title: Biomarkers Predictive of Exacerbations in the SPIROMICS and COPDGene Cohorts.
abstract: 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.
  
  
  
  To determine the value of adding blood biomarkers to clinical variables to predict exacerbations.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors: 1 University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors: Jason D
authors: JD
authors: Keene
authors: 2 National Jewish Health, Denver, Colorado.
authors: Sean
authors: S
authors: Jacobson
authors: 3 Department of Biostatics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors: Katerina
authors: K
authors: Kechris
authors: 3 Department of Biostatics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors: Gregory L
authors: GL
authors: Kinney
authors: 4 Department of Medicine, Morehouse School of Medicine, Atlanta, Georgia.
authors: Marilyn G
authors: MG
authors: Foreman
authors: 5 Marsico Lung Institute/Cystic Fibrosis Research Center, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors: Claire M
authors: CM
authors: Doerschuk
authors: 2 National Jewish Health, Denver, Colorado.
authors: Barry J
authors: BJ
authors: Make
authors: 6 Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan.|7 VA Ann Arbor Healthcare System, Ann Arbor, Michigan.
authors: Jeffrey L
authors: JL
authors: Curtis
authors: 8 Division of Pulmonary and Critical Care Medicine, University of Nebraska, Omaha, Nebraska.
authors: Stephen I
authors: SI
authors: Rennard
authors: 9 Department of Medicine, Columbia University Medical Center, New York, New York.
authors: R Graham
authors: RG
authors: Barr
authors: 10 Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors: Eugene R
authors: ER
authors: Bleecker
authors: 11 Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Utah, Salt Lake City, Utah.
authors: Richard E
authors: RE
authors: Kanner
authors: 12 Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
authors: Eric C
authors: EC
authors: Kleerup
authors: 13 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Nadia N
authors: NN
authors: Hansel
authors: 14 Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine and Cardiovascular Research Institute, University of California San Francisco, School of Medicine, San Francisco, California; and.
authors: Prescott G
authors: PG
authors: Woodruff
authors: 6 Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan.
authors: MeiLan K
authors: MK
authors: Han
authors: 11 Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Utah, Salt Lake City, Utah.
authors: Robert
authors: R
authors: Paine
authors: 15 Department of Medicine, Weill Cornell Medical College, New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, New York.
authors: Fernando J
authors: FJ
authors: Martinez
authors: 2 National Jewish Health, Denver, Colorado.
authors: Russell P
authors: RP
authors: Bowler
authors: 5 Marsico Lung Institute/Cystic Fibrosis Research Center, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors: Wanda K
authors: WK
authors: O'Neal
mesh_terms: D015415:Biomarkers / Q000097:blood; D018450:Disease Progression; D005260:Female; D005541:Forced Expiratory Volume; D005764:Gastroesophageal Reflux / Q000209:etiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011446:Prospective Studies; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood* / Q000150:complications*; D012044:Regression Analysis; D012189:Retrospective Studies; D012720:Severity of Illness Index; D012907:Smoking / Q000009:adverse effects / Q000097:blood
chemical_list: D015415:Biomarkers
keywords: COPD; biomarker; exacerbation