Optimal, two-stage, adaptive enrichment designs for randomized trials, using sparse linear programming

• 成果类型: Article
• 署名作者: Rosenblum, Michael; Fang, Ethan X.; Liu, Han
• 署名单位: Johns Hopkins University; Johns Hopkins Bloomberg School of Public Health; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; Northwestern University
• 刊物名称: JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY
• ISSN/ISSBN: 1369-7412
• DOI: 10.1111/rssb.12366
• 发表日期: 2020
• 页码: 749-772
• 关键词: ii/iii clinical-trials; hypotheses selection; subgroup selection; targeted therapy; interim; DECISION; subpopulations; population

摘要

Adaptive enrichment designs involve preplanned rules for modifying enrolment criteria based on accruing data in a randomized trial. We focus on designs where the overall population is partitioned into two predefined subpopulations, e.g. based on a biomarker or risk score measured at baseline. The goal is to learn which populations benefit from an experimental treatment. Two critical components of adaptive enrichment designs are the decision rule for modifying enrolment, and the multiple-testing procedure. We provide a general method for simultaneously optimizing these components for two-stage, adaptive enrichment designs. We minimize the expected sample size under constraints on power and the familywise type I error rate. It is computationally infeasible to solve this optimization problem directly because of its non-convexity. The key to our approach is a novel, discrete representation of this optimization problem as a sparse linear program, which is large but computationally feasible to solve by using modern optimization techniques. We provide an R package that implements our method and is compatible with linear program solvers in several software languages. Our approach produces new, approximately optimal trial designs.