COPD exacerbation biomarkers validated using multiple reaction monitoring mass spectrometry

Janice M. Leung, Virginia Chen, Zsuzsanna Hollander, Darlene Dai, Scott J. Tebbutt, Shawn D. Aaron, Kathy L. Vandemheen, Stephen I. Rennard, J. Mark FitzGerald, Prescott G. Woodruff, Stephen C. Lazarus, John E. Connett, Harvey O. Coxson, Bruce Miller, Christoph Borchers, Bruce M. McManus, Raymond T. Ng, Don D. Sin

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish (US)
Article numbere0161129
JournalPloS one
Volume11
Issue number8
DOIs
StatePublished - Aug 2016

Bibliographical note

Funding Information:
Funding was provided by Genome Canada, Genome British Columbia, Genome Quebec, the Canadian Institutes of Health Research, PROOF Centre of Excellence, St. Paul's Hospital Foundation, the Canadian Respiratory Research Network, and the National Heart, Lung, and Blood Institute's COPD Clinical Research Network (Grants U10 HL074441, U10 HL074418, U10 HL074428, U10 HL074409, U10 HL074407, U10 HL074422, U10 HL074416, U10 HL074408, U10 HL074439, U10 HL0744231, and U10 HL074424). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. GlaxoSmithKline provided support in the form of salaries for author BM, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section.

Publisher Copyright:
© 2016 Leung et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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