On evaluating how well a biomarker can predict treatment response with survival data

One of the objectives of personalized medicine is to take treatment decisions based on a biomarker measurement. Therefore, it is often interesting to evaluate how well a biomarker can predict the response to a treatment. To do so, a popular methodology consists of using a regression model and testing for an interaction between treatment assignment and biomarker. However, the existence of an interaction is not sufficient for a biomarker to be predictive. It is only necessary. Hence, the use of the marker‐by‐treatment predictiveness curve has been recommended. In addition to evaluate how well a single continuous biomarker predicts treatment response, it can further help to define an optimal threshold. This curve displays the risk of a binary outcome as a function of the quantiles of the biomarker, for each treatment group. Methods that assume a binary outcome or rely on a proportional hazard model for a time‐to‐event outcome have been proposed to estimate this curve. In this work, we propose some extensions for censored data. They rely on a time‐dependent logistic model, and we propose to estimate this model via inverse probability of censoring weighting. We present simulations results and three applications to prostate cancer, liver cirrhosis, and lung cancer data. They suggest that a large number of events need to be observed to define a threshold with sufficient accuracy for clinical usefulness. They also illustrate that when the treatment effect varies with the time horizon which defines the outcome, then the optimal threshold also depends on this time horizon.     

A visualization method measuring the performance of biomarkers for guiding treatment decisions

Biomarkers that predict efficacy and safety for a given drug therapy become increasingly important for treatment strategy and drug evaluation in personalized medicine. Methodology for appropriately identifying and validating such biomarkers is critically needed, although it is very challenging to develop, especially in trials of terminal diseases with survival endpoints. The marker‐by‐treatment predictiveness curve serves this need by visualizing the treatment effect on survival as a function of biomarker for each treatment. In this article, we propose the weighted predictiveness curve (WPC). Based on the nature of the data, it generates predictiveness curves by utilizing either parametric or nonparametric approaches. Especially for nonparametric predictiveness curves, by incorporating local assessment techniques, it requires minimum model assumptions and provides great flexibility to visualize the marker‐by‐treatment relationship. WPC can be used to compare biomarkers and identify the one with the highest potential impact. Equally important, by simultaneously viewing several treatment‐specific predictiveness curves across the biomarker range, WPC can also guide the biomarker‐based treatment regimens. Simulations representing various scenarios are employed to evaluate the performance of WPC. Application on a well‐known liver cirrhosis trial sheds new light on the data and leads to discovery of novel patterns of treatment biomarker interactions. Copyright © 2015 John Wiley & Sons, Ltd.     

Detecting diagnostic accuracy of two biomarkers through a bivariate log-normal ROC curve

In biomedical research, two or more biomarkers may be available for diagnosis of a particular disease. Selecting one single biomarker which ideally discriminate a diseased group from a healthy group is confront in a diagnostic process. Frequently, most of the people use the accuracy measure, area under the receiver operating characteristic (ROC) curve to choose the best diagnostic marker among the available markers for diagnosis. Some authors have tried to combine the multiple markers by an optimal linear combination to increase the discriminatory power. In this paper, we propose an alternative method that combines two continuous biomarkers by direct bivariate modeling of the ROC curve under log-normality assumption. The proposed method is applied to simulated data set and prostate cancer diagnostic biomarker data set.     

Can a treatment be licenced on the basis of post‐treatment predictive biomarkers?

In recent years, there has been a great deal of literature published concerning the identification of predictive biomarkers and indeed, an increasing number of therapies have been licenced on this basis. However, this progress has been made almost exclusively on the basis of biomarkers measured prior to exposure to treatment. There are quite different challenges when the responding population can only be identified on the basis of outcomes observed following exposure to treatment, especially if it represents only a small proportion of patients. The purpose of this paper is to explore whether or when a treatment could be licenced on the basis of post‐treatment predictive biomarkers (PTPB), the focus is on oncology but the concepts should apply to all therapeutic areas. We review the potential pitfalls in hypothesising the presence of a PTPB. We also present challenges in trial design required to confirm and licence on the basis of a PTPB: what's the control population?, could there be a detriment to non‐responders by exposure to the new treatment?, can responders be identified rapidly?, could prior exposure to the new treatment adversely affect performance of the control in responders? Nevertheless, if the patients to be treated could be rapidly identified after prior exposure to treatment, and without harm to non‐responders, in appropriately designed and analysed trials, may be more targeted therapies could be made available to patients. Copyright © 2014 John Wiley & Sons, Ltd.     

