

Update on adjuvant chemotherapy for early breast cancer.

PubMed

Rampurwala, Murtuza M; Rocque, Gabrielle B; Burkard, Mark E

2014-01-01

Breast cancer is the second most common cancer in women worldwide. Although most women are diagnosed with early breast cancer, a substantial number recur due to persistent micro-metastatic disease. Systemic adjuvant chemotherapy improves outcomes and has advanced from first-generation regimens to modern dose-dense combinations. Although chemotherapy is the cornerstone of adjuvant therapy, new biomarkers are identifying patients who can forego such treatment. Neo-adjuvant therapy is a promising platform for drug development, but investigators should recognize the limitations of surrogate endpoints and clinical trials. Previous decades have focused on discovering, developing, and intensifying adjuvant chemotherapy. Future efforts should focus on customizing therapy and reducing chemotherapy for patients unlikely to benefit. In some cases, it may be possible to replace chemotherapy with treatments directed at specific genetic or molecular breast cancer subtypes. Yet, we anticipate that chemotherapy will remain a critical component of adjuvant therapy for years to come.

An ecotoxicological characterization of nanocrystalline cellulose (NCC).

PubMed

Kovacs, Tibor; Naish, Valerie; O'Connor, Brian; Blaise, Christian; Gagné, Francois; Hall, Lauren; Trudeau, Vance; Martel, Pierre

2010-09-01

The pulp and paper industry in Canada is developing technology for the production and use of nanocrystalline cellulose (NCC). A key component of the developmental work is an assessment of potential environmental risks. Towards this goal, NCC samples as well as carboxyl methyl cellulose (CMC), a surrogate of the parent cellulosic material, were subjected to an ecotoxicological evaluation. This involved toxicity tests with rainbow trout hepatocytes and nine aquatic species. The hepatocytes were most sensitive (EC20s between 10 and 200 mg/l) to NCC, although neither NCC nor CMC caused genotoxicity. In tests with the nine species, NCC affected the reproduction of the fathead minnow at (IC25) 0.29 g/l, but no other effects on endpoints such as survival and growth occurred in the other species at concentrations below 1 g/l, which was comparable to CMC. Based on this ecotoxicological characterization, NCC was found to have low toxicity potential and environmental risk.

Chromium picolinate intake and risk of type 2 diabetes: an evidence-based review by the United States Food and Drug Administration.

PubMed

Trumbo, Paula R; Ellwood, Kathleen C

2006-08-01

The labeling of both health claims that meet significant scientific agreement (SSA) and qualified health claims on conventional foods and dietary supplements requires pre-market approval by the US Food and Drug Administration (FDA). Approval by the FDA involves, in part, a thorough review of the scientific evidence to support an SSA or a qualified health claim. This article discusses FDA's evidence-based review of the scientific evidence on the role of chromium picolinate supplements in reducing the risk of type 2 diabetes. Based on this evidence-based review, FDA issued a letter of enforcement discretion for one qualified health claim on chromium picolinate and risk of insulin resistance, a surrogate endpoint for type 2 diabetes. The agency concluded that the relationship between chromium picolinate intake and insulin resistance is highly uncertain.

Minimal residual disease in chronic lymphocytic leukaemia.

PubMed

García Vela, José Antonio; García Marco, José Antonio

2018-02-23

Minimal residual disease (MRD) assessment is an important endpoint in the treatment of chronic lymphocytic leukaemia (CLL). It is highly predictive of prolonged progression-free survival (PFS) and overall survival and could be considered a surrogate for PFS in the context of chemoimmunotherapy based treatment. Evaluation of MRD level by flow cytometry or molecular techniques in the era of the new BCR and Bcl-2 targeted inhibitors could identify the most cost-effective and durable treatment sequencing. A therapeutic approach guided by the level of MRD might also determine which patients would benefit from an early stop or consolidation therapy. In this review, we discuss the different MRD methods of analysis, which source of tumour samples must be analysed, the future role of the detection of circulating tumour DNA, and the potential role of MRD negativity in clinical practice in the modern era of CLL therapy. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

Ultrasonographic measurements of subclinical carotid atherosclerosis in prediction of ischemic stroke.

PubMed

Mathiesen, E B; Johnsen, S H

2009-01-01

Carotid intima-media thickness (IMT) and plaque measurements are widely used to quantify atherosclerosis and assess the risk of future stroke, and are used as surrogate endpoints for clinical disease. In recent years, it has become clear that carotid IMT and plaque reflect biologically and genetically different aspects of the atherosclerotic process, and are differentially related to risk factors and cardiovascular disease. Plaques are focal manifestations of atherosclerosis while increased IMT represents mainly hypertensive medial hypertrophy. Several prospective studies have showed that IMT and plaque measurements, such as total plaque area and plaque number, are predictive of future stroke. Plaque echogenicity predicts future stroke independent of plaque size. The contribution of IMT and plaque measurements in individual stroke risk prediction in the general population seems to be limited, but may be useful as a tool for individual stratification of high-risk patients.

Development of an acceptable factor to estimate chronic end points from acute toxicity data

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

Venman, B.C.; Flaga, C.

