@article{9f37b745aea049368e5a857aec2e14e8,
title = "Integrative multi-omics analysis reveals novel idiopathic pulmonary fibrosis endotypes associated with disease progression",
abstract = "BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of extracellular matrix in the pulmonary interstitium and progressive functional decline. We hypothesized that integration of multi-omics data would identify clinically meaningful molecular endotypes of IPF.METHODS: The IPF-PRO Registry is a prospective registry of patients with IPF. Proteomic and transcriptomic (including total RNA [toRNA] and microRNA [miRNA]) analyses were performed using blood collected at enrollment. Molecular data were integrated using Similarity Network Fusion, followed by unsupervised spectral clustering to identify molecular subtypes. Cox proportional hazards models tested the relationship between these subtypes and progression-free and transplant-free survival. The molecular subtypes were compared to risk groups based on a previously described 52-gene (toRNA expression) signature. Biological characteristics of the molecular subtypes were evaluated via linear regression differential expression and canonical pathways (Ingenuity Pathway Analysis [IPA]) over-representation analyses.RESULTS: Among 232 subjects, two molecular subtypes were identified. Subtype 1 (n = 105, 45.3%) and Subtype 2 (n = 127, 54.7%) had similar distributions of age (70.1 +/- 8.1 vs. 69.3 +/- 7.6 years; p = 0.31) and sex (79.1% vs. 70.1% males, p = 0.16). Subtype 1 had more severe disease based on composite physiologic index (CPI) (55.8 vs. 51.2; p = 0.002). After adjusting for CPI and antifibrotic treatment at enrollment, subtype 1 experienced shorter progression-free survival (HR 1.79, 95% CI 1.28,2.56; p = 0.0008) and similar transplant-free survival (HR 1.30, 95% CI 0.87,1.96; p = 0.20) as subtype 2. There was little agreement in the distribution of subjects to the molecular subtypes and the risk groups based on 52-gene signature (kappa = 0.04, 95% CI= -0.08, 0.17), and the 52-gene signature risk groups were associated with differences in transplant-free but not progression-free survival. Based on heatmaps and differential expression analyses, proteins and miRNAs (but not toRNA) contributed to classification of subjects to the molecular subtypes. The IPA showed enrichment in pulmonary fibrosis-relevant pathways, including mTOR, VEGF, PDGF, and B-cell receptor signaling.CONCLUSIONS: Integration of transcriptomic and proteomic data from blood enabled identification of clinically meaningful molecular endotypes of IPF. If validated, these endotypes could facilitate identification of individuals likely to experience disease progression and enrichment of clinical trials.TRIAL REGISTRATION: NCT01915511.",
keywords = "Biomarkers, Cluster analysis, Computational biology, Lung fibrosis, Proteomics, RNA, Humans, Lung, Male, Multiomics, Disease Progression, MicroRNAs, Female, Idiopathic Pulmonary Fibrosis/diagnosis",
author = "Peifeng Ruan and Todd, {Jamie L.} and Hongyu Zhao and Yi Liu and Richard Vinisko and Soellner, {Julia F.} and Ramona Schmid and Kaner, {Robert J.} and Luckhardt, {Tracy R.} and Neely, {Megan L.} and Imre Noth and Mary Porteous and Rishi Raj and Zeenat Safdar and Strek, {Mary E.} and Christian Hesslinger and Palmer, {Scott M.} and Leonard, {Thomas B.} and Salisbury, {Margaret L.}",
note = "Funding Information: Peifeng Ruan, Hongyu Zhao and Mary Porteous have nothing to report. Jamie L Todd, Megan L Neely and Scott M Palmer are employees of the Duke Clinical Research Institute (DCRI) which receives funding support from Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) to coordinate the IPF-PRO/ILD-PRO Registry. Jamie L Todd also reports grants from AstraZeneca, BI, CareDx and has participated on Data Safety Monitoring Boards or Advisory Boards for Altavant Sciences, Natera, Theravance. Megan L Neely also reports honoraria for a lecture from North Carolina State University. Yi Liu, Richard Vinisko, Julia F Soellner, Ramona Schmid, Christian Hesslinger and Thomas B Leonard are employees of BI. Robert J Kaner reports grants paid to his institution from Bellerophon, BI, Genentech, the National Institutes of Health, Respivant, Toray, the US Department of Defense; royalties or licenses from UpToDate; consulting fees from AstraZeneca and Galapagos; speaker fees from BI, the France Foundation, Genentech, Vindico; has participated on Data Safety Monitoring Boards or Advisory Boards for BI, Genentech, Pliant, PureTech; holds unpaid leadership or fiduciary roles with the Pulmonary Wellness Foundation and the Stony Wold Foundation; holds stock or stock options with Air Cycle Systems and Doximity; and has received medical writing support from AstraZeneca, BI, Galapagos, Genentech. Tracy R Luckhardt reports grants from Bellerophon and FibroGen for her role as a clinical trial investigator. Imre Noth reports a contract for biospecimens from Veracyte; royalties from UpToDate; consulting fees from BI, Genentech, Sanofi; he holds a patent for a gene signature predictor of FVC and has a PCSK6 patent pending; he holds licenses for protein markers in IPF; he was a member of the Yale COVID Data Safety Monitoring Board. Rishi Raj has received an investigator-initiated research grant from BI and served on an advisory board for BI. Zeenat Safdar reports consulting fees and honoraria for lectures from BI and Genentech. Mary E Strek has served as Principal Investigator for institutional and investigator-initiated grants from BI, and for institutional grants from Galapagos, Novartis, the Pulmonary Fibrosis Foundation; received honoraria for lectures and a