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Assessing the impact of unmeasured confounders for credible and reliable real-world evidence

Purpose: We review statistical methods for assessing the possible impact of bias due to unmeasured confounding in real world data analysis and provide detailed recommendations for choosing among the methods. Methods: By updating an earlier systematic review, we summarize modern statistical best practices for evaluating and correcting for potential bias due to unmeasuredconfounding in estimating causal treatment effect from non-interventional studies. Results: We suggest a hierarchical structure for assessing unmeasured confounding.First, for initial sensitivity analyses, we strongly recommend applying a recently developed method, the E-value, that is straightforward to apply and does not require prior knowledge or assumptions about the unmeasured confounder(s). When some such knowledge is available, the E-value could be supplemented by the rule-out or array method at this step. If these initial analyses suggest results may not be robust to unmeasured confounding, subsequent analyses could be conducted using more specialized statistical methods, which we categorize based on whether they requireaccess to external data on the suspected unmeasured confounder(s), internal data, or no data. Other factors for choosing the subsequent sensitivity analysis methods arealso introduced and discussed, including the types of unmeasured confounders and whether the subsequent sensitivity analysis is intended to provide a corrected causaltreatment effect. Conclusion: Various analytical methods have been proposed to address unmeasured confounding, but little research has discussed a structured approach to select appropriate methods in practice. In providing practical suggestions for choosing appropriate initial and, potentially, more specialized subsequent sensitivity analyses, we hopeto facilitate the widespread reporting of such sensitivity analyses in non-interventional studies. The suggested approach also has the potential to inform pre-specificationof sensitivity analyses before executing the analysis, and therefore increase the transparency and limit selective study reporting.