1985-12-01

Acceptable daily intake (ADI) values are routinely developed for threshold toxicants from NOAELs determined from human or animal chronic or subchronic data. These NOAELs are then divided by appropriate uncertainty factors ranging from 10 to 1000 depending on the quality of the data. However, for the vast majority of chemicals used industrially, adequate toxicity data needed to use this process are not available. Thus, a procedure to estimate a chronic toxicity endpoint from acute toxicity data, such as an oral rat LD50, becomes necessary. An acute-to-chronic application factor of 0.0001 was developed, which when multiplied by an oral LD50 formore » an individual chemical, yields a surrogate chronic NOAEL. This figure can then be used to estimate an acceptable daily exposure for humans. The process used to estimate this application factor is detailed.« less

Biological markers in animals can provide information on exposure and bioavailability of environmental contaminants

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

Shugart, L.R.; Adams, S.M.; Jimenez, B.D.

1987-01-01

Epidemiologic studies of agents present in the environment seek to identify the extent to which they contribute to the causation of a specific toxic, clinical, or pathological endpoint. The multifactorial nature of disease etiology, long latency periods and the complexity of exposure, all contribute to the difficulty of establishing associations and casual relationships between a specific exposure and an adverse outcome. These barriers to studies of exposures and subsequent risk assessment cannot generally be changed. However, the appropriate use of biological markers in animal species living in a contaminated habitat can provide a measure of potential damage from that exposuremore » and, in some instances, act as a surrogate for human environmental exposures. Quantitative predictivity of the effect of exposure to environmental pollutants is being approached by employing an appropriate array of biological end points. 34 refs., 1 fig., 6 tabs.« less

Tracing Surrogates for Enteric Pathogens Inoculated on Hide through the Beef Harvesting Process.

PubMed

Villarreal-Silva, Mariana; Genho, Daniel P; Ilhak, Irfan; Lucia, Lisa M; Dickson, James S; Gehring, Kerri B; Savell, Jeffrey W; Castillo, Alejandro

2016-11-01

Multiple antimicrobial interventions have been validated for use during the beef postharvesting process. However, little has been done to determine the impact of the postharvest environment on pathogen contamination. In this study, surrogate microorganisms were used to simulate pathogen cross-contamination through the postharvest environment at three different abattoirs. At each abattoir, the brisket areas of 13 hide-on carcasses were inoculated after stunning, with a gelatin slurry containing a cocktail (~7 log CFU/ml) of fluorescent Escherichia coli biotype I. These microorganisms are approved as surrogates for E. coli O157:H7 and Salmonella . From these carcasses, samples (300 cm 2 ) were taken at different stages during the harvesting process: after hide opening, prior to evisceration, after evisceration, after splitting, and after final intervention. The carcass (noninoculated) immediately following (adjacent to) each hide-inoculated carcass was also tested to determine cross-contamination. Environmental (floor, walls, air) and personal garment (gloves, boots, aprons) samples were collected. Other sampled equipment included knives, meat hooks, hide pullers, and splitting saws. Results demonstrated that cross-contamination occurred between the inoculated hide and the carcass and also by transfer of microorganisms to the adjacent, noninoculated carcasses. Microbial transfer also occurred from hides or carcasses to the environment, personal garments, and equipment. Counts of the surrogate bacteria used were higher in equipment samples (15%) than in environment samples (10%). Personal garments had the lowest occurrence of cross-contamination (7%). For all abattoirs, surrogates were undetected on the carcass (<1.4 log CFU/300cm 2 ) after the final intervention stage. This study confirms the importance of following adequate procedures for carcass dressing and highlights an adequate hide opening procedure as a crucial step to prevent carcass contamination.

Comparison of bedside screening methods for frailty assessment in older adult trauma patients in the emergency department.

PubMed

Shah, Sachita P; Penn, Kevin; Kaplan, Stephen J; Vrablik, Michael; Jablonowski, Karl; Pham, Tam N; Reed, May J

2018-04-14

Frailty is linked to poor outcomes in older patients. We prospectively compared the utility of the picture-based Clinical Frailty Scale (CFS9), clinical assessments, and ultrasound muscle measurements against the reference FRAIL scale in older adult trauma patients in the emergency department (ED). We recruited a convenience sample of adults 65 yrs. or older with blunt trauma and injury severity scores <9. We queried subjects (or surrogates) on the FRAIL scale, and compared this to: physician-based and subject/surrogate-based CFS9; mid-upper arm circumference (MUAC) and grip strength; and ultrasound (US) measures of muscle thickness (limbs and abdominal wall). We derived optimal diagnostic thresholds and calculated performance metrics for each comparison using sensitivity, specificity, predictive values, and area under receiver operating characteristic curves (AUROC). Fifteen of 65 patients were frail by FRAIL scale (23%). CFS9 performed well when assessed by subject/surrogate (AUROC 0.91 [95% CI 0.84-0.98] or physician (AUROC 0.77 [95% CI 0.63-0.91]. Optimal thresholds for both physician and subject/surrogate were CFS9 of 4 or greater. If both physician and subject/surrogate provided scores <4, sensitivity and negative predictive value were 90.0% (54.1-99.5%) and 95.0% (73.1-99.7%). Grip strength and MUAC were not predictors. US measures that combined biceps and quadriceps thickness showed an AUROC of 0.75 compared to the reference standard. The ED needs rapid, validated tools to screen for frailty. The CFS9 has excellent negative predictive value in ruling out frailty. Ultrasound of combined biceps and quadriceps has modest concordance as an alternative in trauma patients who cannot provide a history. Copyright © 2017 Elsevier Inc. All rights reserved.

