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

Abstract

A stepped wedge design is an unidirectional crossover design where clusters are randomized to distinct treatment sequences. While model-based analysis of stepped wedge designs is a 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 error 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.