Primary Submission Category: Applications in Health and Biology
A CV-TMLE global test Approach to Multiple-Component Endpoints in Rare Disease Clinical Trials
Authors: Tianyue Zhou, Susan Gruber, Mark van der Laan, Hana Lee, Wonyul Lee, Lei Nie,
Presenting Author: Tianyue Zhou*
Rare disease trials face unique statistical challenges due to limited patient populations and heterogeneous clinical manifestations among patients. Multiple endpoints are often necessary to comprehensively capture treatment benefits. A global test is an approach for evaluating whether a treatment has any beneficial effect across multiple endpoints. We propose a new global test based on a weighted composite endpoint. The proposed global test employs shrinkage-based cross-validated targeted maximum likelihood estimation (CV TMLE) to learn data-adaptive weights that maximize power while maintaining Type I error control. Shrinkage can be tailored to incorporate existing domain knowledge, such as anticipated relative effect sizes. In simulation studies designed to reflect real rare disease trial settings, the proposed procedure demonstrated improved power over standard multiplicity adjustments and classical global tests (e.g., O’Brien test), while maintaining nominal type I error, when effects are heterogeneous across endpoints. The proposed method simultaneously learns an optimal weighted composite outcome and provides an efficient and unbiased TMLE for the average treatment effect (ATE) on that weighted outcome, with valid inference taking into account that the ATE is data dependent.