Recovery Efficiency, False Negative Rate, and Limit of Detection Performance of a Validated Macrofoam-Swab Sampling Method with Low Surface Concentrations of Two Bacillus anthracis Surrogates

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

Piepel, Gregory F.; Hutchison, Janine R.; Kaiser, Brooke L. D.

The performance of a macrofoam-swab sampling method was evaluated using Bacillus anthracis Sterne (BAS) and Bacillus atrophaeus Nakamura (BG) spores applied at nine low target amounts (2-500 spores) to positive-control plates and test coupons (2 in × 2 in) of four surface materials (glass, stainless steel, vinyl tile, and plastic). Test results from cultured samples were used to evaluate the effects of surrogate, surface concentration, and surface material on recovery efficiency (RE), false negative rate (FNR), and limit of detection. For RE, surrogate and surface material had statistically significant effects, but concentration did not. Mean REs were the lowest formore » vinyl tile (50.8% with BAS, 40.2% with BG) and the highest for glass (92.8% with BAS, 71.4% with BG). FNR values ranged from 0 to 0.833 for BAS and 0 to 0.806 for BG, with values increasing as concentration decreased in the range tested (0.078 to 19.375 CFU/cm2, where CFU denotes ‘colony forming units’). Surface material also had a statistically significant effect. A FNR-concentration curve was fit for each combination of surrogate and surface material. For both surrogates, the FNR curves tended to be the lowest for glass and highest for vinyl title. The FNR curves for BG tended to be higher than for BAS at lower concentrations, especially for glass. Results using a modified Rapid Viability-Polymerase Chain Reaction (mRV-PCR) analysis method were also obtained. The mRV-PCR results and comparisons to the culture results are discussed in a separate report.« less

Recovery Efficiency, False Negative Rate, and Limit of Detection Performance of a Validated Macrofoam-Swab Sampling Method with Low Surface Concentrations of Two Bacillus anthracis Surrogates

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

Piepel, Gregory F.; Hutchison, Janine R.; Deatherage Kaiser, Brooke L

The performance of a macrofoam-swab sampling method was evaluated using Bacillus anthracis Sterne (BAS) and Bacillus atrophaeus Nakamura (BG) spores applied at nine low target amounts (2-500 spores) to positive-control plates and test coupons (2 in. × 2 in.) of four surface materials (glass, stainless steel, vinyl tile, and plastic). Test results from cultured samples were used to evaluate the effects of surrogate, surface concentration, and surface material on recovery efficiency (RE), false negative rate (FNR), and limit of detection. For RE, surrogate and surface material had statistically significant effects, but concentration did not. Mean REs were the lowest formore » vinyl tile (50.8% with BAS, 40.2% with BG) and the highest for glass (92.8% with BAS, 71.4% with BG). FNR values ranged from 0 to 0.833 for BAS and 0 to 0.806 for BG, with values increasing as concentration decreased in the range tested (0.078 to 19.375 CFU/cm 2, where CFU denotes ‘colony forming units’). Surface material also had a statistically significant effect. A FNR-concentration curve was fit for each combination of surrogate and surface material. For both surrogates, the FNR curves tended to be the lowest for glass and highest for vinyl title. The FNR curves for BG tended to be higher than for BAS at lower concentrations, especially for glass. Results using a modified Rapid Viability-Polymerase Chain Reaction (mRV-PCR) analysis method were also obtained. The mRV-PCR results and comparisons to the culture results will be discussed in a subsequent report.« less

Comparing Thermal Process Validation Methods for Salmonella Inactivation on Almond Kernels.

PubMed

Jeong, Sanghyup; Marks, Bradley P; James, Michael K

2017-01-01

Ongoing regulatory changes are increasing the need for reliable process validation methods for pathogen reduction processes involving low-moisture products; however, the reliability of various validation methods has not been evaluated. Therefore, the objective was to quantify accuracy and repeatability of four validation methods (two biologically based and two based on time-temperature models) for thermal pasteurization of almonds. Almond kernels were inoculated with Salmonella Enteritidis phage type 30 or Enterococcus faecium (NRRL B-2354) at ~10 8 CFU/g, equilibrated to 0.24, 0.45, 0.58, or 0.78 water activity (a w ), and then heated in a pilot-scale, moist-air impingement oven (dry bulb 121, 149, or 177°C; dew point <33.0, 69.4, 81.6, or 90.6°C; v air = 2.7 m/s) to a target lethality of ~4 log. Almond surface temperatures were measured in two ways, and those temperatures were used to calculate Salmonella inactivation using a traditional (D, z) model and a modified model accounting for process humidity. Among the process validation methods, both methods based on time-temperature models had better repeatability, with replication errors approximately half those of the surrogate ( E. faecium ). Additionally, the modified model yielded the lowest root mean squared error in predicting Salmonella inactivation (1.1 to 1.5 log CFU/g); in contrast, E. faecium yielded a root mean squared error of 1.2 to 1.6 log CFU/g, and the traditional model yielded an unacceptably high error (3.4 to 4.4 log CFU/g). Importantly, the surrogate and modified model both yielded lethality predictions that were statistically equivalent (α = 0.05) to actual Salmonella lethality. The results demonstrate the importance of methodology, a w , and process humidity when validating thermal pasteurization processes for low-moisture foods, which should help processors select and interpret validation methods to ensure product safety.

