Dr. O’Byrne's research focuses on improving outcomes in patients with congenital and acquired heart disease. To accomplish this, his research portfolio includes studies that leverage large observational datasets (clinical registries, administrative datasets, and claims databases) to assess quality of care and practice variation between hospitals, comparative effectiveness research, and economic outcomes.

Separately, he also leads a team evaluating patient-centered outcomes of patients and families with cardiac disease evaluating the biological and psychological determinants of health-related quality of life in this population. He is supported by a patient-centered career development award from the National Heart Lung and Blood Institute as well as project support from foundations.