Typically, subgroup analyses in clinical trials are conducted by comparing the intervention effect in each subgroup by means of an interaction test. However, trials are rarely, if ever, adequately powered for interaction tests, so clinically important interactions may go undetected. We discuss the application of Bayesian methods by using expert opinions alongside the trial data. We applied this methodology to the VeRDiCT trial investigating the effect of preoperative volume replacement therapy (VRT) versus no VRT (usual care) in diabetic patients undergoing cardiac surgery. Two subgroup effects were of clinical interest, a) preoperative renal failure and b) preoperative type of antidiabetic medication.
Clinical experts were identified within the VeRDiCT trial centre in the UK. A questionnaire was designed to elicit opinions on the impact of VRT on the primary outcome of time from surgery until medically fit for hospital discharge, in the different subgroups. Prior beliefs of the subgroup effect of VRT were elicited face-to-face using two unconditional and one conditional questions per subgroup analysis. The robustness of results to the ‘community of priors’ was assessed. The community of priors was built using the expert priors for the mean average treatment effect, the interaction effect or both in a Bayesian Cox proportional hazards model implemented in the STAN software in R.
Expert opinions were obtained from 7 clinicians (6 cardiac surgeons and 1 cardiac anaesthetist). Participating experts believed VRT could reduce the length of recovery compared to usual care and the greatest benefit was expected in the subgroups with the more severe comorbidity. The Bayesian posterior estimates were more precise compared to the frequentist maximum likelihood estimate and were shifted toward the overall mean treatment effect.
In the VeRDiCT trial, the Bayesian analysis did not provide evidence of a difference in treatment effect across subgroups. However, this approach increased the precision of the estimated subgroup effects and produced more stable treatment effect point estimates than the frequentist approach. Trial methodologists are encouraged to prospectively consider Bayesian subgroup analyses when low-powered interaction tests are planned.
ISRCTN, ISRCTN02159606. Registered 29th October 2008.
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