Analytic Validation of RNA In Situ Hybridization (RISH) for AR and AR-V7 Expression in Human Prostate Cancer

PubMed Central

Guedes, Liana B.; Morais, Carlos L.; Almutairi, Fawaz; Haffner, Michael C.; Zheng, Qizhi; Isaacs, John T.; Antonarakis, Emmanuel S.; Lu, Changxue; Tsai, Harrison; Luo, Jun; De Marzo, Angelo M.; Lotan, Tamara L.

2016-01-01

Purpose RNA expression of androgen receptor splice variants may be a biomarker of resistance to novel androgen deprivation therapies in castrate resistant prostate cancer (CRPC). We analytically validated an RNA in situ hybridization (RISH) assay for total AR and AR-V7 for use in formalin fixed paraffin embedded (FFPE) prostate tumors. Experimental Design We used prostate cell lines and xenografts to validate chromogenic RISH to detect RNA containing AR exon 1 (AR-E1, surrogate for total AR RNA species) and cryptic exon 3 (AR-CE3, surrogate for AR-V7 expression). RISH signals were quantified in FFPE primary tumors and CRPC specimens, comparing to known AR and AR-V7 status by immunohistochemistry and RT-PCR. Results The quantified RISH results correlated significantly with total AR and AR-V7 levels by RT-PCR in cell lines, xenografts and autopsy metastases. Both AR-E1 and AR-CE3 RISH signals were localized in nuclear punctae in addition to the expected cytoplasmic speckles. Compared to admixed benign glands, AR-E1 expression was significantly higher in primary tumor cells with a median fold increase of 3.0 and 1.4 in two independent cohorts (p<0.0001 and p=0.04, respectively). While AR-CE3 expression was detectable in primary prostatic tumors, levels were substantially higher in a subset of CRPC metastases and cell lines, and were correlated with AR-E1 expression. Conclusions RISH for AR-E1 and AR-CE3 is an analytically valid method to examine total AR and AR-V7 RNA levels in FFPE tissues. Future clinical validation studies are required to determine whether AR RISH is a prognostic or predictive biomarker in specific clinical contexts. PMID:27166397

2'-Deoxyguanosine as a surrogate trapping agent for DNA reactive drug metabolites.

PubMed

Häkkinen, Merja R; Laine, Jaana E; Juvonen, Risto O; Auriola, Seppo; Häyrinen, Jukka; Pasanen, Markku

2011-11-10

Drug metabolism can result in the production of highly reactive metabolites that may form adducts with cellular macromolecules, and thus initiate adverse drug reactions, cause toxicity, and even require the withdrawal of drug from the market. In this study, a 2'-deoxyguanosine (dG)-based chemical trapping test system was developed for use as a fast screening tool for DNA adducting metabolites of new drug candidates. Reactive metabolites were generated from parent compounds in in vitro incubations with phenobarbital-induced mouse liver microsomes, human liver microsomes and different recombinant human CYP enzymes in the presence of dG. The formed dG-adducts were separated, characterized and their stability was studied by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The method was evaluated with six test compounds, aflatoxin B1, estrone, clozapine, tolcapone, ticlopidine and imipramine. Estrone and aflatoxin B1 formed dG adducts with phenobarbital-induced mouse liver microsomes, human liver microsomes and human recombinant CYP enzymes. Adduct formation was also observed with tolcapone when phenobarbital-induced mouse liver microsomes were used as the enzyme source. The stability of each formed adduct was independent of the different enzyme sources. No dG-adducts were identified with ticlopidine, clozapine and imipramine. Compared to other classical DNA reactivity tests, e.g. Ames test, the present surrogate endpoint, the dG adduct, is faster, enables the characterization of the formed compounds, and also permits the investigation of more unstable adducts. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Advances in shock timing experiments on the National Ignition Facility

NASA Astrophysics Data System (ADS)

Robey, H. F.; Celliers, P. M.; Moody, J. D.; Sater, J.; Parham, T.; Kozioziemski, B.; Dylla-Spears, R.; Ross, J. S.; LePape, S.; Ralph, J. E.; Hohenberger, M.; Dewald, E. L.; Berzak Hopkins, L.; Kroll, J. J.; Yoxall, B. E.; Hamza, A. V.; Boehly, T. R.; Nikroo, A.; Landen, O. L.; Edwards, M. J.

