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Novel severe traumatic brain injury blood outcome biomarkers identified with proximity extension assay

  • Douglas D. Fraser EMAIL logo , Michelle Chen , Annie Ren , Michael R. Miller , Claudio Martin , Mark Daley , Eleftherios P. Diamandis ORCID logo and Ioannis Prassas EMAIL logo
Published/Copyright: June 21, 2021
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Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 59 Issue 10

Abstract

Objectives

Severe traumatic brain injury (sTBI) patients suffer high mortality. Accurate prognostic biomarkers have not been identified. In this exploratory study, we performed targeted proteomics on plasma obtained from sTBI patients to identify potential outcome biomarkers.

Methods

Blood sample was collected from patients admitted to the ICU suffering a sTBI, using standardized clinical and computerized tomography (CT) imaging criteria. Age- and sex-matched healthy control subjects and sTBI patients were enrolled. Targeted proteomics was performed on plasma with proximity extension assays (1,161 proteins).

Results

Cohorts were well-balanced for age and sex. The majority of sTBI patients were injured in motor vehicle collisions and the most frequent head CT finding was subarachnoid hemorrhage. Mortality rate for sTBI patients was 40%. Feature selection identified the top performing 15 proteins for identifying sTBI patients from healthy control subjects with a classification accuracy of 100%. The sTBI proteome was dominated by markers of vascular pathology, immunity/inflammation, cell survival and macrophage/microglia activation. Receiver operating characteristic (ROC) curve analyses demonstrated areas-under-the-curves (AUC) for identifying sTBI that ranged from 0.870-1.000 (p≤0.005). When mortality was used as outcome, ROC curve analyses identified the top 3 proteins as Willebrand factor (vWF), Wnt inhibitory factor-1 (WIF-1), and colony stimulating factor-1 (CSF-1). Combining vWF with either WIF-1 or CSF-1 resulted in excellent mortality prediction with AUC of 1.000 for both combinations (p=0.011).

Conclusions

Targeted proteomics with feature classification and selection distinguished sTBI patients from matched healthy control subjects. Two protein combinations were identified that accurately predicted sTBI patient mortality. Our exploratory findings require confirmation in larger sTBI patient populations.

Keywords: biomarkers; intensive care unit; outcome; proteomics; traumatic brain injury
Corresponding authors: Dr. Douglas D. Fraser, London Health Sciences Centre, Lawson Health Research Institute, Room C2-C82, 800 Commissioners Road East , London, ON N6A 5W9, Canada; Pediatrics, Western University, London, ON, Canada; Clinical Neurological Sciences, Western University, London, ON, Canada; Physiology and Pharmacology, Western University, London, ON, Canada; and NeuroLytixs Inc., Toronto, ON, Canada, Phone: +519 685 2767, Fax: +519 685 8166, E-mail: ; and Dr. Ioannis Prassas, Pathology and Laboratory Medicine, Mount Sinai Hospital, Joseph and Wolf Lebovic Centre, 60 Murray St [Box 32]; Floor 6, Room L6-201, Toronto, ON M5T 3L9, Canada; and Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada, Phone: +416 586 8443, Fax: +416 619 5521, E-mail:
Douglas D. Fraser and Michelle Chen contributed equally to this work.

Funding source: Children’s Health Foundation

Acknowledgments

We thank Dr. Carolina Gillio-Meina for biological sample collection and processing (Translational Research Centre, London, Ontario, Canada; https://translationalresearchcentre.com) and the frontline Critical Care Nursing Staff at London Health Sciences Centre (London, Ontario, Canada).

  1. Research funding: This research is funded by Children’s Health Foundation.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Informed consent was obtained from all individuals included in this study.

  5. Ethical approval: The study was approved by the Western University, Human Research Ethics Board (HREB; REB# 6970; REB# 100036).

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Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/cclm-2021-0103).

Received: 2021-01-22
Accepted: 2021-04-28
Published Online: 2021-06-21
Published in Print: 2021-09-27

© 2021 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/cclm-2021-0103
Keywords for this article
biomarkers; intensive care unit; outcome; proteomics; traumatic brain injury

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Ageing, ACE2 deficiency and bad outcome in COVID-19
  4. Review
  5. Harmonization status of procalcitonin measurements: what do comparison studies and EQA schemes tell us?
  6. Opinion Papers
  7. Role of ACE2 polymorphism in COVID-19: impact of age
  8. The importance of correct stratifications when comparing directly and indirectly estimated reference intervals
  9. General Clinical Chemistry and Laboratory Medicine
  10. The clinical laboratory: a decision maker hub
  11. Simultaneous measurement of 13 circulating vitamin D3 and D2 mono and dihydroxy metabolites using liquid chromatography mass spectrometry
  12. Cerebrospinal fluid hemoglobin levels as markers of blood contamination: relevance for α-synuclein measurement
  13. Novel severe traumatic brain injury blood outcome biomarkers identified with proximity extension assay
  14. Hemoglobin Yamagata [β132(H10)Lys→Asn; (HBB: c.399A>T)]: a mosaic to be put together
  15. Reference Values and Biological Variations
  16. Pediatric reference interval verification for endocrine and fertility hormone assays on the Abbott Alinity system
  17. Hematology and Coagulation
  18. Neonatal lymphocyte subpopulations analysis and maternal preterm premature rupture of membranes: a pilot study
  19. Pro-coagulant imbalance in patients with community acquired pneumonia assessed on admission and one month after hospital discharge
  20. A multi-laboratory assessment of congenital thrombophilia assays performed on the ACL TOP 50 family for harmonisation of thrombophilia testing in a large laboratory network
  21. Cardiovascular Diseases
  22. Exercise-induced changes in miRNA expression in coronary artery disease
  23. Diabetes
  24. Recommendations for proficiency testing criteria for hemoglobin A1c based on the Shanghai Center for Clinical Laboratory’s study
  25. Infectious Diseases
  26. The versatility of external quality assessment for the surveillance of laboratory and in vitro diagnostic performance: SARS-CoV-2 viral genome detection in Austria
  27. Letters to the Editor
  28. Monitoring of the immunogenic response to Pfizer BNT162b2 mRNA COVID-19 vaccination in healthcare workers with Snibe SARS-CoV-2 S-RBD IgG chemiluminescent immunoassay
  29. SARS-CoV-2 antibody assay after vaccination: one size does not fit all
  30. Analysis of leptin-adiponectin ratio and C-reactive protein as potential biomarkers of metabolic syndrome in adolescents
  31. Hb Johnstown is detected on Mindray BC 6800 Plus analyzer
  32. Long-term stability of 25-hydroxyvitamin D: importance of the analytical method and of the patient matrix
  33. Development of chronic myeloid leukemia in a patient previously diagnosed with a JAK2-positive myeloproliferative neoplasm
  34. Acquired Pelger-Huet anomaly in two patients with chronic lymphocytic leukemia treated with venetoclax
  35. Novel variant of MYH9 associated with mild evaluation of MYH9 related disorder in a Chinese family
  36. The successful inclusion of ADA SCID in Tuscany expanded newborn screening program
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