Interstitial lung disease (ILD) is a highly morbid and potentially fatal complication of myositis. Current myositis phenotypes do not capture significant heterogeneity in ILD clinical behavior. Existing prediction models and biomarkers perform poorly in patients with myositis-ILD and require longitudinal validation in diverse patient populations. Because clinicians lack tools to prognosticate long-term myositis-ILD outcomes, many patients receive either inadequate or overly aggressive treatment. We have shown that the GAP-ILD Index performs poorly in myositis- ILD. Myositis-ILD specific prediction tools do not adequately model disease progression and do not generalize to populations outside of Asia. Previously, we demonstrated that specific human leukocyte antigen (HLA) alleles are myositis-ILD susceptibility factors. Our preliminary model of progression-free survival containing clinical data and HLA genotypes discriminated progression, suggesting that HLA haplotypes are also biomarkers of myositis-ILD disease activity and treatment responsiveness. As a next step, we plan to refine and validate our preliminary model. The goal of Specific Aim 1 is to utilize a large, diverse multicenter cohort of patients with myositis- ILD in North America to develop a prediction model of progression free survival using known and novel biomarkers. While increasingly recognized, there is no current strategy to confront the clinical and biological heterogeneity within myositis-ILD subgroups. Our preliminary data demonstrates two clusters of myositis-ILD. We hypothesize that these myositis-ILD clusters carry distinct pathobiology, treatment responsiveness, and outcomes. The goal of specific Aim 2 is to apply cluster analysis to clinical, genomic, and serological data from patients with myositis-ILD to identify novel subphenotypes. The data generated from this proposal will result in a novel classification of myositis-ILD subphenotypes and a superior tool for prognosticating important clinical outcomes. Our approach is feasible because we are building on existing clinical and biorepository data from five demographically diverse myositis-ILD referral centers in the United States. This contribution is significant because it will establish a validated clinical signature for precision therapy in patients with myositis-ILD and generate novel treatment approaches.