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Emulating a target trial reduces the potential for bias in observational comparative effectiveness research. Owing to feasibility constraints, large cohort studies often use electronic health records without validating key variables or collecting additional data. A case-control design allows researchers to validate, supplement, or collect additional data on key measurements in a much smaller sample compared with the entire cohort. In this article, Rasouli and colleagues describe methods to emulate a target trial using a nested case-control design, and provide a detailed guideline, an analytical program, and results of a clinical example. #### Summary points Randomized controlled trials are considered the ideal study design for comparative effectiveness research. Given that such trials are usually costly, lengthy, and, in some instances, unethical or infeasible, interest is increasing in using observational studies such as those conducted using data from electronic health records and

District of columbiaUnited statesRogerw loganMiguela hernMatthew nguyenKerril wigginsBrucem psatyBarbraa dickermanKelly meyersGoodarz danaeiJessica chubakBahareh rasouliJamess floydKaiser permanenteKaiser permanente washington health research instituteNovo nordisk foundation