A Simultaneous Inference Procedure to Identify Subgroups from RCTs with Survival Outcomes: Application to Analysis of AMD Progression Studies

Abstract

With the uptake of targeted therapies, instead of the "one-fits-all" approach, modern randomized clinical trials (RCTs) often aim to develop treatments that target a subgroup of patients. Motivated by analyzing the Age-Related Eye Disease Study (AREDS) data, a large RCT to study the efficacy of nutritional supplements in delaying the progression of an eye disease, age-related macular degeneration (AMD), we develop a simultaneous inference procedure to identify and infer subgroups with differential treatment efficacy in RCTs with survival outcome. Specifically, we formulate the multiple testing problem through contrasts and construct their simultaneous confidence intervals, which control both within-and across-marker multiplicity appropriately. Realistic simulations are conducted using real genotype data to evaluate the method performance under various scenarios. The method is then applied to AREDS to assess the efficacy of antioxidants and zinc combination in delaying AMD progression. Multiple gene regions including ESRRB-VASH1 on chromosome 14 have been identified with subgroups showing differential efficacy. We further validate our findings in an independent subsequent RCT, AREDS2, by discovering consistent differential treatment responses in the targeted and nontargeted subgroups been identified from AREDS. This simultaneous inference approach provides a step forward to confidently identify and infer subgroups in modern drug development.