Background: Large population-based DNA biobanks linked to electronic health records (EHRs) may provide advantages over traditional study designs for identifying genetic drivers of ARDS. Research Question: Can ARDS be identified in an EHR biobank, and can this approach validate a previously reported genetic risk factor for ARDS? Study Design and Methods: We analyzed two genotyped cohorts from one academic medical center: a prospective biomarker study of critically ill adults (VALID cohort), and hospitalized participants in a de-identified EHR biobank (BioVU). ARDS status was assessed by clinician-investigator review in VALID and an EHR-derived algorithm in BioVU (EHR-ARDS). We tested the association between the MUC5B promoter polymorphism (rs35705950) with development of ARDS/EHR-ARDS in each cohort. Results: In VALID, 2,795 patients were included, age was 55 [43, 66] (median [IQR]) years, and 718 (25.7%) developed ARDS. In BioVU, 9,025 hospitalized participants were included, age was 60 [48, 70] , and 1,056 (11.7%) developed EHR-ARDS. We observed a significant interaction between age and rs35705950 on ARDS risk in VALID: in older patients rs35705950 was associated with increased ARDS risk (OR: 1.44; 95%CI 1.08-1.92; p=0.012) whereas among younger patients this effect was attenuated (OR: 0.84; 95%CI: 0.62-1.14; p=0.26). In BioVU, rs35705950 was associated with increased risk for EHR-ARDS among all participants (OR: 1.20; 95%CI: 1.00-1.43, p=0.043) and this relationship did not vary by age. The polymorphism was also associated with more severe oxygenation impairment among BioVU participants who required mechanical ventilation. Interpretation: The MUC5B promoter polymorphism was associated with ARDS in two cohorts of at-risk hospitalized adults. Although age-related effect modification was observed only in the prospective biomarker cohort, the EHR cohort identified a consistent association between MUC5B and ARDS risk regardless of age and a novel association with oxygenation impairment. Our study highlights the potential for EHR biobanks to enable precision-medicine ARDS studies.

Dr. Ware reports consulting fees from Novartis, Arrowhead, Akebia, and Global Blood Therapeutics, stock ownership in Virtuoso Surgical, and an institutional research contract with Genentech, Inc. The remaining authors report no conflicts of interest with the reported study.

Research reported in this publication was supported by the National Institutes of Health under award numbers: NIH K01HL157755 (VEK) NIH R01HL158906 and R01HL164937 (LBW) NIH R01 HL126671 (JAB) and DoD W81XWH-18-1-0683 (JAB), and research contract funds from Genentech Inc. The project publication described was also supported by CTSA award No. UL1TR002243 from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. This research was also supported by Courtneys Race for the Acute Respiratory Distress Syndrome Cure and the Courtney Charneco Family.

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