Project Summary Pulmonary fibrosis (PF) is one of the most common forms of interstitial lung disease (ILD) and is often progressive leading to loss of lung function and death. Given that anti-fibrotic therapy can reduce progression, even in patients with less severe disease, there is more urgency to detect early stages of PF. Dr. Rose’s research group has helped to define imaging patterns, called interstitial lung abnormalities (ILA), that can help to predict early stages of PF. The fact that ILA is so much more prevalent than IPF, however, compels us to identify the subsets of ILA most likely to experience adverse outcomes. Dr. Rose’s initial work in the COPDGene cohort demonstrated that a combination of advanced imaging findings and pulmonary function identifies a high-risk group of ILA. The optimal method for predicting adverse outcomes, however, remains unclear and replication in other populations is warranted. Furthermore, novel biomarkers are needed, and the mechanisms of severity in this disease need to be better understood. The overall goal of this project is to identify the best method for the risk-stratification of ILA in order to identify a subset that may benefit from early intervention. In the first aim, Dr. Rose will assess the ability of clinical variables to predict a range of longitudinal outcomes and identify the optimal set of clinical criteria that helps to classify high-risk ILA. In the second aim, he will utilize proteomic measures to evaluate plasma proteins and multi-protein models that help to risk-stratify ILA. Finally in the third aim, he will explore genetic predictors of the proteins most significantly associated with high-risk ILA. This work will be performed in the Division of Pulmonary and Critical Care Medicine, at Brigham and Women’s Hospital (BWH), a core teaching hospital of Harvard Medical School. Dr. Rose will perform this work under the mentorship of Dr. Hunninghake, an expert in the field of early IPF characterization and Dr. Raby, an expert in genetic epidemiology. With the guidance of his mentors and scientific advisory committee, Dr. Rose has developed a comprehensive five-year training program to develop the skills needed to complete the project and become an independent investigator with expertise in imaging characterization, machine-learning techniques, complex multi-omic analyses, and their integration. Dr. Rose is dedicated to a career in academic medicine. His goal is to become a physician-investigator using the knowledge and skills gained during this project to better our understanding of adverse outcomes in pulmonary fibrosis and the biologic processes that lead to progressive disease, in a way that will ultimately benefit the patients suffering from this disease.