Estimation and inference of the win ratio for two hierarchical endpoints subject to censoring and missing data.

The win ratio (WR) is a widely used metric to compare treatments in randomized clinical trials with hierarchically ordered endpoints. Counting-based approaches, such as Pocock's algorithm, are the standard for WR estimation. However, this algorithm treats participants with censored or missing data inadequately, which may lead to biased and inefficient estimates, particularly in the presence of heterogeneous censoring or missing data between treatment groups. Although recent extensions have addressed some of these limitations for hierarchical time-to-event endpoints, no existing methods - aside from the computationally intensive multiple-imputation approach - can accommodate settings that include nonsurvival endpoints that are subject to missing data. In this paper, we propose a simple nonparametric maximum likelihood estimator (NPMLE) of WR for two hierarchical endpoints that are subject to censoring and missing data. Our method uses all observed data, avoid strong parametric assumptions and come with a closed-form asymptotic variance estimator. We demonstrate its performance using simulation studies and two data examples, based on the HEART-FID and ISCHEMIA trials. The proposed method provides a consistent estimator, improves estimation efficiency, and is robust under noninformative censoring and missing at random (MAR) assumptions, offering a flexible alternative to existing WR estimation methods. A user-friendly R package, WinRS, is available to facilitate implementation.

Duke Scholars

Author Huiman Xie Barnhart Biostatistics & Bioinformatics, Division of Biostatistics

Author Yuliya Vladimirovna Lokhnygina Biostatistics & Bioinformatics, Division of Biostatistics

Author Roland Albert Matsouaka Biostatistics & Bioinformatics, Division of Biostatistics