arXiv subjects

Roland A. Matsouaka

Publications and source records attributed to Roland A. Matsouaka.

13 recordsLinked to original sources

arXiv2026

Estimation and Inference for Win Measures with Multiple Ordinal Endpoints Subject to Missingness

Win measures, including the win ratio, win odds, net benefit, and desirability of outcome ranking, are increasingly used in randomized clinical trials with multiple hierarchical ordinal endpoints. In practice, however, one or more component endpoints may have missing data. The standard pairwise-comparison approach, which treats pairs with missing outcomes as ties, can produce biased estimates, even if the data are missing completely at random. Although inverse probability of censoring weighting methods have been developed for censored survival endpoints, corresponding methods for addressing missing hierarchical ordinal endpoints are not yet available. To address this gap, we develop inverse probability weighted (IPW) and augmented IPW (AIPW) estimators for win measures with hierarchical ordinal endpoints subject to missing data, allowing missingness to depend on treatment assignment and baseline covariates. The IPW estimator corrects bias by reweighting complete observed outcomes using joint non-missingness probabilities involved in estimating the joint cell probabilities that define the win measures. The AIPW estimator additionally incorporates outcome modeling, potentially improving estimation precision and achieving double robustness. For inference, we derive closed-form variance estimators for both methods based on influence functions. Simulation studies show that the standard approach can be substantially biased, whereas the proposed IPW and AIPW estimators exhibit small bias and near-nominal coverage under their respective identifying and model conditions. Applications to the SCOUT-CAP and ACTT-1 trials illustrate the practical utility of the proposed methods. An R package WinMO is provided for implementation.

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arXiv2026

Win Time In Favor of Treatment (WINFT) for Hierarchical Endpoints

Standard win statistics methods determine a win, loss, or tie for a pair of subjects based on their worst outcomes (up to the end of study) that may not fully utilize all patients' conditions or disease experience throughout the follow-up period. While the newly developed win-time statistics fully utilize all patients' longitudinal information, these statistics have been limited to time-to-event endpoints and require monotonic pattern of the events. As such, they are not applicable to any type nor number of hierarchical longitudinal endpoints. We propose the win time in favor of treatment (WINFT), a general measure for any hierarchical longitudinal endpoints, that summarizes the total time a subject in the treatment group spends in a more favorable health state than a subject in the control group. Unlike existing win time methods, the WINFT does not require the component outcomes to be monotone and does not rely on modeling assumptions for estimating state probabilities. This flexibility allows analysis of a complex and diverse set of endpoints, and includes existing win time methods as special cases. Moreover, the WINFT is estimated based on U-statistics, which provide direct framework for variance estimation and confidence interval derivation, under independent censoring and missing at random assumptions, without expensive bootstrapping. We examine the performance of the proposed WINFT estimation method through simulation studies, and illustrate the method using data from the ACTT-1 COVID-19 and HF-ACTION trials. Overall, the WINFT offers a flexible and interpretable estimand for assessing treatment in clinical trial data with complex longitudinal outcomes.

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arXiv2026

The FORSS Framework for Sample Size and Power Calculations With Win Statistics for Hierarchical Endpoints

Win statistics have gained increasing popularity as primary analysis methods for clinical trials with hierarchical endpoints (HEs) as primary endpoints. However, existing sample size and power calculation approaches in trial design still face several limitations and challenges: simulation-based approaches are computationally intensive, while existing formula-based methods often rely on simplifying assumptions such as independence among HEs, or require specification of overall win statistics and tie probability that are difficult to elicit a priori in practice. To address these challenges, we propose the FORSS framework, a FORmula-based Super-Sample approach that allows investigators to specify marginal treatment effects using familiar metrics (e.g., hazard ratios, mean differences, and risk differences) together with a flexible joint working distribution for the HEs. Rather than repeatedly simulating full trials at each candidate sample size, FORSS uses super-samples to estimate the population-level plug-in quantities required by analytical formulas for both power and sample size calculation. We evaluated the performance of the proposed FORSS through extensive simulation studies. The results show that the formula-based FORSS closely matches empirical power across a wide range of scenarios while maintaining Type~I error rates near the nominal 5\% level. An illustration based on the HEART-FID trial further shows that endpoint-dependence specifications can materially affect projected power and required sample size when planning trials with HEs.

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arXiv2026

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 non-survival 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, avoids strong parametric assumptions, and comes 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 non-informative 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.

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arXiv2025

A tutorial for propensity score weighting methods under violations of the positivity assumption

Violations of the positivity assumption can render conventional causal estimands unidentifiable, including the average treatment effect (ATE), the average treatment effect on the treated (ATT), and the average treatment effect on the controls (ATC). Shifting the inferential focus to their alternative counterparts -- the weighted ATE (WATE), the weighted ATT (WATT), and the weighted ATC (WATC) -- offers valuable insights into treatment effects while preserving internal validity. In this tutorial, we provide a comprehensive review of recent advances in propensity score (PS) weighting methods, along with practical guidance on how to select a primary target estimand (while other estimands serve as supplementary analyses), implement the corresponding PS-weighted estimators, and conduct post-weighting diagnostic assessments. The tutorial is accompanied by a user-friendly R package, ChiPS. We demonstrate the pertinence of various estimators through extensive simulation studies. We illustrate the flow of the tutorial on two real-world case studies: (i) Effect of smoking on blood lead level using data from the 2007-2008 National Health and Nutrition Examination Survey (NHANES); and (ii) Impact of history of sex work on HIV status among transgender women in South Africa.