2016-03-01

Recent advances in shock timing experiments and analysis techniques now enable shock measurements to be performed in cryogenic deuterium-tritium (DT) ice layered capsule implosions on the National Ignition Facility (NIF). Previous measurements of shock timing in inertial confinement fusion (ICF) implosions were performed in surrogate targets, where the solid DT ice shell and central DT gas were replaced with a continuous liquid deuterium (D2) fill. These previous experiments pose two surrogacy issues: a material surrogacy due to the difference of species (D2 vs. DT) and densities of the materials used and a geometric surrogacy due to presence of an additional interface (ice/gas) previously absent in the liquid-filled targets. This report presents experimental data and a new analysis method for validating the assumptions underlying this surrogate technique.

Lost in translation?: Comparing three Scandinavian translations of the Beliefs about Medicines Questionnaire.

PubMed

Granas, Anne Gerd; Nørgaard, Lotte Stig; Sporrong, Sofia Kälvemark

2014-08-01

The "Beliefs about Medicines Questionnaire" (BMQ) assess balance of necessity and concern of medicines. The BMQ has been translated from English to many languages. However, the original meaning of statements, such as "My medicine is a mystery to me", may be lost in translation. The aim of this study is to compare three Scandinavian translations of the BMQ. (1) How reliable are the translations? (2) Are they still valid after translation? Translated Norwegian, Swedish and Danish versions of the BMQ were scrutinized by three native Scandinavian researchers. Linguistic differences and ambiguities in the 5-point Likert scale and the BMQ statements were compared. In the Scandinavian translations, the Likert scale expanded beyond the original version at one endpoint (Swedish) or both endpoints (Danish). In the BMQ statements, discrepancies ranged from smaller inaccuracies toward completely different meaning. Some dissimilarities reflect different cultural beliefs about medicines. When translating questionnaires, bilingual researchers should scrutinize translations across similar languages to address content validity across different countries and languages. Our findings are of relevance to other BMQ translations in non-English countries, as direct comparisons between different translations might not be reliable or valid. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Comparative Effectiveness of Renin-Angiotensin System Antagonists in Maintenance Dialysis Patients

PubMed Central

Shireman, Theresa I.; Mahnken, Jonathan D.; Phadnis, Milind A.; Ellerbeck, Edward F.; Wetmore, James B.

2017-01-01

Background/Aims Whether angiotensin converting enzyme inhibitors (ACE) and angiotensin receptor blockers (ARB) are differentially associated with reductions in cardiovascular events and mortality in patients receiving maintenance dialysis is uncertain. We compared outcomes between ACE and ARB users among hypertensive, maintenance dialysis patients. Methods National retrospective cohort study of hypertensive, Medicare-Medicaid eligible patients initiating chronic dialysis between 1/1/2000 to 12/31/2005. The exposure of interest was new use of either an ACEI or ARB. Outcomes were all-cause mortality (ACM) and combined cardiovascular hospitalization or death (CV-endpoint). Cox proportion hazards models were used to compare the effect of ACEI vs ARB use on ACM and, separately, CV-endpoint. Results ACM models were based on 3,555 ACEI and 1,442 ARB new users, while CV-endpoint models included 3,289 ACEI and 1,346 ARB new users. After statistical adjustments, ACEI users had higher hazard ratios for ACM (AHR = 1.22, 99% CI 1.05–1.42) and CV-endpoint (AHR = 1.12, 99% CI 0.99–1.27). Conclusions Patients initiating maintenance dialysis who received an ACEI faced an increased risk for mortality and a trend towards an increased risk for CV-endpoints when compared to patients who received an ARB. Validation of these results in a rigorous clinical trial is warranted. PMID:27871075

Comparative Effectiveness of Renin-Angiotensin System Antagonists in Maintenance Dialysis Patients.

PubMed

Shireman, Theresa I; Mahnken, Jonathan D; Phadnis, Milind A; Ellerbeck, Edward F; Wetmore, James B

2016-01-01

Whether angiotensin converting enzyme inhibitors (ACE) and angiotensin receptor blockers (ARB) are differentially associated with reductions in cardiovascular events and mortality in patients receiving maintenance dialysis is uncertain. We compared outcomes between ACE and ARB users among hypertensive, maintenance dialysis patients. National retrospective cohort study of hypertensive, Medicare-Medicaid eligible patients initiating chronic dialysis between 1/1/2000 to 12/31/2005. The exposure of interest was new use of either an ACEI or ARB. Outcomes were all-cause mortality (ACM) and combined cardiovascular hospitalization or death (CV-endpoint). Cox proportion hazards models were used to compare the effect of ACEI vs ARB use on ACM and, separately, CV-endpoint. ACM models were based on 3,555 ACEI and 1,442 ARB new users, while CV-endpoint models included 3,289 ACEI and 1,346 ARB new users. After statistical adjustments, ACEI users had higher hazard ratios for ACM (AHR = 1.22, 99% CI 1.05-1.42) and CV-endpoint (AHR = 1.12, 99% CI 0.99-1.27). Patients initiating maintenance dialysis who received an ACEI faced an increased risk for mortality and a trend towards an increased risk for CV-endpoints when compared to patients who received an ARB. Validation of these results in a rigorous clinical trial is warranted. © 2016 The Author(s) Published by S. Karger AG, Basel.

