A class of proportional win-fractions regression models for composite outcomes.

The win ratio is gaining traction as a simple and intuitive approach to analysis of prioritized composite endpoints in clinical trials. To extend it from two-sample comparison to regression, we propose a novel class of semiparametric models that includes as special cases both the two-sample win ratio and the traditional Cox proportional hazards model on time to the first event. Under the assumption that the covariate-specific win and loss fractions are proportional over time, the regression coefficient is unrelated to the censoring distribution and can be interpreted as the log win ratio resulting from one-unit increase in the covariate. U-statistic estimating functions, in the form of an arbitrary covariate-specific weight process integrated by a pairwise residual process, are constructed to obtain consistent estimators for the regression parameter. The asymptotic properties of the estimators are derived using uniform weak convergence theory for U-processes. Visual inspection of a "score" process provides useful clues as to the plausibility of the proportionality assumption. Extensive numerical studies using both simulated and real data from a major cardiovascular trial show that the regression methods provide valid inference on covariate effects and outperform the two-sample win ratio in both efficiency and robustness. The proposed methodology is implemented in the R-package WR, publicly available from the Comprehensive R Archive Network (CRAN).

Mao L ，Wang T 《-》

Stratified proportional win-fractions regression analysis.

The recently proposed proportional win-fractions (PW) model extends the two-sample win ratio analysis of prioritized composite endpoints to regression. Its proportionality assumption ensures that the covariate-specific win ratios are invariant to the follow-up time. However, this assumption is strong and may not be satisfied by every covariate in the model. We develop a stratified PW model that adjusts for certain prognostic factors without setting them as covariates, thus bypassing the proportionality requirement. We formulate the stratified model based on pairwise comparisons within each stratum, with a common win ratio across strata modeled as a multiplicative function of the covariates. Correspondingly, we construct an estimating function for the regression coefficients in the form of an incomplete U $$ U $$ -statistic consisting of within-stratum pairs. Two types of asymptotic variance estimators are developed depending on the number of strata relative to the sample size. This in particular allows valid inference even when the strata are extremely small, such as with matched pairs. Simulation studies in realistic settings show that the stratified model outperforms the unstratified version in robustness and efficiency. Finally, real data from a major cardiovascular trial are analyzed to illustrate the potential benefits of stratification. The proposed methods are implemented in the R package WR, publicly available on the Comprehensive R Archive Network (CRAN).

Wang T ，Mao L 《-》

A win ratio approach to the re-analysis of Multiple Risk Factor Intervention Trial.

Kotalik A ，Eaton A ，Lian Q ，Serrano C ，Connett J ，Neaton JD ... -  《-》

Weighted win loss approach for analyzing prioritized outcomes.

To analyze prioritized outcomes, Buyse (2010) and Pocock et al. (2012) proposed the win loss approach. In this paper, we first study the relationship between the win loss approach and the traditional survival analysis on the time to the first event. We then propose the weighted win loss statistics to improve the efficiency of the unweighted methods. A closed-form variance estimator of the weighted win loss statistics is derived to facilitate hypothesis testing and study design. We also calculated the contribution index to better interpret the results of the weighted win loss approach. Simulation studies and real data analysis demonstrated the characteristics of the proposed statistics. Copyright © 2017 John Wiley & Sons, Ltd.

Luo X ，Qiu J ，Bai S ，Tian H ... -  《-》

Sample size formula for general win ratio analysis.

Originally proposed for the analysis of prioritized composite endpoints, the win ratio has now expanded into a broad class of methodology based on general pairwise comparisons. Complicated by the non-i.i.d. structure of the test statistic, however, sample size estimation for the win ratio has lagged behind. In this article, we develop general and easy-to-use formulas to calculate sample size for win ratio analysis of different outcome types. In a nonparametric setting, the null variance of the test statistic is derived using U-statistic theory in terms of a dispersion parameter called the standard rank deviation, an intrinsic characteristic of the null outcome distribution and the user-defined rule of comparison. The effect size can be hypothesized either on the original scale of the population win ratio, or on the scale of a "usual" effect size suited to the outcome type. The latter approach allows one to measure the effect size by, for example, odds/continuation ratio for totally/partially ordered outcomes and hazard ratios for composite time-to-event outcomes. Simulation studies show that the derived formulas provide accurate estimates for the required sample size across different settings. As illustration, real data from two clinical studies of hepatic and cardiovascular diseases are used as pilot data to calculate sample sizes for future trials.

Mao L ，Kim K ，Miao X 《-》