title: Discovery of novel plasma protein biomarkers to predict imminent cystic fibrosis pulmonary exacerbations using multiple reaction monitoring mass spectrometry.
abstract: BACKGROUND
  Despite the significant morbidity and mortality related to pulmonary exacerbations in cystic fibrosis (CF), there remains no reliable predictor of imminent exacerbation.
  
  
  OBJECTIVE
  To identify blood-based biomarkers to predict imminent (<4 months from stable blood draw) CF pulmonary exacerbations using targeted proteomics.
  
  
  METHODS
  104 subjects provided plasma samples when clinically stable and were randomly split into discovery (n=70) and replication (n=34) cohorts. Multiple reaction monitoring mass spectrometry (MRM-MS) was used to measure 117 peptides (79 proteins) from plasma. Plasma proteins with differential abundance between subjects who did versus did not develop an imminent exacerbation were analysed and proteins with fold difference >1.5 between the groups were included in an MRM-MS classifier model to predict imminent exacerbations. Performance characteristics were compared with clinical predictors and candidate plasma protein biomarkers.
  
  
  RESULTS
  Six proteins were included in the final MRM-MS protein panel. The area under the curve (AUC) for the prediction of imminent exacerbations was highest for the MRM-MS protein panel (AUC 0.74) in comparison to FEV1% predicted (AUC 0.55) and the top candidate plasma protein biomarkers, including C-reactive protein (AUC 0.61) and interleukin-6 (AUC 0.60). The MRM-MS protein panel performed similarly in the replication cohort (AUC 0.73).
  
  
  CONCLUSIONS
  Using MRM-MS, a six-protein panel measured from plasma can distinguish individuals with versus without an imminent exacerbation. With further replication and assay development, this biomarker panel may be clinically applicable for prediction of exacerbations in individuals with CF.
authors.affiliation: Centre for Heart Lung Innovation, University of British Columbia and St. Paul's Hospital, Vancouver, British Columbia, Canada Division of Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Quon
authors.affiliation: PRevention Of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada.
authors.forename: Darlene L Y
authors.initials: DL
authors.lastname: Dai
authors.affiliation: PRevention Of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Hollander
authors.affiliation: PRevention Of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada Department of Computer Science, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Ng
authors.affiliation: Centre for Heart Lung Innovation, University of British Columbia and St. Paul's Hospital, Vancouver, British Columbia, Canada Division of Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada PRevention Of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Tebbutt
authors.affiliation: Centre for Heart Lung Innovation, University of British Columbia and St. Paul's Hospital, Vancouver, British Columbia, Canada Division of Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: S F Paul
authors.initials: SF
authors.lastname: Man
authors.affiliation: Centre for Heart Lung Innovation, University of British Columbia and St. Paul's Hospital, Vancouver, British Columbia, Canada Division of Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Pearce G
authors.initials: PG
authors.lastname: Wilcox
authors.affiliation: Centre for Heart Lung Innovation, University of British Columbia and St. Paul's Hospital, Vancouver, British Columbia, Canada Division of Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Don D
authors.initials: DD
authors.lastname: Sin
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood*; D001798:Blood Proteins / Q000032:analysis*; D003550:Cystic Fibrosis / Q000097:blood*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D013058:Mass Spectrometry / Q000379:methods*; D008991:Monitoring, Physiologic / Q000379:methods*; D040901:Proteomics / Q000379:methods*; D012189:Retrospective Studies; D013997:Time Factors
chemical_list: D015415:Biomarkers; D001798:Blood Proteins
keywords: Cystic Fibrosis