Mediation analysis in longitudinal studies in the presence of measurement error and missing data

Abstract

Mediation analysis hypothesizes that an exposure causes a mediator and in turn the mediator causes the outcome, so mediation is inherently longitudinal. Unfortunately, potential mediators may be measured with error and regression estimators obtained by ignoring measurement error can be severely biased. This can induce bias in the estimation of causal direct and indirect effects. In Chapter 2, using regression calibration, we show how to adjust for measurement error in longitudinal studies with repeated measurements of the mediator, and evaluate the effect of ignoring measurement error on direct and indirect effects. Rather than assuming normality for the random effects in the linear mixed effects calibration model, we correct for measurement error in the mediator allowing flexibility in the distribution of subject-specific random effects. On the other hand, longitudinal studies face challenges of missing data resulting from loss to follow-up, death, or withdrawal. In mediation analysis, multiple imputation has been shown to perform well for data missing completely at random (MCAR) and missing at random (MAR) in cross-sectional studies, but it is unclear how it performs in longitudinal studies under misspecification of the imputation model, specifically, where the misspecification ignores clustering by subject. In Chapter 3, we examine the impact of ignoring clustering on mediated effect estimates under MCAR and MAR mechanisms with varying degrees of missingness. In Chapter 4, using data from a randomized controlled trial, we examine the mediation effects on child neurodevelopment of intermittent preventive malaria treatment in pregnant women. Chapter 5 concludes and discusses future work.