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

• Published in: Statistics in medicine 2015-12, Vol.34 (29), p.3866-3887
• Main Authors: Strohmaier, Susanne, Røysland, Kjetil, Hoff, Rune, Borgan, Ørnulf, Pedersen, Terje R., Aalen, Odd O.
• Format: Article
• Language: English
• Subjects: additive hazard regression; Biomarkers; Clinical trials; Clinical Trials as Topic - standards; Clinical Trials as Topic - statistics & numerical data; Computer Simulation; Data Interpretation, Statistical; direct effect; directed acyclic graphs; Humans; IDEAL study; indirect effect; Information; Lipids; mediation analysis; Medical statistics; Proportional Hazards Models; Research Design - standards; Research Design - statistics & numerical data; Survival Analysis; Time Factors; Treatment Outcome
• ISSN: 0277-6715; 1097-0258
• DOI: 10.1002/sim.6598

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, much 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 because of 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. Copyright © 2015 John Wiley & Sons, Ltd.