Predictive Modeling of Apical Toxicity Endpoints Using Data ...

EPA Pesticide Factsheets

The US EPA and other regulatory agencies face a daunting challenge of evaluating potential toxicity for tens of thousands of environmental chemicals about which little is currently known. The EPA’s ToxCast program is testing a novel approach to this problem by screening compounds using a variety of in vitro assays and using the results to prioritize chemicals for further, more detailed testing. Phase I of ToxCast is testing 320 chemicals (mainly pesticide active ingredients) against ~400 cell-based and biochemical assays. In order to anchor these studies, we are using in vivo guideline study data for subchronic, chronic, cancer, reproductive and developmental endpoints. This data is compiled in the EPA toxicity reference database, ToxRefDB. The main goal of ToxCast is the discovery and validation of “signatures” linking in vitro assay data to in vivo toxicity endpoints. These signatures will be collections of assays that are correlated with particular endpoints. These assay collections should also help define molecular-and cellular-level mechanisms of toxicity. This talk will discuss our strategy to use a combination of statistical and machine learning methods, coupled with biochemical network or systems biology approaches. Our initial examples will focus signatures for endpoints from 2 year rodent cancer bioassays. Most of the data we have analyzed is in dose or concentration response series, so to effectively use this data we have developed novel appro

Clinical endpoint adjudication in a contemporary all-comers coronary stent investigation: methodology and external validation.

PubMed

Vranckx, Pascal; McFadden, Eugene; Cutlip, Donald E; Mehran, Roxana; Swart, Michael; Kint, P P; Zijlstra, Felix; Silber, Sigmund; Windecker, Stephan; Serruys, Patrick W C J

2013-01-01

Globalisation in coronary stent research calls for harmonization of clinical endpoint definitions and event adjudication. Little has been published about the various processes used for event adjudication or their impact on outcome reporting. We performed a validation of the clinical event committee (CEC) adjudication process on 100 suspected events in the RESOLUTE All-comers trial (Resolute-AC). Two experienced Clinical Research Organisations (CRO) that had already extensive internal validation processes in place, participated in the study. After initial adjudication by the primary-CEC, events were cross-adjudicated by an external-CEC using the same definitions. Major discrepancies affecting the primary end point of target-lesion failure (TLF), a composite of cardiac death, target vessel myocardial infarction (TV-MI), or clinically-indicated target-lesion revascularization (CI-TLR), were analysed by an independent oversight committee who provided recommendations for harmonization. Discordant adjudications were reconsidered by the primary CEC. Subsequently, the RAC database was interrogated for cases that based on these recommendations merited re-adjudication and these cases were also re-adjudicated by the primary CEC. Final discrepancies in adjudication of individual components of TLF occurred in 7 out of 100 events in 5 patients. Discrepancies for the (hierarchical) primary endpoint occurred in 5 events (2 cardiac deaths and 3 TV-MI). After application of harmonization recommendations to the overall RAC population (n=2292), the primary CEC adjudicated 3 additional clinical-TLRs and considered 1 TV-MI as no event. A harmonization process provided a high level of concordance for event adjudication and improved accuracy for final event reporting. These findings suggest it is feasible to pool clinical event outcome data across clinical trials even when different CECs are responsible for event adjudication. Copyright © 2012 Elsevier Inc. All rights reserved.

The Pareidolia Test: A Simple Neuropsychological Test Measuring Visual Hallucination-Like Illusions.

PubMed

Mamiya, Yasuyuki; Nishio, Yoshiyuki; Watanabe, Hiroyuki; Yokoi, Kayoko; Uchiyama, Makoto; Baba, Toru; Iizuka, Osamu; Kanno, Shigenori; Kamimura, Naoto; Kazui, Hiroaki; Hashimoto, Mamoru; Ikeda, Manabu; Takeshita, Chieko; Shimomura, Tatsuo; Mori, Etsuro

2016-01-01

Visual hallucinations are a core clinical feature of dementia with Lewy bodies (DLB), and this symptom is important in the differential diagnosis and prediction of treatment response. The pareidolia test is a tool that evokes visual hallucination-like illusions, and these illusions may be a surrogate marker of visual hallucinations in DLB. We created a simplified version of the pareidolia test and examined its validity and reliability to establish the clinical utility of this test. The pareidolia test was administered to 52 patients with DLB, 52 patients with Alzheimer's disease (AD) and 20 healthy controls (HCs). We assessed the test-retest/inter-rater reliability using the intra-class correlation coefficient (ICC) and the concurrent validity using the Neuropsychiatric Inventory (NPI) hallucinations score as a reference. A receiver operating characteristic (ROC) analysis was used to evaluate the sensitivity and specificity of the pareidolia test to differentiate DLB from AD and HCs. The pareidolia test required approximately 15 minutes to administer, exhibited good test-retest/inter-rater reliability (ICC of 0.82), and moderately correlated with the NPI hallucinations score (rs = 0.42). Using an optimal cut-off score set according to the ROC analysis, and the pareidolia test differentiated DLB from AD with a sensitivity of 81% and a specificity of 92%. Our study suggests that the simplified version of the pareidolia test is a valid and reliable surrogate marker of visual hallucinations in DLB.

