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Discovery of novel plasma protein biomarkers to predict imminent cystic fibrosis pulmonary exacerbations using multiple reaction monitoring mass spectrometry
  1. Bradley S Quon1,2,
  2. Darlene L Y Dai3,
  3. Zsuzsanna Hollander3,
  4. Raymond T Ng3,4,
  5. Scott J Tebbutt1,2,3,
  6. S F Paul Man1,2,
  7. Pearce G Wilcox1,2,
  8. Don D Sin1,2
  1. 1Centre for Heart Lung Innovation, University of British Columbia and St. Paul's Hospital, Vancouver, British Columbia, Canada
  2. 2Division of Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
  3. 3PRevention Of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada
  4. 4Department of Computer Science, University of British Columbia, Vancouver, British Columbia, Canada
  1. Correspondence to Dr Bradley S Quon, Division of Respiratory Medicine, Department of Medicine, University of British Columbia, 1081 Burrard Street, 8B Providence Wing, Vancouver, British Columbia, Canada V6Z 1Y6; bradley.quon{at}hli.ubc.ca

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.

  • Cystic Fibrosis

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