This application is for a K23 award for Dr. Joyce S. Lee, an Assistant Professor at the University of Colorado (CU) Denver. Career Goals: This k23 award will facilitate the following goals: (1) to understand the application of genetic and genomic epidemiology in the field of interstitial lung disease (ILD); (2) to gain knowledge in computational approaches to big data analysis; (3) to develop training in biomarker testing and development in subclinical disease states; (4) to conduct clinical and translational investigations to better understand subclinical rheumatoid arthritis-associated ILD (RA-ILD); and (5) to achieve her long-term career goal of becoming an independent clinical and translational research investigator in the field of ILD. Mentorship: To achieve these goals, Dr. Lee has assembled a mentoring team comprised of Dr. David Schwartz (primary mentor), an internationally recognized scientist in the field of ILD; Dr. Michael Holers (co- mentor), an internationally recognized expert in the immunologic investigations of early RA; and a research advisory committee that includes Dr. Tasha Fingerlin, an expert statistical geneticist and genetic epidemiologist, and content experts including Dr. Kevin Deane and Dr. Jill Norris. Training and Environment: She has constructed a rigorous career development plan that includes specific coursework, high-impact workshops, and mentorship, centered at CU, which provides the infrastructure, resources and collaborators necessary for high impact clinical research. Research Objective: The overall goal of this research proposal is to define the clinical and molecular/genetic phenotype of subclinical RA-ILD. Relationship to Health: Deaths from RA-ILD are increasing despite an overall decline in RA mortality. Early detection of subclinical RA-ILD will identify patients with a lower burden of lung disease, potentially more salvageable lung, and may reveal novel molecular targets for intervention that are effective in the subclinical and/or early clinical stages of this progressive disease. Rationale: Preliminary data demonstrate clinical, genetic and biologic similarities between RA-ILD and idiopathic pulmonary fibrosis (IPF). This proposal leverages the progress that has been made in the understanding of established and subclinical forms of IPF. Hypothesis: Patients at risk for RA-ILD and IPF have shared clinical, genetic, and biological risk factors. Aims: This research proposal will define the phenotype and estimate the prevalence of subclinical RA-ILD (Aim 1), test the role of the MUC5B variant in subclinical RA-ILD (Aim 2A), and derive and validate a biomarker profile in subclinical RA-ILD (Aim 2B). Approach: To address this hypothesis and accomplish these aims, 400 RA patients will be enrolled and abnormalities of ILD identified using high-resolution computed tomography scans. This information will be used to develop a robust risk prediction algorithm to identify RA patients at highest risk for ILD in the clinical setting. Using this cohort, the genetic and biologic factors associated with subclinical RA-ILD will be investigated.