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arXiv2025

Variance Estimation for Weighted Average Treatment Effects

Common variance estimation methods for weighted average treatment effects (WATEs) in observational studies include nonparametric bootstrap and model-based, closed-form sandwich variance estimation. However, the computational cost of bootstrap increases with the size of the data at hand. Besides, some replicates may exhibit random violations of the positivity assumption even when the original data do not. Sandwich variance estimation relies on regularity conditions that may be structurally violated. Moreover, the sandwich variance estimation is model-dependent on the propensity score model, the outcome model, or both; thus it does not have a unified closed-form expression. Recent studies have explored the use of wild bootstrap to estimate the variance of the average treatment effect on the treated (ATT). This technique adopts a one-dimensional, nonparametric, and computationally efficient resampling strategy. In this article, we propose a "post-weighting" bootstrap approach as an alternative to the conventional bootstrap, which helps avoid random positivity violations in replicates and improves computational efficiency. We also generalize the wild bootstrap algorithm from ATT to the broader class of WATEs by providing new justification for correctly accounting for sampling variability from multiple sources under different weighting functions. We evaluate the performance of all four methods through extensive simulation studies and demonstrate their application using data from the National Health and Nutrition Examination Survey (NHANES). Our findings offer several practical recommendations for the variance estimation of WATE estimators.

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arXiv2024

Overlap, matching, or entropy weights: what are we weighting for?

There has been a recent surge in statistical methods for handling the lack of adequate positivity when using inverse probability weights (IPW). However, these nascent developments have raised a number of questions. Thus, we demonstrate the ability of equipoise estimators (overlap, matching, and entropy weights) to handle the lack of positivity. Compared to IPW, the equipoise estimators have been shown to be flexible and easy to interpret. However, promoting their wide use requires that researchers know clearly why, when to apply them and what to expect. In this paper, we provide the rationale to use these estimators to achieve robust results. We specifically look into the impact imbalances in treatment allocation can have on the positivity and, ultimately, on the estimates of the treatment effect. We zero into the typical pitfalls of the IPW estimator and its relationship with the estimators of the average treatment effect on the treated (ATT) and on the controls (ATC). Furthermore, we also compare IPW trimming to the equipoise estimators. We focus particularly on two key points: What fundamentally distinguishes their estimands? When should we expect similar results? Our findings are illustrated through Monte-Carlo simulation studies and a data example on healthcare expenditure.

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arXiv2022

A framework for causal inference in the presence of extreme inverse probability weights: the role of overlap weights

In this paper, we consider recent progress in estimating the average treatment effect when extreme inverse probability weights are present and focus on methods that account for a possible violation of the positivity assumption. These methods aim at estimating the treatment effect on the subpopulation of patients for whom there is a clinical equipoise. We propose a systematic approach to determine their related causal estimands and develop new insights into the properties of the weights targeting such a subpopulation. Then, we examine the roles of overlap weights, matching weights, Shannon's entropy weights, and beta weights. This helps us characterize and compare their underlying estimators, analytically and via simulations, in terms of the accuracy, precision, and root mean squared error. Moreover, we study the asymptotic behaviors of their augmented estimators (that mimic doubly robust estimators), which lead to improved estimations when either the propensity or the regression models are correctly specified. Based on the analytical and simulation results, we conclude that overall overlap weights are preferable to matching weights, especially when there is moderate or extreme violations of the positivity assumption. Finally, we illustrate the methods using a real data example marked by extreme inverse probability weights.

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arXiv2022

Variance estimation for the average treatment effects on the treated and on the controls

Common causal estimands include the average treatment effect (ATE), the average treatment effect of the treated (ATT), and the average treatment effect on the controls (ATC). Using augmented inverse probability weighting methods, parametric models are judiciously leveraged to yield doubly robust estimators, i.e., estimators that are consistent when at least one the parametric models is correctly specified. Three sources of uncertainty are associated when we evaluate these estimators and their variances, i.e., when we estimate the treatment and outcome regression models as well as the desired treatment effect. In this paper, we propose methods to calculate the variance of the normalized, doubly robust ATT and ATC estimators and investigate their finite sample properties. We consider both the asymptotic sandwich variance estimation, the standard bootstrap as well as two wild bootstrap methods. For the asymptotic approximations, we incorporate the aforementioned uncertainties via estimating equations. Moreover, unlike the standard bootstrap procedures, the proposed wild bootstrap methods use perturbations of the influence functions of the estimators through independently distributed random variables. We conduct an extensive simulation study where we vary the heterogeneity of the treatment effect as well as the proportion of participants assigned to the active treatment group. We illustrate the methods using an observational study of critical ill patients on the use of right heart catherization.

