Accounting for dropout bias using mixed-effects models

Abstract

Treatment effects are often evaluated by comparing change over time in outcome measures. However, valid analyses of longitudinal data can be problematic when subjects discontinue (dropout) prior to completing the study. This study assessed the merits of likelihood-based repeated measures analyses (MMRM) compared with fixed-effects analysis of variance where missing values were imputed using the last observation carried forward approach (LOCF) in accounting for dropout bias. Comparisons were made in simulated data and in data from a randomized clinical trial. Subject dropout was introduced in the simulated data to generate ignorable and nonignorable missingness. Estimates of treatment group differences in mean change from baseline to endpoint from MMRM were, on average, markedly closer to the true value than estimates from LOCF in every scenario simulated. Standard errors and confidence intervals from MMRM accurately reflected the uncertainty of the estimates, whereas standard errors and confidence intervals from LOCF underestimated uncertainty.