Integrating biomarker information within trials to evaluate treatment mechanisms and efficacy for personalised medicine

Abstract

Personalised (stratified) medicine and treatment-effect mechanisms evaluation are inextricably linked. Stratification without corresponding mechanisms evaluation lacks credibility. In the presence of mediator-outcome confounding, mechanisms evaluation is dependent on stratification for its validity. Both stratification and treatment-effect mediation can be evaluated using a biomarker stratified trial design together with detailed baseline measurement of all known prognostic biomarkers and other prognostic covariates. Direct and indirect (mediated) effects should be estimated through the use of IV methods (the IV being the predictive marker by treatment interaction) together with adjustments for all known prognostic markers (confounders) - the latter adjustments contributing to increased precision (as in a conventional analysis of treatment effects) rather than bias reduction.