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Bingkai Wang

Publications and source records attributed to Bingkai Wang.

At least 19 recordsLinked to original sources

Optimizing precision in stepped-wedge designs via machine learning and quadratic inference functions

Stepped-wedge designs are increasingly used in randomized experiments to accommodate logistical and ethical constraints by staggering treatment roll-out over time. Despite their popularity, existing analytical methods largely rely on parametric models with linear covariate adjustment and prespecified correlation structures, which may limit achievable precision in practice. We propose a new class of estimators for the causal average treatment effect in stepped-wedge designs that optimizes precision through flexible, machine-learning-based covariate adjustment to capture complex outcome-covariate relationships, together with quadratic inference functions to adaptively learn the correlation structure. We establish consistency and asymptotic normality under mild conditions requiring only $L_2$ convergence of nuisance estimators, even under model misspecification, and characterize when the estimator attains the minimal asymptotic variance. Moreover, we prove that the proposed estimator never reduces efficiency relative to an independence working correlation. The proposed method further accommodates treatment-effect heterogeneity across both exposure duration and calendar time. Finally, we demonstrate our methods through simulation studies and reanalyses of two empirical studies that differ substantially in research area and key design parameters.

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How should covariates be handled in randomized trials? Empirical evidence from 50 trials and recommendations for practice

Background and Objective: Covariate adjustment can improve precision and power in randomized clinical trials and is recommended by major regulatory agencies. However, there is limited empirical evidence on how different adjustment strategies perform across diverse real-world trials, leaving uncertainty about which methods and covariates should be prespecified in statistical analysis plans. We aim to address this gap and provide practical recommendations. Methods: We conducted a large-scale empirical study using individual-level data from 50 publicly available randomized trials (29,094 participants; 574 treatment-outcome comparisons). We compared commonly used covariate-adjusted estimators, including analysis of covariance, inverse-probability weighting, g-computation, and machine-learning-based approaches, combined with three covariate-selection strategies. Performance was evaluated using precision gains, changes in point estimates, computational reliability, and the probability that covariate adjustment altered statistical significance relative to an unadjusted analysis. Results: Covariate adjustment improved precision in most settings, with a median variance reduction of 13.3\% for continuous outcomes and 4.6\% for binary outcomes. Parsimonious regression approaches using a small prespecified set of prognostic covariates performed as well as or better than more complex methods, particularly in small to medium samples. Machine-learning-based estimators did not provide additional precision and were more prone to computational failure for binary outcomes. Conclusions: Across trials, parsimonious covariate adjustment provided consistent efficiency gains without introducing systematic bias. These findings support routine covariate adjustment in primary trial analyses. All curated datasets and analysis code are openly released to support future clinical research.

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Doubly robust estimators of the restricted mean time in favor estimands in individual- and cluster-randomized trials

Progressive multi-state survival outcomes are common in trials with recurrent or sequential events and require treatment effect estimands that remain interpretable without proportional intensity or Markov assumptions. The restricted mean time in favor of treatment (RMT-IF) extends the restricted mean survival time to ordered multi-state processes and provides such an interpretable estimand. However, existing RMT-IF methods are nonparametric, assume covariate-independent censoring for independent observations, and do not accommodate cluster-randomized trials (CRTs), limiting both efficiency and applicability. We develop a class of doubly robust estimators for RMT-IF under right censoring using an augmented inverse-probability weighting framework that combines stage-specific outcome regression with arm-specific censoring models, yielding consistency when either nuisance model is correctly specified. We further extend the framework to CRTs by formalizing both cluster-level and individual-level average RMT-IF estimands to address informative cluster size and by constructing corresponding doubly robust estimators that account for within-cluster correlation. For inference, we employ model-agnostic jackknife variance estimators in both individually randomized and cluster-randomized settings. Extensive simulation studies demonstrate finite-sample performance, and the methods are illustrated using two randomized trial examples.

