Electronic Health Record Biobank Cohort Recapitulates an Association Between the Promoter Polymorphism and ARDS in Critically Ill Adults

Background: Large population-based DNA biobanks linked to electronic health records (EHRs) may provide novel opportunities to identify genetic drivers of ARDS.

Research Question: Can we develop an EHR-based algorithm to identify ARDS in a biobank database, and can this validate a previously reported ARDS genetic risk factor?

Study Design And Methods: We analyzed two parallel genotyped cohorts: a prospective biomarker cohort of critically ill adults (VALID), and a retrospective cohort of hospitalized participants enrolled in a de-identified EHR biobank (BioVU). ARDS was identified by clinician-investigator review in VALID and an EHR algorithm in BioVU (EHR-ARDS). We tested the association between the promoter polymorphism rs35705950 with development of ARDS, and assessed if age modified this genetic association 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] years, and 1,056 (11.7%) developed EHR-ARDS. We observed a significant age-related interaction effect on ARDS in VALID: among 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 absent (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 did not vary by age. The polymorphism was also associated worse oxygenation in mechanically ventilated BioVU participants, but had no association with oxygenation in VALID.

Interpretation: The promoter polymorphism was associated with ARDS in two cohorts of at-risk adults. Although age-related effect modification was observed only in VALID, BioVU identified a consistent association between 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.