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With the uptake of targeted therapies, instead of the "one-fits-all"approach, modern randomized clinical trials (RCTs) often aim to developtreatments that target a subgroup of patients. Motivated by analyzing theAge-Related Eye Disease Study (AREDS) data, a large RCT to study the efficacyof nutritional supplements in delaying the progression of an eye disease,age-related macular degeneration (AMD), we develop a simultaneous inferenceprocedure to identify and infer subgroups with differential treatment efficacyin RCTs with survival outcome. Specifically, we formulate the multiple testingproblem through contrasts and construct their simultaneous confidenceintervals, which control both within- and across- marker multiplicityappropriately. Realistic simulations are conducted using real genotype data toevaluate the method performance under various scenarios. The method is thenapplied to AREDS to assess the efficacy of antioxidants and zinc combination indelaying AMD progression. Multiple gene regions including ESRRB-VASH1 onchromosome 14 have been identified with subgroups showing differentialefficacy. We further validate our findings in an independent subsequent RCT,AREDS2, by discovering consistent differential treatment responses in thetargeted and non-targeted subgroups been identified from AREDS. Thissimultaneous inference approach provides a step forward to confidently identifyand infer subgroups in modern drug development.

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