Confidence intervals for two-stage adaptive designs with subpopulation selection

2026-03-13

AI Summary

This study addresses the challenge of constructing valid confidence intervals in two-stage adaptive enrichment clinical trials, where patient subgroups are selected based on interim data, thereby compromising the nominal coverage of conventional intervals. The authors propose a novel method that constructs confidence intervals conditional on the interim selection decision, leveraging conditional inference and inversion of uniformly most accurate unbiased (UMAU) tests to guarantee exact coverage within the selected subgroup. The approach is broadly applicable to various adaptive enrichment designs and is implemented via an efficient numerical algorithm. Extensive simulation studies demonstrate that the proposed intervals consistently achieve the desired coverage probability across diverse design configurations, substantially outperforming existing methods in both validity and precision.

Technology Category

• Machine Learning: Calibration & Uncertainty Quantification
• Reasoning under Uncertainty: Stochastic Optimization
• Intelligent Robots: State Estimation

Application Category

• User Modeling, Personalization and Recommendation: Fairness-aware retrieval and ranking
• Graph Algorithms and Modeling for the Web: Representation, reconstruction, and subgraph or motif discovery in Web-related graphs
• Security and Privacy: Large-scale security measurements

Abstract

We consider clinical trials in which an experimental treatment is compared with a control in pre-specified patient subpopulations. In such settings, adaptive enrichment designs allow the enrolled population to be modified at an interim analysis, with subpopulations selected according to preplanned rules. Since these interim decisions are data-dependent, valid statistical inference must account for them. We focus on constructing confidence intervals for the treatment effect in the selected population. Confidence interval methods that ignore the possibility of population modification may fail to achieve the desired coverage probability. We propose a new approach that constructs confidence intervals with exact nominal coverage conditional on the interim decision. Importantly, our method applies to a broad class of adaptive enrichment designs, rather than a single specific design. Our method involves deriving the distribution of the naive estimator of the treatment effect in the selected population conditional on the interim decision and inverting uniformly most accurate unbiased tests to obtain the confidence interval. We provide an efficient computational procedure and show through extensive simulations that the resulting confidence intervals satisfy the theoretical coverage guarantees.

Problem

• adaptive enrichment designs
• subpopulation selection
• confidence intervals
• treatment effect
• coverage probability

Innovation

• adaptive enrichment design
• confidence interval
• subpopulation selection
• conditional inference
• uniformly most accurate unbiased test