Analyzing multi-center randomized trials with covariate adjustment while accounting for clustering

Augmented inverse probability weighting (AIPW) and G-computation with canonical generalized linear models have become increasingly popular for estimating the average treatment effect in randomized experiments. These estimators leverage outcome prediction models to adjust for imbalances in baseline covariates across treatment arms, improving statistical power compared to unadjusted analyses, while maintaining control over Type I error rates, even when the models are misspecified. Practical application of such estimators often overlooks the clustering present in multi-center clinical trials. Even when prediction models account for center effects, this neglect can degrade the coverage of confidence intervals, reduce the efficiency of the estimators, and complicate the interpretation of the corresponding estimands. These issues are particularly pronounced for estimators of counterfactual means, though less severe for those of the average treatment effect, as demonstrated through Monte Carlo simulations and supported by theoretical insights. To address these challenges, we develop efficient estimators of counterfactual means and the average treatment effect in a random center. These extract information from baseline covariates by relying on outcome prediction models, but remain unbiased in large samples when these models are misspecified. We also introduce an accompanying inference framework inspired by random-effects meta-analysis and relevant for settings where data from many small centers are being analyzed. Adjusting for center effects yields substantial gains in efficiency, especially when treatment effect heterogeneity across centers is large. Monte Carlo simulations and application to the WASH Benefits Bangladesh study demonstrate adequate performance of the proposed methods.