Triangulating Instrumental Variable, confounder adjustment and Difference-in-Difference methods for comparative effectiveness research in observational data

Observational studies can play a useful role in assessing the comparative effectiveness of competing treatments. In a clinical trial the randomization of participants to treatment and control groups generally results in well-balanced groups with respect to possible confounders, which makes the analysis straightforward. However, when analysing observational data, the potential for unmeasured confounding makes comparing treatment effects much more challenging. Causal inference methods such as the Instrumental Variable and Prior Even Rate Ratio approaches make it possible to circumvent the need to adjust for confounding factors that have not been measured in the data or measured with error. Direct confounder adjustment via multivariable regression and Propensity score matching also have considerable utility. Each method relies on a different set of assumptions and leverages different data. In this paper, we describe the assumptions of each method and assess the impact of violating these assumptions in a simulation study. We propose the prior outcome augmented Instrumental Variable method that leverages data from before and after treatment initiation, and is robust to the violation of key assumptions. Finally, we propose the use of a heterogeneity statistic to decide two or more estimates are statistically similar, taking into account their correlation. We illustrate our causal framework to assess the risk of genital infection in patients prescribed Sodium-glucose Co-transporter-2 inhibitors versus Dipeptidyl Peptidase-4 inhibitors as second-line treatment for type 2 diabets using observational data from the Clinical Practice Research Datalink.