Subgroup Identification in Clinical Trials by Stochastic SIDEScreen Methods

Abstract

ABSTRACTSubgroup identification for personalized medicine has become very popular in the last decade. Efficient recursive partitioning procedures adapted from machine learning are natural approaches for performing subgroup identification based on pre-defined biomarkers since they provide subgroups as terminal nodes in the decision tree. However, recursive partitioning is also known as a potentially unstable procedure with results being quite sensitive to normal sampling variability in the data. One common approach, borrowed from ensemble learning, to overcome such instability is application of recursive partitioning to multiple data sets sampled from the observed data followed by averaging the results over the collection of subgroups.This article proposes an alternative approach to subgroup identification in clinical trials that first evaluates the predictive strength of biomarkers based on variable importance and then applies recursive partitioning to the biomarkers with the highest variable importance scores. A deterministic version of this idea was implemented in the Adaptive SIDEScreen method that generates a collection of patient subgroups by retaining multiple candidate splits of each parent group by different biomarkers (Lipkovich and Dmitrienko 2014a, 2014b). Now, we extend the Adaptive SIDEScreen and introduce the Stochastic SIDEScreen method. The key idea is to introduce randomness in the subgroup generation process, borrowing from bagging methods, to produce a broader collection of subgroups. Specifically, the SIDES method, where the most promising biomarkers are selected for each parent group from a set of candidate biomarkers, is applied to multiple bootstrap samples of the data. This new approach leads to a more reliable biomarker selection process, which is especially important for smaller, early phase studies when biomarker selection is typically carried out. The method is illustrated using clinical trial examples.