Properties and pitfalls of weighting as an alternative to multilevel multiple imputation in cluster randomized trials with missing binary outcomes under covariate-dependent missingness

Abstract

The generalized estimating equation (GEE) approach can be used to analyze cluster randomized trial data to obtain population-averaged intervention effects. However, most cluster randomized trials have some missing outcome data and a GEE analysis of available data may be biased when outcome data are not missing completely at random. Although multilevel multiple imputation for GEE (MMI-GEE) has been widely used, alternative approaches such as weighted GEE are less common in practice. Using both simulations and a real data example, we evaluate the performance of inverse probability weighted GEE vs. MMI-GEE for binary outcomes. Simulated data are generated assuming a covariate-dependent missing data pattern across a range of missingness clustering (from none to high), where all covariates are measured at baseline and are fully observed (i.e. a type of missing-at-random mechanism). Two types of weights are estimated and used in the weighted GEE: (1) assuming no clustering of missingness (W-GEE) and (2) accounting for such clustering (CW-GEE). Results show that, even in settings with high missingness clustering, CW-GEE can lead to more bias and lower coverage than W-GEE, whereas W-GEE and MMI-GEE provide comparable results. W-GEE should be considered a viable strategy to account for missing outcomes in cluster randomized trials.