Dynamic path analysis - A useful tool to investigate mediation processes in clinical survival trials

TL;DR

This paper advocates for dynamic path analysis in clinical survival trials to better understand mediation by incorporating time-dependent covariates, revealing that ignoring repeated measurements can lead to misleading conclusions.

Contribution

It introduces the use of dynamic path analysis for mediation in survival data with time-dependent covariates, highlighting its advantages over traditional methods.

Findings

Dynamic path analysis effectively captures mediation effects in survival data.

Ignoring repeated measurements can lead to incorrect inferences.

Linearity of the additive hazard model prevents survival from confounding treatment-mediator associations.

Abstract

When it comes to clinical survival trials, regulatory restrictions usually require the application of methods that solely utilize baseline covariates and the intention-to-treat principle. Thereby a lot of potentially useful information is lost, as collection of time-to-event data often goes hand in hand with collection of information on biomarkers and other internal time-dependent covariates. However, there are tools to incorporate information from repeated measurements in a useful manner that can help to shed more light on the underlying treatment mechanisms. We consider dynamic path analysis, a model for mediation analysis in the presence of a time-to-event outcome and time-dependent covariates to investigate direct and indirect effects in a study of different lipid lowering treatments in patients with previous myocardial infarctions. Further, we address the question whether survival in itself may produce associations between the treatment and the mediator in dynamic path analysis and give an argument that, due to linearity of the assumed additive hazard model, this is not the case. We further elaborate on our view that, when studying mediation, we are actually dealing with underlying processes rather than single variables measured only once during the study period. This becomes apparent in results from various models applied to the study of lipid lowering treatments as well as our additionally conducted simulation study, where we clearly observe, that discarding information on repeated measurements can lead to potentially erroneous conclusions.