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Estimands and doubly robust estimation for cluster-randomized trials with survival outcomes

Cluster-randomized trials (CRTs) are experimental designs where groups or clusters of participants, rather than the individual participants themselves, are randomized to intervention groups. Analyzing CRT requires distinguishing between treatment effects at the cluster level and the individual level, which requires a clear definition of the estimands under the potential outcomes framework. For analyzing survival outcomes, it is common to assess the treatment effect by comparing survival functions or restricted mean survival times between treatment groups. In this article, we formally characterize cluster-level and individual-level treatment effect estimands with right-censored survival outcomes in CRTs and propose doubly robust estimators for targeting such estimands. Under covariate-dependent censoring, our estimators ensure consistency when either the censoring model or the outcome model is correctly specified, but not necessarily both. We explore different modeling options for the censoring and outcome models to estimate the censoring and survival distributions, and investigate a deletion-based jackknife method for variance and interval estimation. Extensive simulations demonstrate that the proposed methods perform adequately in finite samples. Finally, we illustrate our method by analyzing a completed CRT with survival endpoints.

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Model-robust standardization in stepped wedge cluster randomized trials

Stepped-wedge cluster-randomized trials (SW-CRTs) are widely used in healthcare and implementation science, enabling all clusters to receive the intervention through a staggered rollout. Traditional model-based methods, including generalized estimating equations and mixed models, yield estimates that depend on implicit weighting schemes and parametric assumptions, and therefore may target ambiguous estimands under model misspecification. In this article, we propose a model-robust standardization framework for SW-CRTs that generalizes existing methods from parallel-arm CRTs to address informative sizes. We define causal estimands including horizontal-individual, horizontal-cluster, vertical-individual, and vertical-cluster average treatment effects under a super population framework and introduce a simple procedure that standardizes parametric and semiparametric working models for estimand-aligned analysis. For any specified working model, the resulting estimators remain consistent for their target estimands even if the working regression model is misspecified; moreover, their efficiency improves as the working model more closely approximates the true data-generating process. We evaluate the finite-sample properties of our proposed estimators through extensive simulations. Finally, we illustrate the application of our methods through reanalyses of two real-world SW-CRTs.

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Model-robust standardization in cluster-randomized trials

In cluster-randomized trials, generalized linear mixed models and generalized estimating equations have conventionally been the default analytic methods for estimating the average treatment effect as routine practice. However, recent studies have demonstrated that their treatment effect coefficient estimators may correspond to ambiguous estimands when the models are misspecified or when there exists informative cluster sizes. In this article, we present a unified approach that standardizes output from a given regression model to ensure estimand-aligned inference for the treatment effect parameters in cluster-randomized trials. We introduce estimators for both the cluster-average and the individual-average treatment effects (marginal estimands) that are always consistent regardless of whether the specified working regression models align with the unknown data generating process. We further explore the use of a deletion-based jackknife variance estimator for inference. The development of our approach also motivates a natural test for informative cluster size. Extensive simulation experiments are designed to demonstrate the advantage of the proposed estimators under a variety of scenarios. The proposed model-robust standardization methods are implemented in the MRStdCRT R package.

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How to achieve model-robust inference in stepped wedge trials with model-based methods?

A stepped wedge design is a unidirectional crossover design where clusters are randomized to distinct treatment sequences. While model-based analysis of stepped wedge designs is standard practice to evaluate treatment effects accounting for clustering and adjusting for covariates, their properties under misspecification have not been systematically explored. In this article, we focus on model-based methods, including linear mixed models and generalized estimating equations with an independence, simple exchangeable, or nested exchangeable working correlation structure. We study when a potentially misspecified working model can offer consistent estimation of the marginal treatment effect estimands, which are defined nonparametrically with potential outcomes and may be functions of calendar time and/or exposure time. We prove a central result that consistency for nonparametric estimands usually requires a correctly specified treatment effect structure, but generally not the remaining aspects of the working model (functional form of covariates, random effects, and residual distribution), and valid inference is obtained via the sandwich variance estimator. Furthermore, an additional g-computation step is required to achieve model-robust inference under non-identity link functions or for ratio estimands. The theoretical results are illustrated via several simulation experiments and re-analysis of a completed stepped wedge cluster randomized trial.

