title: COPD Exacerbation Biomarkers Validated Using Multiple Reaction Monitoring Mass Spectrometry.
abstract: BACKGROUND
  Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) result in considerable morbidity and mortality. However, there are no objective biomarkers to diagnose AECOPD.
  
  
  METHODS
  We used multiple reaction monitoring mass spectrometry to quantify 129 distinct proteins in plasma samples from patients with COPD. This analytical approach was first performed in a biomarker cohort of patients hospitalized with AECOPD (Cohort A, n = 72). Proteins differentially expressed between AECOPD and convalescent states were chosen using a false discovery rate <0.01 and fold change >1.2. Protein selection and classifier building were performed using an elastic net logistic regression model. The performance of the biomarker panel was then tested in two independent AECOPD cohorts (Cohort B, n = 37, and Cohort C, n = 109) using leave-pair-out cross-validation methods.
  
  
  RESULTS
  Five proteins were identified distinguishing AECOPD and convalescent states in Cohort A. Biomarker scores derived from this model were significantly higher during AECOPD than in the convalescent state in the discovery cohort (p<0.001). The receiver operating characteristic cross-validation area under the curve (CV-AUC) statistic was 0.73 in Cohort A, while in the replication cohorts the CV-AUC was 0.77 for Cohort B and 0.79 for Cohort C.
  
  
  CONCLUSIONS
  A panel of five biomarkers shows promise in distinguishing AECOPD from convalescence and may provide the basis for a clinical blood test to diagnose AECOPD. Further validation in larger cohorts is necessary for future clinical translation.
authors.affiliation: Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada.|Division of Respiratory Medicine, Department of Medicine, St. Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Janice M
authors.initials: JM
authors.lastname: Leung
authors.affiliation: PROOF Center of Excellence, St. Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Virginia
authors.initials: V
authors.lastname: Chen
authors.affiliation: PROOF Center of Excellence, St. Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Hollander
authors.affiliation: PROOF Center of Excellence, St. Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Darlene
authors.initials: D
authors.lastname: Dai
authors.affiliation: Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada.|Division of Respiratory Medicine, Department of Medicine, St. Paul's Hospital, Vancouver, British Columbia, Canada.|PROOF Center of Excellence, St. Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Tebbutt
authors.affiliation: Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Aaron
authors.affiliation: Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Vandemheen
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.|AstraZeneca, Cambridge, United Kingdom.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Rennard
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, Vancouver General Hospital and the Institute for Heart and Lung Health, Vancouver, British Columbia, Canada.
authors.forename: J Mark
authors.initials: JM
authors.lastname: FitzGerald
authors.affiliation: Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine and Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Prescott G
authors.initials: PG
authors.lastname: Woodruff
authors.affiliation: Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine and Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Lazarus
authors.affiliation: University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: John E
authors.initials: JE
authors.lastname: Connett
authors.affiliation: Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Harvey O
authors.initials: HO
authors.lastname: Coxson
authors.affiliation: GlaxoSmithKline Research and Development, King of Prussia, Pennsylvania, United States of America.
authors.forename: Bruce
authors.initials: B
authors.lastname: Miller
authors.affiliation: University of Victoria-Genome British Columbia Proteomics Centre, Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: Christoph
authors.initials: C
authors.lastname: Borchers
authors.affiliation: Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada.|PROOF Center of Excellence, St. Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: McManus
authors.affiliation: PROOF Center of Excellence, St. Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Ng
authors.affiliation: Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada.|Division of Respiratory Medicine, Department of Medicine, St. Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Don D
authors.initials: DD
authors.lastname: Sin
mesh_terms: D000208:Acute Disease; D000368:Aged; D015415:Biomarkers / Q000097:blood*; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood*
chemical_list: D015415:Biomarkers