Continuous-time mediation analysis for repeatedly measured mediators and outcomes

Mediation analysis aims to decipher the underlying causal mechanisms between an exposure, an outcome, and intermediate variables called mediators. Initially developed for fixed-time mediator and outcome, it has been extended to the framework of longitudinal data by discretizing the assessment times of mediator and outcome. Yet, processes in play in longitudinal studies are usually defined in continuous time and measured at irregular and subject-specific visits. This is the case in dementia research when cerebral and cognitive changes measured at planned visits in cohorts are of interest. We thus propose a methodology to estimate the causal mechanisms between a time-fixed exposure ($X$), a mediator process ($\mathcal {M}_t$), and an outcome process ($\mathcal {Y}_t$) both measured repeatedly over time in the presence of a time-dependent confounding process ($\mathcal {L}_t$). We consider 2 types of causal estimands, the natural effects and path-specific effects. We provide identifiability assumptions, and we employ a multivariate mixed model based on differential equations for their estimation. The performances of the method are assessed in simulations, and the method is illustrated in 2 real-world examples motivated by the 3C cerebral aging study to assess (1) the effect of educational level on functional dependency through depressive symptomatology and cognitive functioning and (2) the effect of a genetic factor on cognitive functioning potentially mediated by vascular brain lesions and confounded by neurodegeneration.