Introduction: Electronic nicotine delivery systems (ENDS) are driving an epidemic of vaping. Identifying biomarkers of vaping and dual use (concurrent vaping and smoking), will facilitate studies of the health effects of vaping. We conducted a blood biomarker discovery study for vaping and dual use in a longitudinal cohort of current and former adult smokers with high-throughput transcriptomic and proteomic data, and we tested biomarkers for association to multiple health outcomes. Methods: We studied 3,892 COPDGene study participants with blood transcriptomics and/or plasma proteomics data according to their self-reported current vaping and smoking behavior. Biomarkers of vaping and dual use were identified through differential expression analysis and related to prospective health events over six years of follow-up. To assess the predictive accuracy of multi-biomarker panels, we constructed predictive models for vaping and smoking categories and prospective health outcomes. Results: We identified 3 transcriptomic and 3 proteomic associations to vaping, and 90 transcriptomic and 100 proteomic associations to dual use (FDR 10%). Many of these vaping or dual use biomarkers were significantly associated with prospective health outcomes, such as FEV1 decline (3 transcripts and 62 proteins), overall mortality (18 transcripts and 73 proteins), respiratory mortality (2 transcripts and 23 proteins), respiratory exacerbations (13 proteins) and incident cardiovascular disease (24 proteins). Multimarker models showed good performance discriminating between vaping and smoking behavior and produced informative, modestly powerful predictions of future FEV1 decline, mortality and respiratory exacerbations. Conclusion: Vaping and dual use are associated with multiple blood-based biomarkers that are also associated with adverse health outcomes.

Competing Interests: EKS and PJC have received grant support from GlaxoSmithKline and Bayer. JY has received institutional grant support from Bayer and personal fees from Bride Biotherapeutics outside the submitted work.

Funding Sources: This work was supported by NHLBI K08HL141601, K08HL146972, K01HL157613, R01HL124233, U01 HL089897, R01 HL147326, and U01 HL089856. The COPDGene study (NCT00608764) is also supported by the COPD Foundation through contributions made to an Industry Advisory Committee that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion.

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Clinical Center Institution Title Protocol Number National Jewish Health National Jewish IRB HS1883a Brigham and Womens Hospital Partners Human Research Committee 2007P000554 BWH Baylor College of Medicine Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals H22209 Michael E. DeBakey VAMC Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals H22202 Columbia University Medical Center Columbia University Medical Center IRB IRB AAAC9324 Duke University Medical Center The Duke University Health System Institutional Review Board for Clinical Investigations (DUHS IRB) Pro00004464 Johns Hopkins University Johns Hopkins Medicine Institutional Review Boards (JHM IRB) NA00011524 Los Angeles Biomedical Research Institute The John F. Wolf MD Human Subjects Committee of Harbor UCLA Medical Center 1275601 Morehouse School of Medicine Morehouse School of Medicine Institutional Review Board 071029 Temple University Temple University Office for Human Subjects Protections Institutional Review Board 11369 University of Alabama at Birmingham The University of Alabama at Birmingham Institutional Review Board for Human Use FO70712014 University of California San Diego University of California San Diego Human Research Protections Program 070876 University of Iowa The University of Iowa Human Subjects Office 200710717 Ann Arbor VA VA Ann Arbor Healthcare System IRB PCC 2008110732 University of Minnesota University of Minnesota Research Subjects Protection Programs (RSPP) 0801M24949 University of Pittsburgh University of Pittsburgh Institutional Review Board PRO07120059 University of Texas Health Sciences Center at San Antonio UT Health Science Center San Antonio Institutional Review Board HSC20070644H Health Partners Research Foundation Health Partners Research Foundation Institutional Review Board 07127 University of Michigan Medical School Institutional Review Board (IRBMED) HUM00014973 Minneapolis VA Medical Center Minneapolis VAMC IRB 4128A Fallon Clinic IRB/Research Review Committee St. Vincent Hospital Fallon Clinic Fallon Community Health Plan 1143

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