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Asymptotic inference with flexible covariate adjustment under rerandomization and stratified rerandomization

Rerandomization is an effective treatment allocation procedure to control for baseline covariate imbalance. For estimating the average treatment effect, rerandomization has been previously shown to improve the precision of the unadjusted and the linearly-adjusted estimators over simple randomization without compromising consistency. However, it remains unclear whether such results apply more generally to the class of M-estimators, including the g-computation formula with generalized linear regression and doubly-robust methods, and more broadly, to efficient estimators with data-adaptive machine learners. In this paper, we develop the asymptotic theory for a more general class of covariate-adjusted estimators under rerandomization and its stratified extension. We prove that the asymptotic linearity and the influence function remain identical for any M-estimator under simple randomization and rerandomization, but rerandomization may lead to a non-Gaussian asymptotic distribution. We further explain, drawing examples from several common M-estimators, that asymptotic normality can be achieved if rerandomization variables are appropriately adjusted for in the final estimator. These results are extended to stratified rerandomization. Finally, we study the asymptotic theory for efficient estimators based on data-adaptive machine learners, and prove their efficiency optimality under rerandomization and stratified rerandomization. Our results are demonstrated via simulations and re-analyses of a cluster-randomized experiment that used stratified rerandomization.

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Handling incomplete outcomes and covariates in cluster-randomized trials: doubly-robust estimation, efficiency considerations, and sensitivity analysis

In cluster-randomized trials (CRTs), missing data can occur in various ways, including missing values in outcomes and baseline covariates at the individual or cluster level, or completely missing information for non-participants. Among the various types of missing data in CRTs, missing outcomes have attracted the most attention. However, no existing methods simultaneously address all aforementioned types of missing data in CRTs. To fill in this gap, we propose a doubly-robust estimator for the average treatment effect on a variety of effect measure scales. The proposed estimator simultaneously handles missing outcomes under missingness at random, missing covariates without constraining the missingness mechanism, and missing cluster-population sizes via a uniform sampling mechanism. Furthermore, we detail key considerations to improve precision by specifying the optimal weights, leveraging machine learning, and modeling the treatment assignment mechanism. Finally, to evaluate the impact of violating missing data assumptions, we contribute a new sensitivity analysis framework tailored to CRTs. We assess the performance of the proposed methods through simulations and illustrate their use in a real data application.

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Conformal causal inference for cluster randomized trials: model-robust inference without asymptotic approximations

Traditional statistical inference in cluster randomized trials typically invokes the asymptotic theory that requires the number of clusters to approach infinity. In this article, we propose an alternative conformal causal inference framework for analyzing cluster randomized trials that achieves the target inferential goal in finite samples without the need for asymptotic approximations. Different from traditional inference focusing on estimating the average treatment effect, our conformal causal inference aims to provide prediction intervals for the difference of counterfactual outcomes, thereby providing a new decision-making tool for clusters and individuals in the same target population. We prove that this framework is compatible with arbitrary working outcome models -- including data-adaptive machine learning methods that maximally leverage information from baseline covariates, and enjoys robustness against misspecification of working outcome models. Under our conformal causal inference framework, we develop efficient computation algorithms to construct prediction intervals for treatment effects at both the cluster and individual levels, and further extend to address inferential targets defined based on pre-specified covariate subgroups. Finally, we demonstrate the properties of our methods via simulations and a real data application based on a completed cluster randomized trial for treating chronic pain.

