Assessing The Performance of Physician’s Prescribing Preference As An Instrumental Variable in Comparative Effectiveness Research With Moderate and Small Sample Sizes: A Simulation Study

BackgroundInstrumental variable (IV) analyses are used to account for unmeasured confounding in Comparative Effectiveness Research (CER) in pharmacoepidemiology. To date, simulation studies assessing the performance of IV analyses have been based on large samples. However, in many settings, sample sizes are not large.Objective In this simulation study, we assess the utility of Physician’s Prescribing Preference (PPP) as an IV for moderate and smaller sample sizes.MethodsWe designed a simulation study in a CER setting with moderate (around 2500) and small (around 600) sample sizes. The outcome and treatment variables were binary and three variables were used to represent confounding (a binary and a continuous variable representing measured confounding, and a further continuous variable representing unmeasured confounding). We compare the performance of IV and non-IV approaches using two-stage least squares (2SLS) and ordinary least squares (OLS) methods, respectively. Further, we test the performance of different forms of proxies for PPP as an IV.ResultsThe PPP IV approach results in a percent bias of approximately 20%, while the percent bias of OLS is close to 60%. The sample size is not associated with the level of bias for the PPP IV approach. However, smaller sample sizes led to lower statistical power for the PPP IV. Using proxies for PPP based on longer prescription histories result in stronger IVs, partly offsetting the effect on power of smaller sample sizes.Conclusion Irrespective of sample size, the PPP IV approach leads to less biased estimates of treatment effectiveness than conventional multivariable regression adjusting for known confounding only. Particularly for smaller sample sizes, we recommend constructing PPP from long prescribing histories to improve statistical power.