Proteomic Biomarkers of Survival in Idiopathic Pulmonary Fibrosis
Justin M. Oldham, Yong Huang, Swaraj Bose, Shwu‐Fan Ma, John S. Kim, Alexandra Schwab, Christopher Ting, Kaniz Mou, Cathryn T. Lee, Ayodeji Adegunsoye, Sahand Ghodrati, Janelle Vu Pugashetti, Nazanin Nazemi, Mary E. Strek, A. Linderholm, Ching‐Hsien Chen, Susan Murray, Rachel L. Zemans, Kevin R. Flaherty, Fernando J. Martínez, Imre Noth
Abstract
Abstract Rationale Idiopathic pulmonary fibrosis (IPF) causes progressive lung scarring and high mortality. Reliable and accurate prognostic biomarkers are urgently needed. Objectives To identify and validate circulating protein biomarkers of IPF survival. Methods High-throughput proteomic data were generated using prospectively collected plasma samples from patients with IPF from the Pulmonary Fibrosis Foundation Patient Registry (discovery cohort) and the Universities of California, Davis; Chicago; and Virginia (validation cohort). Proteins associated with three-year transplant-free survival (TFS) were identified using multivariable Cox proportional hazards regression. Those associated with TFS after adjustment for false discovery in the discovery cohort were advanced for testing in the validation cohort, with proteins maintaining TFS association with consistent effect direction considered validated. After combining cohorts, functional analyses were performed, and machine learning was used to derive a proteomic signature of TFS. Measurements and Main Results Of 2,921 proteins tested in the discovery cohort (n = 871), 231 were associated with differential TFS. Of these, 140 maintained TFS association with consistent effect direction in the validation cohort (n = 355). After cohorts were combined, the validated proteins with the strongest TFS association were latent-transforming growth factor β-binding protein 2 (hazard ratio [HR], 2.43; 95% confidence interval [CI] = 2.09–2.82), collagen α-1(XXIV) chain (HR, 2.21; 95% CI = 1.86–2.39), and keratin 19 (HR, 1.60; 95% CI = 1.47–1.74). In decision curve analysis, a proteomic signature of TFS outperformed a similarly derived clinical prediction model. Conclusions In the largest proteomic investigation of IPF outcomes performed to date, we identified and validated 140 protein biomarkers of TFS. These results shed important light on potential drivers of IPF progression.