Comparison of alternative models for linking drug exposure with adverse effects

Pharmacoepidemiology investigates associations between time-varying medication use/dose and risk of adverse events. Applied research typically relies on a priori chosen simple conventional models, such as current dose or any use in the past 3 months. However, different models imply different risk predictions, and only one model can be etiologically correct in any specific applications. We first formally defined several candidate models mapping the time vector of past drug doses (X (t), t  =  1, … ,u) into the value of a time-varying exposure metric M(u) at current time u. In addition to conventional one-parameter models, we considered two-parameter models accounting for recent dose increase or withdrawal and a flexible spline-based weighted cumulative exposure (WCE) model that defines M(u) as the weighted sum of past doses. In simulations, we generated event times assuming one of the models was correct and then analyzed the data with all candidate models. We demonstrated that the minimum AIC criterion is able to identify the correct model as the best-fitting model or one of the equivalent (within 4 AIC points of the minimum) models in a vast majority of simulated samples, especially with 500 or more events. We also showed how relying on an incorrect a priori chosen model may largely reduce the power to test for an association. Finally, we demonstrated how the flexible WCE estimates may help with model diagnostics even if the correct model is not WCE. We illustrated the practical advantages of AIC-based a posteriori model selection and WCE modeling in a real-life pharmacoepidemiology example.