textbook from CHEST; served on an adjudication committee for FibroGen; is on the American Thoracic Society Clinical Problems Committee and Research Innovation Summit Planning Committee; is Chair of the PFF Registry Scientific Review Committee. Scott M Palmer reports research funding to Duke/DCRI from AstraZeneca, Bristol Myers Squibb, CareDx; royalties or licenses from UpToDate; and speaker fees from Altavant Sciences, Bristol Myers Squibb, Mereo Biopharma, Theravance. Margaret L Salisbury reports grants paid to her institution from the National Institutes of Health; consulting fees from BI, Orinove Inc., Roche; payment for lectures from BI; and reimbursement to attend an investigators{\textquoteright} meeting from BI. Funding Information: We thank the principal investigators and enrolling centers in the IPF-PRO Registry: Albert Baker, Lynchburg Pulmonary Associates, Lynchburg, VA; Scott Beegle, Albany Medical Center, Albany, NY; John A Belperio, University of California Los Angeles, Los Angeles, CA; Rany Condos, NYU Medical Center, New York, NY; Francis Cordova, Temple University, Philadelphia, PA; Daniel A Culver, Cleveland Clinic, Cleveland, OH; Daniel Dilling, Loyola University Health System, Maywood, IL; John Fitzgerald (formerly Leann Silhan), UT Southwestern Medical Center, Dallas, TX; Kevin R Flaherty, University of Michigan, Ann Arbor, MI; Kevin Gibson, University of Pittsburgh, Pittsburgh, PA; Mridu Gulati, Yale School of Medicine, New Haven, CT; Kalpalatha Guntupalli, Baylor College of Medicine, Houston, TX; Nishant Gupta, University of Cincinnati Medical Center, Cincinnati, OH; Amy Hajari Case, Piedmont Healthcare, Atlanta, GA; David Hotchkin, The Oregon Clinic, Portland, OR; Tristan J Huie, National Jewish Health, Denver, CO; Robert J Kaner, Weill Cornell Medical College, New York, NY; Hyun J Kim, University of Minnesota, Minneapolis, MN; Lisa H Lancaster (formerly Mark Steele), Vanderbilt University Medical Center, Nashville, TN; Joseph A Lasky, Tulane University, New Orleans, LA; Doug Lee, Wilmington Health and PMG Research, Wilmington, NC; Timothy Liesching, Lahey Clinic, Burlington, MA; Randolph Lipchik, Froedtert & The Medical College of Wisconsin Community Physicians, Milwaukee, WI; Jason Lobo, UNC Chapel Hill, Chapel Hill, NC; Tracy R Luckhardt (formerly Joao A de Andrade), University of Alabama at Birmingham, Birmingham, AL; Yolanda Mageto (formerly Howard Huang), Baylor University Medical Center at Dallas, Dallas, TX; Marta Kokoszynska (formerly Yolanda Mageto, Prema Menon), Vermont Lung Center, Colchester, VT; Lake Morrison, Duke University Medical Center, Durham, NC; Andrew Namen, Wake Forest University, Winston Salem, NC; Justin M Oldham, University of California, Davis, Sacramento, CA; Tessy Paul, University of Virginia, Charlottesville, VA; David Zhang (formerly Anna Podolanczuk, David Lederer, Nina M Patel), Columbia University Medical Center/New York Presbyterian Hospital, New York, NY; Mary Porteous (formerly Maryl Kreider), University of Pennsylvania, Philadelphia, PA; Rishi Raj (formerly Paul Mohabir), Stanford University, Stanford, CA; Murali Ramaswamy, PulmonIx LLC, Greensboro, NC; Tonya Russell, Washington University, St. Louis, MO; Paul Sachs, Pulmonary Associates of Stamford, Stamford, CT; Zeenat Safdar, Houston Methodist Lung Center, Houston, TX; Shirin Shafazand (formerly Marilyn Glassberg), University of Miami, Miami, FL; Ather Siddiqi (formerly Wael Asi), Renovatio Clinical, The Woodlands, TX; Reginald Fowler (formerly Barry Sigal), Salem Chest and Southeastern Clinical Research Center, Winston Salem, NC; Mary E Strek (formerly Imre Noth), University of Chicago, Chicago, IL; Hiram Rivas-Perez (formerly Jesse Roman, Sally Suliman), University of Louisville, Louisville, KY; Jeremy Tabak, South Miami Hospital, South Miami, FL; Rajat Walia, St. Joseph{\textquoteright}s Hospital, Phoenix, AZ; Timothy PM Whelan, Medical University of South Carolina, Charleston, SC. The authors thank Janine Roy, Staburo GmbH, Munich, Germany for conducting the primary analysis of the sequencing data and Naftali Kaminski and Jose D. Herazo-Maya from Yale University, New Haven, USA for confirming how the 52-gene signature should be applied. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The authors did not receive payment for development of this article. Editorial support was provided by Melanie Stephens and Wendy Morris of Fleishman-Hillard, London, UK, which was contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc. Boehringer Ingelheim was given the opportunity to review the article for medical and scientific accuracy as well as intellectual property considerations. Funding Information: The authors thank Janine Roy, Staburo GmbH, Munich, Germany for conducting the primary analysis of the sequencing data and Naftali Kaminski and Jose D. Herazo-Maya from Yale University, New Haven, USA for confirming how the 52-gene signature should be applied. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The authors did not receive payment for development of this article. Editorial support was provided by Melanie Stephens and Wendy Morris of Fleishman-Hillard, London, UK, which was contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc. Boehringer Ingelheim was given the opportunity to review the article for medical and scientific accuracy as well as intellectual property considerations. Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2023",
month = may,
day = "31",
doi = "10.1186/s12931-023-02435-0",
language = "English (US)",
volume = "24",
pages = "141",
journal = "Respiratory Research",
issn = "1465-9921",
publisher = "BioMed Central Ltd.",
number = "1",
}