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Test-negative designs with various reasons for testing: statistical bias and solution

Test-negative designs are widely used for post-market evaluation of vaccine effectiveness, particularly in cases when randomized trials are not feasible. Differing from classical test-negative designs where only healthcare-seekers with symptoms are included, recent test-negative designs have involved individuals with various reasons for testing, especially in an outbreak setting. While including these data can increase sample size and hence improve precision, concerns have been raised about whether they introduce bias into the current framework of test-negative designs, thereby demanding a formal statistical examination of this modified design. In this article, using statistical derivations, causal graphs, and numerical demonstrations, we show that the standard odds ratio estimator may be biased if various reasons for testing are not accounted for. To eliminate this bias, we identify three categories of reasons for testing, including symptoms, mandatory screening, and case contact tracing, and characterize associated statistical properties and estimands. Based on our characterization, we show how to consistently estimate each estimand via stratification. Furthermore, we describe when these estimands correspond to the same vaccine effectiveness parameter, and, when appropriate, propose a stratified estimator that can incorporate multiple reasons for testing and improve precision. The performance of our proposed method is demonstrated through simulation studies.

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On the mixed-model analysis of covariance in cluster-randomized trials

In the analyses of cluster-randomized trials, mixed-model analysis of covariance (ANCOVA) is a standard approach for covariate adjustment and handling within-cluster correlations. However, when the normality, linearity, or the random-intercept assumption is violated, the validity and efficiency of the mixed-model ANCOVA estimators for estimating the average treatment effect remain unclear. Under the potential outcomes framework, we prove that the mixed-model ANCOVA estimators for the average treatment effect are consistent and asymptotically normal under arbitrary misspecification of its working model. If the probability of receiving treatment is 0.5 for each cluster, we further show that the model-based variance estimator under mixed-model ANCOVA1 (ANCOVA without treatment-covariate interactions) remains consistent, clarifying that the confidence interval given by standard software is asymptotically valid even under model misspecification. Beyond robustness, we discuss several insights on precision among classical methods for analyzing cluster-randomized trials, including the mixed-model ANCOVA, individual-level ANCOVA, and cluster-level ANCOVA estimators. These insights may inform the choice of methods in practice. Our analytical results and insights are illustrated via simulation studies and analyses of three cluster-randomized trials.

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Improving the mixed model for repeated measures to robustly increase precision in randomized trials

In randomized trials, repeated measures of the outcome are routinely collected. The mixed model for repeated measures (MMRM) leverages the information from these repeated outcome measures, and is often used for the primary analysis to estimate the average treatment effect at the primary endpoint. MMRM, however, can suffer from bias and precision loss when it models intermediate outcomes incorrectly, and hence fails to use the post-randomization information harmlessly. This paper proposes an extension of the commonly used MMRM, called IMMRM, that improves the robustness and optimizes the precision gain from covariate adjustment, stratified randomization, and adjustment for intermediate outcome measures. Under regularity conditions and missing completely at random, we prove that the IMMRM estimator for the average treatment effect is robust to arbitrary model misspecification and is asymptotically equal or more precise than the analysis of covariance (ANCOVA) estimator and the MMRM estimator. Under missing at random, IMMRM is less likely to be misspecified than MMRM, and we demonstrate via simulation studies that IMMRM continues to have less bias and smaller variance. Our results are further supported by a re-analysis of a randomized trial for the treatment of diabetes.

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Model-robust and efficient covariate adjustment for cluster-randomized experiments

Cluster-randomized experiments are increasingly used to evaluate interventions in routine practice conditions, and researchers often adopt model-based methods with covariate adjustment in the statistical analyses. However, the validity of model-based covariate adjustment is unclear when the working models are misspecified, leading to ambiguity of estimands and risk of bias. In this article, we first adapt two conventional model-based methods, generalized estimating equations and linear mixed models, with weighted g-computation to achieve robust inference for cluster-average and individual-average treatment effects. To further overcome the limitations of model-based covariate adjustment methods, we propose an efficient estimator for each estimand that allows for flexible covariate adjustment and additionally addresses cluster size variation dependent on treatment assignment and other cluster characteristics. Such cluster size variations often occur post-randomization and, if ignored, can lead to bias of model-based estimators. For our proposed efficient covariate-adjusted estimator, we prove that when the nuisance functions are consistently estimated by machine learning algorithms, the estimator is consistent, asymptotically normal, and efficient. When the nuisance functions are estimated via parametric working models, the estimator is triply-robust. Simulation studies and analyses of three real-world cluster-randomized experiments demonstrate that the proposed methods are superior to existing alternatives.

