Abstract

When analyzing data from randomized clinical trials, covariate adjustment can be used to account for chance imbalance in baseline covariates and to increase precision of the treatment effect estimate. A practical barrier to covariate adjustment is the presence of missing data. In this paper, in the light of recent theoretical advancement, we review several covariate adjustment methods with incomplete covariate data. We investigate the implications of the missing data mechanism on estimating the average treatment effect in randomized clinical trials with continuous or binary outcomes. We consider settings where the outcome data are fully observed or are missing at random; in the latter setting, we propose a full weighting approach that combines inverse probability weighting for adjusting for missing outcomes and overlap weighting for covariate adjustment. We conduct comprehensive simulation studies to examine the finite-sample performance of the proposed methods and compare with a range of common alternatives. We find that conducting the proposed adjustment methods generally improves the precision of treatment effect estimates regardless of the imputation methods when the proportion of missingness is not too large and the adjusted covariate is associated with the outcome. We apply the methods to the Childhood Adenotonsillectomy Trial to assess the effect of adenotonsillectomy on neurocognitive functioning scores.