An efficient doubly-robust imputation framework for longitudinal dropout, with an application to an Alzheimer’s clinical trial

Abstract

We develop a novel doubly-robust (DR) imputation framework for longitudinal studies with monotone dropout, motivated by the informative dropout that is common in FDA-regulated trials for Alzheimer’s disease. In this approach the missing data are first imputed using a doubly-robust augmented inverse probability weighting (AIPW) estimator; then the imputed completed data are substituted into a full-data estimating equation, and the estimate is obtained using standard software. The imputed completed data may be inspected and compared to the observed data, and standard model diagnostics are available. The same imputed completed data can be used for several different estimands, such as subgroup analyses in a clinical trial, allowing for reduced computation and increased consistency across analyses. We present two specific DR imputation estimators, AIPW-I and AIPW-S, study their theoretical properties, and investigate their performance by simulation. AIPW-S has substantially reduced computational burden, compared to many other DR estimators, at the cost of some loss of efficiency and the requirement of stronger assumptions. Simulation studies support the theoretical properties and good performance of the DR imputation framework. Importantly, we demonstrate their ability to address time-varying covariates, such as a time by treatment interaction. We illustrate using data from a large randomized Phase III trial, investigating the effect of donepezil in Alzheimer’s disease, from the Alzheimer’s Disease Cooperative Study (ADCS) group.