PROJECT SUMMARY/ABSTRACT Pulmonary hypertension (PH) is a heterogeneous disorder characterized by elevated pulmonary artery pressure and is a frequent complication of chronic lung diseases, including chronic obstructive pulmonary disease and interstitial lung disease. Despite significant impairment in quality of life and elevated mortality risk associated with lung disease-PH, there is a single FDA approved therapy, which is appropriate for only a small subset of patients. For this reason, drugs approved for pulmonary arterial hypertension (PAH) are frequently used off- label. Clinical trials evaluating the efficacy of PAH therapy in lung disease-PH have by-and-large demonstrated no consistent benefit. However, cumulative data suggest a signal towards clinical improvement in certain lung disease-PH subgroups. Small sample size and heterogeneity of patient inclusion in these trials limit understanding of which lung disease-PH patients per se may benefit from repurposing existing PAH therapies. Therefore, efforts to sub-phenotype lung disease-PH patients and decipher heterogeneity of treatment effect are critical to improving outcomes for at-risk patients. The Veteran’s Health Administration (VA) is the largest integrated national health system, and includes a patient population enriched for lung disease-PH in whom off- label prescribing of PAH therapies is common. To this end, leveraging a national cohort of Veterans with lung disease-PH established by my sponsor, I propose the study, “Novel methods to sub-phenotype patients with pulmonary hypertension due to chronic lung disease with implications for treatment.” This study includes two foundational steps towards unraveling the heterogeneous diagnosis of lung disease-PH to advance treatments: 1) characterize sub-phenotypes of lung disease-PH using cluster analysis and 2) explore how treatment outcomes vary across lung disease-PH sub-phenotypes. The first objective will be achieved through the application of k-means cluster analysis to physiologic and functional variables relevant to the diagnosis of lung disease-PH and assessment of disease severity. The second objective will be achieved through within cluster Cox proportional hazard assessments of acute respiratory, renal and right heart failure or death. These aims are directly in line with one major research priority of the NHLBI, to identify disease sub-phenotypes and patients likely to respond to disease-specific treatments. Completion of this proposal will advance the field of lung disease-PH by identifying sub-phenotypes of patients to then refine patient enrollment in clinical trials, advance therapeutic options and improve disease survival. The skills I anticipate gaining through this mentored project across three academic institutions, Boston University Medical Center, Boston Veteran Affairs Center for Healthcare Organization & Implementation Research and The Division of Cardiovascular Medicine at Brigham and Women’s Hospital/Harvard Med...