Subgroup identification using covariate-adjusted interaction trees.

We consider the problem of identifying subgroups of participants in a clinical trial that have enhanced treatment effect. Recursive partitioning methods that recursively partition the covariate space based on some measure of between groups treatment effect difference are popular for such subgroup identification. The most commonly used recursive partitioning method, the classification and regression tree algorithm, first creates a large tree by recursively partitioning the covariate space using some splitting criteria and then selects the final tree from all the subtrees of the large tree. In the context of subgroup identification, calculation of the splitting criteria and the evaluation measure used for final tree selection rely on comparing differences in means between the treatment and control arm. When covariates are prognostic for the outcome, covariate adjusted estimators have the ability to improve efficiency compared to using differences in averages between the treatment and control group. This manuscript develops two covariate adjusted estimators that can be used to both make splitting decisions and for final tree selection. The performance of the resulting covariate adjusted recursive partitioning algorithm is evaluated using simulations and by analyzing a clinical trial that evaluates if motivational interviews improve treatment engagement for substance abusers.