天池铺构造石炭系油气地球化学特征与成因

四川盆地东部天池铺构造天然气为干气,具有原油裂解气的特征,同时存在少部分后期高演化干酪根裂解气的贡献,原油为轻质油,油碳同位素偏重,是以汽油烃为主的凝析油,没有受到生物降解。通过对油气碳同位素、轻烃及油岩生物标志化合物等的综合研究,指出天池铺构造石炭系油气为腐泥型成因,成熟度高,均来自下伏志留系源岩。天然气与上二叠统煤系气具有明显的区别,凝析油碳同位素偏重主要与原油热蚀变（热裂解）和反凝析作用有关。成藏地球化学方法研究表明天池铺构造石炭系存在印支期古油藏,根据埋藏与热演化生烃史及古地温梯度计算可知石炭系已聚集的原油在白垩纪末期发生热蚀变(裂解)而转化为含油气藏。系统阐明了川东地区石炭系气藏属于古油藏裂解成因,并为川东地区寻找原油裂解气提供了科学依据。     

A Bayesian approach for generalized linear models with explanatory biomarker measurement variables subject to detection limit: an application to acute lung injury

Biomarkers have the potential to improve our understanding of disease diagnosis and prognosis. Biomarker levels that fall below the assay detection limits (DLs), however, compromise the application of biomarkers in research and practice. Most existing methods to handle non-detects focus on a scenario in which the response variable is subject to the DL; only a few methods consider explanatory variables when dealing with DLs. We propose a Bayesian approach for generalized linear models with explanatory variables subject to lower, upper, or interval DLs. In simulation studies, we compared the proposed Bayesian approach to four commonly used methods in a logistic regression model with explanatory variable measurements subject to the DL. We also applied the Bayesian approach and other four methods in a real study, in which a panel of cytokine biomarkers was studied for their association with acute lung injury (ALI). We found that IL8 was associated with a moderate increase in risk for ALI in the model based on the proposed Bayesian approach.     

A comparison of subgroup identification methods in clinical drug development: Simulation study and regulatory considerations

With advancement of technologies such as genomic sequencing, predictive biomarkers have become a useful tool for the development of personalized medicine. Predictive biomarkers can be used to select subsets of patients, which are most likely to benefit from a treatment. A number of approaches for subgroup identification were proposed over the last years. Although overviews of subgroup identification methods are available, systematic comparisons of their performance in simulation studies are rare. Interaction trees (IT), model‐based recursive partitioning, subgroup identification based on differential effect, simultaneous threshold interaction modeling algorithm (STIMA), and adaptive refinement by directed peeling were proposed for subgroup identification. We compared these methods in a simulation study using a structured approach. In order to identify a target population for subsequent trials, a selection of the identified subgroups is needed. Therefore, we propose a subgroup criterion leading to a target subgroup consisting of the identified subgroups with an estimated treatment difference no less than a pre‐specified threshold. In our simulation study, we evaluated these methods by considering measures for binary classification, like sensitivity and specificity. In settings with large effects or huge sample sizes, most methods perform well. For more realistic settings in drug development involving data from a single trial only, however, none of the methods seems suitable for selecting a target population. Using the subgroup criterion as alternative to the proposed pruning procedures, STIMA and IT can improve their performance in some settings. The methods and the subgroup criterion are illustrated by an application in amyotrophic lateral sclerosis.     

Bayesian adaptive patient enrollment restriction to identify a sensitive subpopulation using a continuous biomarker in a randomized phase 2 trial

With the development of molecular targeted drugs, predictive biomarkers have played an increasingly important role in identifying patients who are likely to receive clinically meaningful benefits from experimental drugs (i.e., sensitive subpopulation) even in early clinical trials. For continuous biomarkers, such as mRNA levels, it is challenging to determine cutoff value for the sensitive subpopulation, and widely accepted study designs and statistical approaches are not currently available. In this paper, we propose the Bayesian adaptive patient enrollment restriction (BAPER) approach to identify the sensitive subpopulation while restricting enrollment of patients from the insensitive subpopulation based on the results of interim analyses, in a randomized phase 2 trial with time‐to‐endpoint outcome and a single biomarker. Applying a four‐parameter change‐point model to the relationship between the biomarker and hazard ratio, we calculate the posterior distribution of the cutoff value that exhibits the target hazard ratio and use it for the restriction of the enrollment and the identification of the sensitive subpopulation. We also consider interim monitoring rules for termination because of futility or efficacy. Extensive simulations demonstrated that our proposed approach reduced the number of enrolled patients from the insensitive subpopulation, relative to an approach with no enrollment restriction, without reducing the likelihood of a correct decision for next trial (no‐go, go with entire population, or go with sensitive subpopulation) or correct identification of the sensitive subpopulation. Additionally, the four‐parameter change‐point model had a better performance over a wide range of simulation scenarios than a commonly used dichotomization approach. Copyright © 2016 John Wiley & Sons, Ltd.     

A signature enrichment design with Bayesian adaptive randomization

Clinical trials in the era of precision cancer medicine aim to identify and validate biomarker signatures which can guide the assignment of individually optimal treatments to patients. In this article, we propose a group sequential randomized phase II design, which updates the biomarker signature as the trial goes on, utilizes enrichment strategies for patient selection, and uses Bayesian response-adaptive randomization for treatment assignment. To evaluate the performance of the new design, in addition to the commonly considered criteria of Type I error and power, we propose four new criteria measuring the benefits and losses for individuals both inside and outside of the clinical trial. Compared with designs with equal randomization, the proposed design gives trial participants a better chance to receive their personalized optimal treatments and thus results in a higher response rate on the trial. This design increases the chance to discover a successful new drug by an adaptive enrichment strategy, i.e. identification and selective enrollment of a subset of patients who are sensitive to the experimental therapies. Simulation studies demonstrate these advantages of the proposed design. It is illustrated by an example based on an actual clinical trial in non-small-cell lung cancer.