Biomechanical constraints on the feedforward regulation of endpoint stiffness.

PubMed

Hu, Xiao; Murray, Wendy M; Perreault, Eric J

2012-10-01

Although many daily tasks tend to destabilize arm posture, it is still possible to have stable interactions with the environment by regulating the multijoint mechanics of the arm in a task-appropriate manner. For postural tasks, this regulation involves the appropriate control of endpoint stiffness, which represents the stiffness of the arm at the hand. Although experimental studies have been used to evaluate endpoint stiffness control, including the orientation of maximal stiffness, the underlying neural strategies remain unknown. Specifically, the relative importance of feedforward and feedback mechanisms has yet to be determined due to the difficulty separately identifying the contributions of these mechanisms in human experiments. This study used a previously validated three-dimensional musculoskeletal model of the arm to quantify the degree to which the orientation of maximal endpoint stiffness could be changed using only steady-state muscle activations, used to represent feedforward motor commands. Our hypothesis was that the feedforward control of endpoint stiffness orientation would be significantly constrained by the biomechanical properties of the musculoskeletal system. Our results supported this hypothesis, demonstrating substantial biomechanical constraints on the ability to regulate endpoint stiffness throughout the workspace. The ability to regulate stiffness orientation was further constrained by additional task requirements, such as the need to support the arm against gravity or exert forces on the environment. Together, these results bound the degree to which slowly varying feedforward motor commands can be used to regulate the orientation of maximum arm stiffness and provide a context for better understanding conditions in which feedback control may be needed.

Phase II cancer clinical trials for biomarker-guided treatments.

PubMed

Jung, Sin-Ho

2018-01-01

The design and analysis of cancer clinical trials with biomarker depend on various factors, such as the phase of trials, the type of biomarker, whether the used biomarker is validated or not, and the study objectives. In this article, we demonstrate the design and analysis of two Phase II cancer clinical trials, one with a predictive biomarker and the other with an imaging prognostic biomarker. Statistical testing methods and their sample size calculation methods are presented for each trial. We assume that the primary endpoint of these trials is a time to event variable, but this concept can be used for any type of endpoint.

Challenges to the Therapeutic Pipeline for Irritable Bowel Syndrome: Endpoints and Regulatory Hurdles

PubMed Central

Camilleri, Michael; Chang, Lin

2008-01-01

Recent advances in our understanding of basic neuroenteric mechanisms and the role of effectors and transmitters in the brain-gut axis have provided opportunities to develop new therapeutic agents for irritable bowel syndrome (IBS). Furthermore, human pharmacodynamic studies utilizing transit, colonic or rectal sensitivity, and brain imaging have been useful in determining therapeutic efficacy (particularly for drugs that act on motor function). This review provides an overview of medications that have not yet been approved for treatment of patients with IBS, yet have shown promise in phase IIB trials. These include drugs that act on the serotonin receptor and transporter system, antidepressants, norepinephrine reuptake inhibitors, opioids, cholecystokinin antagonists, neurokinin-antagonists, chloride channel activators, guanylate cyclase C agonists, atypical benzodiazepines, probiotics and antibiotics. The changing landscape in the regulatory approval process has impacted the development of IBS drugs. Guidance documents from regulatory agencies in Europe and the United States have focused on patients’ reported outcomes and associated quality of life. After a decade of experience with different endpoints that have generated some data on psychometric validation and unprecedented information about responsiveness of the binary or global endpoints to drug therapy, it is necessary to pursue further validation studies before or during pivotal phase IIB or III trials. The hope of providing relief to patients should galvanize all parties to achieve these goals. PMID:18848833

Cranberry versus placebo in the prevention of urinary infections in multiple sclerosis: a multicenter, randomized, placebo-controlled, double-blind trial.

PubMed

Gallien, Philippe; Amarenco, Gérard; Benoit, Nicolas; Bonniaud, Véronique; Donzé, Cécile; Kerdraon, Jacques; de Seze, Marianne; Denys, Pierre; Renault, Alain; Naudet, Florian; Reymann, Jean Michel

2014-08-01

Our aim was to assess the usefulness of cranberry extract in multiple sclerosis (MS) patients suffering from urinary disorders. In total, 171 adult MS outpatients with urinary disorders presenting at eight centers were randomized (stratification according to center and use of clean intermittent self-catheterization) to cranberry versus placebo in a 1-year, prospective, double-blind study that was analyzed using a sequential method on an intent-to-treat basis. An independent monitoring board analyzed the results of the analyses each time 40 patients were assessed on the main endpoint. Cranberry extract (36 mg proanthocyanidins per day) or a matching placebo was taken by participants twice daily for 1 year. The primary endpoint was the time to first symptomatic urinary tract infection (UTI), subject to validation by a validation committee. The second sequential analyses allowed us to accept the null hypothesis (no difference between cranberry and placebo). There was no difference in time to first symptomatic UTI distribution across 1 year, with an estimated hazard ratio of 0.99, 95% CI [0.61, 1.60] (p = 0.97). Secondary endpoints and tolerance did not differ between groups. Taking cranberry extract versus placebo twice a day did not prevent UTI occurrence in MS patients with urinary disorders. Trial Registration NCT00280592. © The Author(s) 2014.

