Evaluating surrogate variables for improving microarray multiple testing inference

The use of surrogate variables has been proposed as a means to capture, for a given observed set of data, sources driving the dependency structure among high-dimensional sets of features and remove the effects of those sources and their potential negative impact on simultaneous inference. In this article we illustrate the potential effects of latent variables on testing dependence and the resulting impact on multiple inference, we briefly review the method of surrogate variable analysis proposed by Leek and Storey (PNAS 2008; 105:18718-18723), and assess that method via simulations intended to mimic the complexity of feature dependence observed in real-world microarray data. The method is also assessed via application to a recent Merck microarray data set. Both simulation and case study results indicate that surrogate variable analysis can offer a viable strategy for tackling the multiple testing dependence problem when the features follow a potentially complex correlation structure, yielding improvements in the variability of false positive rates and increases in power.     

Clinical utility estimation for assay cutoffs in early phase oncology enrichment trials

Predictive enrichment strategies use biomarkers to selectively enroll oncology patients into clinical trials to more efficiently demonstrate therapeutic benefit. Because the enriched population differs from the patient population eligible for screening with the biomarker assay, there is potential for bias when estimating clinical utility for the screening eligible population if the selection process is ignored. We write estimators of clinical utility as integrals averaging regression model predictions over the conditional distribution of the biomarker scores defined by the assay cutoff and discuss the conditions under which consistent estimation can be achieved while accounting for some nuances that may arise as the biomarker assay progresses toward a companion diagnostic. We outline and implement a Bayesian approach in estimating these clinical utility measures and use simulations to illustrate performance and the potential biases when estimation naively ignores enrichment. Results suggest that the proposed integral representation of clinical utility in combination with Bayesian methods provide a practical strategy to facilitate cutoff decision‐making in this setting. Copyright © 2015 John Wiley & Sons, Ltd.