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ABSTRACT Platform trials are multi‐arm designs that simultaneously evaluate multiple treatments for a single disease within the same overall trial structure. Unlike traditional randomized controlled trials, they allow treatment arms to enter and exit the trial at distinct times while maintaining a control arm throughout. This control arm comprises both concurrent controls, where participants are randomized concurrently to either the treatment or control arm, and non‐concurrent controls, who enter the trial when the treatment arm under study is unavailable. While flexible, platform trials introduce the challenge of using non‐concurrent controls, raising questions about estimating treatment effects. Specifically, which estimands should be targeted? Under what assumptions can these estimands be identified and estimated? Are there any efficiency gains? In this article, we discuss issues related to the identification and estimation assumptions of common choices of estimand. We conclude that the most robust strategy to increase efficiency without imposing unwarranted assumptions is to target the concurrent average treatment effect (cATE), the ATE among only concurrent units, using a covariate‐adjusted doubly robust estimator. Our studies suggest that, for the purpose of obtaining efficiency gains, collecting important prognostic variables is more important than relying on non‐concurrent controls. We also discuss the perils of targeting ATE due to an untestable extrapolation assumption that will often be invalid. We provide simulations illustrating our points and an application to the ACTT platform trial, resulting in a 20% improvement in precision compared to the naive estimator that ignores non‐concurrent controls and prognostic variables. 

Abstract Marginal structural models (MSMs) can be used to estimate the causal effect of a potentially time-varying treatment in the presence of time-dependent confounding via weighted regression. The standard approach of using inverse probability of treatment weighting (IPTW) can be sensitive to model misspecification and lead to high-variance estimates due to extreme weights. Various methods have been proposed to partially address this, including covariate balancing propensity score (CBPS) to mitigate treatment model misspecification, and truncation and stabilized-IPTW (sIPTW) to temper extreme weights. In this article, we present kernel optimal weighting (KOW), a convex-optimization-based approach that finds weights for fitting the MSMs that flexibly balance time-dependent confounders while simultaneously penalizing extreme weights, directly addressing the above limitations. We further extend KOW to control for informative censoring. We evaluate the performance of KOW in a simulation study, comparing it with IPTW, sIPTW, and CBPS. We demonstrate the use of KOW in studying the effect of treatment initiation on time-to-death among people living with human immunodeficiency virus and the effect of negative advertising on elections in the United States. 

The ability to perform offline A/B-testing and off-policy learning using logged contextual bandit feedback is highly desirable in a broad range of applications, including recommender systems, search engines, ad placement, and personalized health care. Both offline A/B-testing and offpolicy learning require a counterfactual estimator that evaluates how some new policy would have performed, if it had been used instead of the logging policy. In this paper, we present and analyze a family of counterfactual estimators which subsumes most estimators proposed to date. Most importantly, this analysis identifies a new estimator – called Continuous Adaptive Blending (CAB) – which enjoys many advantageous theoretical and practical properties. In particular, it can be substantially less biased than clipped Inverse Propensity Score (IPS) weighting and the Direct Method, and it can have less variance than Doubly Robust and IPS estimators. In addition, it is subdifferentiable such that it can be used for learning, unlike the SWITCH estimator. Experimental results show that CAB provides excellent evaluation accuracy and outperforms other counterfactual estimators in terms of learning performance. 

Inverse probability of treatment weighting (IPTW), which has been used to estimate average treatment effects (ATE) using observational data, tenuously relies on the positivity assumption and the correct specification of the treatment assignment model, both of which are problematic assumptions in many observational studies. Various methods have been proposed to overcome these challenges, including truncation, covariate‐balancing propensity scores, and stable balancing weights. Motivated by an observational study in spine surgery, in which positivity is violated and the true treatment assignment model is unknown, we present the use of optimal balancing by kernel optimal matching (KOM) to estimate ATE. By uniformly controlling the conditional mean squared error of a weighted estimator over a class of models, KOM simultaneously mitigates issues of possible misspecification of the treatment assignment model and is able to handle practical violations of the positivity assumption, as shown in our simulation study. Using data from a clinical registry, we apply KOM to compare two spine surgical interventions and demonstrate how the result matches the conclusions of clinical trials that IPTW estimates spuriously refute.