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A Differential Effect Approach to Partial Identification of Treatment Effects

We consider identification and inference for the average treatment effect and heterogeneous treatment effect conditional on observable covariates in the presence of unmeasured confounding. Since point identification of these treatment effects is not achievable without strong assumptions, we obtain bounds on these treatment effects by leveraging differential effects, a tool that allows for using a second treatment to learn the effect of the first treatment. The differential effect is the effect of using one treatment in lieu of the other. We provide conditions under which differential treatment effects can be used to point identify or partially identify treatment effects. Under these conditions, we develop a flexible and easy-to-implement semi-parametric framework to estimate bounds and leverage a two-stage approach to conduct statistical inference on effects of interest. The proposed method is examined through a simulation study and a case study that investigates the effect of smoking on the blood level of cadmium using the National Health and Nutrition Examination Survey.

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Randomization Inference for Cluster-Randomized Test-Negative Designs with Application to Dengue Studies: Unbiased estimation, Partial compliance, and Stepped-wedge design

In 2019, the World Health Organization identified dengue as one of the top ten global health threats. For the control of dengue, the Applying Wolbachia to Eliminate Dengue (AWED) study group conducted a cluster-randomized trial in Yogyakarta, Indonesia, and used a novel design, called the cluster-randomized test-negative design (CR-TND). This design can yield valid statistical inference with data collected by a passive surveillance system and thus has the advantage of cost-efficiency compared to traditional cluster-randomized trials. We investigate the statistical assumptions and properties of CR-TND under a randomization inference framework, which is known to be robust and efficient for small-sample problems. We find that, when the differential healthcare-seeking behavior comparing intervention and control varies across clusters (in contrast to the setting of Dufault and Jewell, 2020 where the differential healthcare-seeking behavior is constant across clusters), current analysis methods for CR-TND can be biased and have inflated type I error. We propose the log-contrast estimator that can eliminate such bias and improve precision by adjusting for covariates. Furthermore, we extend our methods to handle partial intervention compliance and a stepped-wedge design, both of which appear frequently in cluster-randomized trials. Finally, we demonstrate our results by simulation studies and re-analysis of the AWED study.

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Regularized regression on compositional trees with application to MRI analysis

A compositional tree refers to a tree structure on a set of random variables where each random variable is a node and composition occurs at each non-leaf node of the tree. As a generalization of compositional data, compositional trees handle more complex relationships among random variables and appear in many disciplines, such as brain imaging, genomics and finance. We consider the problem of sparse regression on data that are associated with a compositional tree and propose a transformation-free tree-based regularized regression method for component selection. The regularization penalty is designed based on the tree structure and encourages a sparse tree representation. We prove that our proposed estimator for regression coefficients is both consistent and model selection consistent. In the simulation study, our method shows higher accuracy than competing methods under different scenarios. By analyzing a brain imaging data set from studies of Alzheimer's disease, our method identifies meaningful associations between memory declination and volume of brain regions that are consistent with current understanding.

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Identifying brain hierarchical structures associated with Alzheimer's disease using a regularized regression method with tree predictors

Brain segmentation at different levels is generally represented as hierarchical trees. Brain regional atrophy at specific levels was found to be marginally associated with Alzheimer's disease outcomes. In this study, we propose an L1-type regularization for predictors that follow a hierarchical tree structure. Considering a tree as a directed acyclic graph, we interpret the model parameters from a path analysis perspective. Under this concept, the proposed penalty regulates the total effect of each predictor on the outcome. With regularity conditions, it is shown that under the proposed regularization, the estimator of the model coefficient is consistent in L2-norm and the model selection is also consistent. By applying to a brain structural magnetic resonance imaging dataset acquired from the Alzheimer's Disease Neuroimaging Initiative, the proposed approach identifies brain regions where atrophy in these regions demonstrates the declination in memory. With regularization on the total effects, the findings suggest that the impact of atrophy on memory deficits is localized from small brain regions but at various levels of brain segmentation.

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