Large-Scale Evidence Generation And Evaluation Across A Network Of Databases (Legend): Assessing Validity Using Hypertension As A Case Study

Objectives: To demonstrate the application of the Large-scale Evidence Generation and Evaluation across a Network of Databases (LEGEND) principles described in our companion article to hypertension treatments and assess internal and external validity of the generated evidence.Materials and Methods: LEGEND defines a process for high-quality observational research based on 10 guiding principles. We demonstrate how this process, here implemented through large-scale propensity score modeling, negative and positive control questions, empirical calibration, and full transparency, can be applied to compare antihypertensive drug therapies. We assess internal validity through covariate balance, confidence-interval coverage, between-database heterogeneity, and transitivity of results. We assess external validity through comparison to direct meta-analyses of randomized controlled trials (RCTs).Results: From 21.6 million unique antihypertensive new users, we generate 6 076 775 effect size estimates for 699 872 research questions on 12 946 treatment comparisons. Through propensity score matching, we achieve balance on all baseline patient characteristics for 75% of estimates, observe 95.7% coverage in our effect-estimate 95% confidence intervals, find high between-database consistency, and achieve transitivity in 84.8% of triplet hypotheses. Compared with meta-analyses of RCTs, our results are consistent with 28 of 30 comparisons while providing narrower confidence intervals.Conclusion: We find that these LEGEND results show high internal validity and are congruent with meta-analyses of RCTs. For these reasons we believe that evidence generated by LEGEND is of high quality and can inform medical decision-making where evidence is currently lacking. Subsequent publications will explore the clinical interpretations of this evidence.