@article{89368936dc614c50a8d61675c8ed86dc,
title = "Biomarkers predictive of exacerbations in the SPIROMICS and COPDGene cohorts",
abstract = "Rationale: Chronic obstructive pulmonary disease exacerbations are associated with disease progression, higher healthcare cost, and increased mortality. Published predictors of future exacerbations include previous exacerbation, airflow obstruction, poor overall health, home oxygen use, and gastroesophageal reflux. Objectives: To determine the value of adding blood biomarkers to clinical variables to predict exacerbations. Methods: Subjects from the SPIROMICS (Subpopulations and Intermediate Outcomes Measures in COPD Study) (n = 1,544) and COPDGene (Genetic Epidemiology of COPD) (n = 602) cohorts had 90 plasma or serum candidate proteins measured on study entry using Myriad-RBM multiplex panels. We defined total exacerbations as subject-reported worsening in respiratory health requiring therapy with corticosteroids and/or antibiotics, and severe exacerbations as those leading to hospitalizations or emergency room visits. We assessed retrospective exacerbations during the 12 months before enrollment and then documented prospective exacerbations in each cohort. Exacerbations were modeled for biomarker associations with negative binomial regression including clinical covariates (age, sex, percent predicted FEV1, self-reported gastroesophageal reflux, St. George's Respiratory Questionnaire score, smoking status). We used the Stouffer-Liptak test to combine P values for metaanalysis. Measurements and Main Results: Between the two cohorts, 3,471 total exacerbations (1,044 severe) were reported. We identified biomarkers within each cohort that were significantly associated with a history of exacerbation and with a future exacerbation, but there was minimal replication between the cohorts. Although established clinical features were predictive of exacerbations, of the blood biomarkers only decorin and α2-macroglobulin increased predictive value for future severe exacerbations. Conclusions: Blood biomarkers were significantly associated with the occurrence of exacerbations but were not robust between cohorts and added little to the predictive value of clinical covariates for exacerbations.",
keywords = "Biomarker, COPD, Exacerbation",
author = "Keene, {Jason D.} and Sean Jacobson and Katerina Kechris and Kinney, {Gregory L.} and Foreman, {Marilyn G.} and Doerschuk, {Claire M.} and Make, {Barry J.} and Curtis, {Jeffrey L.} and Rennard, {Stephen I.} and Barr, {R. Graham} and Bleecker, {Eugene R.} and Kanner, {Richard E.} and Kleerup, {Eric C.} and Hansel, {Nadia N.} and Woodruff, {Prescott G.} and Han, {Mei Lan K.} and Robert Paine and Martinez, {Fernando J.} and Bowler, {Russell P.} and O'Neal, {Wanda K.}",
note = "Funding Information: Supported by NHLBI (R01HL 095432, R01 HL089856, and R01 HL089897) and National Center for Research Resources/National Institutes of Health (UL1 RR025680). SPIROMICS (Subpopulations and Intermediate Outcomes in COPD Study) is funded by contracts from the NHLBI (HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN2682009000019C, and HHSN268200900020C), supplemented by contributions made through the Foundation for the National Institutes for Health from AstraZeneca; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals, Inc.; Chiesi Farmaceutici SpA; Forest Research Institute, Inc.; GSK; Grifols Therapeutics, Inc.; Ikaria, Inc.; Nycomed GmbH; Takeda Pharmaceutical Company; Novartis Pharmaceuticals Corporation; Regeneron Pharmaceuticals, Inc.; and Sanofi. Funding Information: SPIROMICS (ClinicalTrials.gov Identifier: NCT 01969344) is an ongoing multicenter prospective observational study funded by the NIH (12) that enrolled 2,982 subjects between November 2011 and January 2015. The institutional review board at all participating sites approved the study protocol. Study participants provided written informed consent. The data reported here include results from the first 1,544 subjects enrolled in strata 2–4 (see APPENDIX in the online supplement for further details) (12, 13). The NIH sponsored multicenter COPDGene (ClinicalTrials.gov Identifier: NCT 01969344) study was approved and reviewed by the institutional review board at all participating centers (14). Study participants provided written informed consent. In brief, all subjects were between 45 and 80 years old, had at least 10 pack-years of smoking, and had not had an acute respiratory exacerbation for at least 30 days (14, 15). Of the larger cohort of 10,300 subjects, 602 were selected to undergo a comprehensive biomarker study. For more details on study population, please see online supplement APPENDIX. Publisher Copyright: {\textcopyright} Copyright 2017 by the American Thoracic Society.",
year = "2017",
month = feb,
day = "15",
doi = "10.1164/rccm.201607-1330OC",
language = "English (US)",
volume = "195",
pages = "473--481",
journal = "American Journal of Respiratory and Critical Care Medicine",
issn = "1073-449X",
publisher = "American Thoracic Society",
number = "4",
}