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arXiv2020

Robust statistical inference for the matched net benefit and the matched win ratio using prioritized composite endpoints

As alternatives to the time-to-first-event analysis of composite endpoints, the {\it net benefit} (NB) and the {\it win ratio} (WR) -- which assess treatment effects using prioritized component outcomes based on clinical importance -- have been proposed. However, statistical inference of NB and WR relies on a large-sample assumptions, which can lead to an invalid test statistic and inadequate, unsatisfactory confidence intervals, especially when the sample size is small or the proportion of wins is near 0 or 1. In this paper, we develop a systematic approach to address these limitations in a paired-sample design. We first introduce a new test statistic under the null hypothesis of no treatment difference. Then, we present the formula to calculate the sample size. Finally, we develop the confidence interval estimations of these two estimators. To estimate the confidence intervals, we use the {\it method of variance estimates recovery} (MOVER), that combines two separate individual-proportion confidence intervals into a hybrid interval for the estimand of interest. We assess the performance of the proposed test statistic and MOVER confidence interval estimations through simulation studies. We demonstrate that the MOVER confidence intervals are as good as the large-sample confidence intervals when the sample is large and when the proportions of wins is bounded away from 0 and 1. Moreover, the MOVER intervals outperform their competitors when the sample is small or the proportions are at or near the boundaries 0 and 1. We illustrate the method (and its competitors) using three examples from randomized clinical studies.

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arXiv2020

Propensity score weighting under limited overlap and model misspecification

Propensity score (PS) weighting methods are often used in non-randomized studies to adjust for confounding and assess treatment effects. The most popular among them, the inverse probability weighting (IPW), assigns weights that are proportional to the inverse of the conditional probability of a specific treatment assignment, given observed covariates. A key requirement for IPW estimation is the positivity assumption, i.e., the PS must be bounded away from 0 and 1. In practice, violations of the positivity assumption often manifest by the presence of limited overlap in the PS distributions between treatment groups. When these practical violations occur, a small number of highly influential IPW weights may lead to unstable IPW estimators, with biased estimates and large variances. To mitigate these issues, a number of alternative methods have been proposed, including IPW trimming, overlap weights (OW), matching weights (MW), and entropy weights (EW). Because OW, MW, and EW target the population for whom there is equipoise (and with adequate overlap) and their estimands depend on the true PS, a common criticism is that these estimators may be more sensitive to misspecifications of the PS model. In this paper, we conduct extensive simulation studies to compare the performances of IPW and IPW trimming against those of OW, MW, and EW under limited overlap and misspecified propensity score models. Across the wide range of scenarios we considered, OW, MW, and EW consistently outperform IPW in terms of bias, root mean squared error, and coverage probability.

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arXiv2020

Regression with a right-censored predictor, using inverse probability weighting methods

In a longitudinal study, measures of key variables might be incomplete or partially recorded due to drop-out, loss to follow-up, or early termination of the study occurring before the advent of the event of interest. In this paper, we focus primarily on the implementation of a regression model with a randomly censored predictor. We examine, particularly, the use of inverse probability weighting methods in a generalized linear model (GLM), when the predictor of interest is right-censored, to adjust for censoring. To improve the performance of the complete-case analysis and prevent selection bias, we consider three different weighting schemes: inverse censoring probability weights, Kaplan-Meier weights, and Cox proportional hazards weights. We use Monte Carlo simulation studies to evaluate and compare the empirical properties of different weighting estimation methods. Finally, we apply these methods to the Framingham Heart Study data as an illustrative example to estimate the relationship between age of onset of a clinically diagnosed cardiovascular event and low-density lipoprotein (LDL) among cigarette smokers.

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arXiv2017

Linear regression model with a randomly censored predictor:Estimation procedures

We consider linear regression model estimation where the covariate of interest is randomly censored. Under a non-informative censoring mechanism, one may obtain valid estimates by deleting censored observations. However, this comes at a cost of lost information and decreased efficiency, especially under heavy censoring. Other methods for dealing with censored covariates, such as ignoring censoring or replacing censored observations with a fixed number, often lead to severely biased results and are of limited practicality. Parametric methods based on maximum likelihood estimation as well as semiparametric and non-parametric methods have been successfully used in linear regression estimation with censored covariates where censoring is due to a limit of detection. In this paper, we adapt some of these methods to handle randomly censored covariates and compare them under different scenarios to recently-developed semiparametric and nonparametric methods for randomly censored covariates. Specifically, we consider both dependent and independent randomly censored mechanisms as well as the impact of using a non-parametric algorithm on the distribution of the randomly censored covariate. Through extensive simulation studies, we compare the performance of these methods under different scenarios. Finally, we illustrate and compare the methods using the Framingham Health Study data to assess the association between low-density lipoprotein (LDL) in offspring and parental age at onset of a clinically-diagnosed cardiovascular event.

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