Clinically relevant behavioral endpoints in a recurrent nitroglycerin migraine model in rats.

PubMed

Sufka, Kenneth J; Staszko, Stephanie M; Johnson, Ainslee P; Davis, Morgan E; Davis, Rachel E; Smitherman, Todd A

2016-01-01

This research sought to further validate the rat nitroglycerin (NTG) migraine model by comparing the effects of single versus recurrent NTG episodes on behavioral endpoints that mirror ICHD-3 diagnostic criteria for migraine, and to determine if the altered behavioral endpoints are reduced after administration of sumatriptan. Separate cohorts of rats were administered NTG (10 mg/kg/2 ml) or saline (Experiment 1: single injection; Experiment 2: repeated injections; Experiment 3: repeated injections with sumatriptan [0.0, 0.3 and 1.0 mg/kg/ml] rescue. Behavioral endpoints were assessed 2 h after final NTG administration and included time in light/dark chambers for photophobia and activity, pain facial ratings, and cool (5 °C) and warm (46 °C) tail dip. The first two experiments demonstrated that repeated (n = 5) but not single NTG injections produced photophobia, decreased activity, and yielded less weight gain than saline injections. Experiment 3 showed that sumatriptan attenuated hypoactivity, reduced facial expressions of pain, and reversed weight alterations in a dose-dependent manner. These findings identify numerous clinical homologies of a recurrent NTG rat migraine model that may be useful for screening novel pharmacotherapies.

Upper Limb Coordination in Individuals With Stroke: Poorly Defined and Poorly Quantified.

PubMed

Tomita, Yosuke; Rodrigues, Marcos R M; Levin, Mindy F

2017-01-01

The identification of deficits in interjoint coordination is important in order to better focus upper limb rehabilitative treatment after stroke. The majority of standardized clinical measures characterize endpoint performance, such as accuracy, speed, and smoothness, based on the assumption that endpoint performance reflects interjoint coordination, without measuring the underlying temporal and spatial sequences of joint recruitment directly. However, this assumption is questioned since improvements of endpoint performance can be achieved through different degrees of restitution or compensation of upper limb motor impairments based on the available kinematic redundancy of the system. Confusion about adequate measurement may stem from a lack a definition of interjoint coordination during reaching. We suggest an operational definition of interjoint coordination during reaching as a goal-oriented process in which joint degrees of freedom are organized in both spatial and temporal domains such that the endpoint reaches a desired location in a context-dependent manner. In this point-of-view article, we consider how current approaches to laboratory and clinical measures of coordination comply with our definition. We propose future study directions and specific research strategies to develop clinical measures of interjoint coordination with better construct and content validity than those currently in use.

Long-term Course of Depression Trajectories in Patients With COPD: A 3-Year Follow-up Analysis of the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints Cohort.

PubMed

Yohannes, Abebaw M; Müllerová, Hana; Hanania, Nicola A; Lavoie, Kim; Tal-Singer, Ruth; Vestbo, Jorgen; Rennard, Steven I; Wouters, Emil F M

2016-04-01

There is insufficient evidence about the long-term course of depressive symptom trajectories and their impact among patients with COPD. We analysed 3-year data obtained from patients with COPD participating in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study. Patients were split into four groups on the basis of Center for Epidemiologic Studies Depression Scale score (< 16 vs ≥ 16) and antidepressant use (yes vs no) at baseline and at 3 years: never depressed, new onset, remittent, and persistent depression. Baseline characteristics were used to assess factors associated with the group by using logistic regression. A total of 1,589 patients with COPD completed the 3-year follow-up. Of these, 55% (n = 869) were classified as never depressed, 24% (n = 377) were classified as persistently depressed, 14% (n = 226) developed new onset of depression, and 7% (n = 117) had depression that remitted. Female sex and history of stroke were associated with substantial increases in the odds of persistent depression (OR, 2.95; 95% CI, 2.05-4.24 and OR, 3.09; 95% CI, 1.43-6.67, respectively). Odds of new onset depression increased with worse health status (OR, 1.10; 95% CI, 1.04-1.17 per 4-point increase in St. George's Respiratory Questionnaire score) and moderate to severe dyspnea (OR, 1.57; 95% CI, 1.07-2.31 for modified Medical Research Council score ≥ 2 vs 0 or 1). During follow-up, patients with persistent or new-onset depression experienced more exacerbations and more pronounced loss in performance as assessed by reduction in the 6-min walk distance (6MWD) test score. About one in four patients with COPD had persistent depressive symptoms over 3 years. Clinicians should be aware of the characteristics of persistent and new onset depressive symptoms, which are associated with risk of exacerbations and loss of performance on the 6MWD test. Interventions that ameliorate the course of depression are needed. ClinicalTrials.gov; No.: NCT00292552; URL: www.clinicaltrials.gov. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.