Optimal Partitioning for Linear Mixed Effects Models: Applications to Identifying Placebo Responders

A longstanding problem in clinical research is distinguishing drug-treated subjects that respond due to specific effects of the drug from those that respond to nonspecific (or placebo) effects of the treatment. Linear mixed effect models are commonly used to model longitudinal clinical trial data. In this paper we present a solution to the problem of identifying placebo responders using an optimal partitioning methodology for linear mixed effects models. Since individual outcomes in a longitudinal study correspond to curves, the optimal partitioning methodology produces a set of prototypical outcome profiles. The optimal partitioning methodology can accommodate both continuous and discrete covariates. The proposed partitioning strategy is compared and contrasted with the growth mixture modeling approach. The methodology is applied to a two-phase depression clinical trial where subjects in a first phase were treated openly for 12 weeks with fluoxetine followed by a double blind discontinuation phase where responders to treatment in the first phase were randomized to either stay on fluoxetine or switched to a placebo. The optimal partitioning methodology is applied to the first phase to identify prototypical outcome profiles. Using time to relapse in the second phase of the study, a survival analysis is performed on the partitioned data. The optimal partitioning results identify prototypical profiles that distinguish whether subjects relapse depending on whether or not they stay on the drug or are randomized to a placebo.