Blood biomarkers on admission in acute traumatic brain injury: Relations to severity, CT findings and care path in the CENTER-TBI study

Endre Czeiter; Krisztina Amrein; Benjamin Y Gravesteijn; Fiona Lecky; David K Menon; Stefania Mondello; Virginia F J Newcombe; Sophie Richter; Ewout W Steyerberg; Thijs Vande Vyvere; Jan Verheyden; Haiyan Xu; Zhihui Yang; Andrew I R Maas; Kevin K W Wang; András Büki; CENTER-TBI Participants and Investigators

doi:10.1016/j.ebiom.2020.102785

Blood biomarkers on admission in acute traumatic brain injury: Relations to severity, CT findings and care path in the CENTER-TBI study

EBioMedicine. 2020 Jun:56:102785. doi: 10.1016/j.ebiom.2020.102785. Epub 2020 May 25.

Authors

Endre Czeiter¹, Krisztina Amrein², Benjamin Y Gravesteijn³, Fiona Lecky⁴, David K Menon⁵, Stefania Mondello⁶, Virginia F J Newcombe⁵, Sophie Richter⁵, Ewout W Steyerberg⁷, Thijs Vande Vyvere⁸, Jan Verheyden⁹, Haiyan Xu¹⁰, Zhihui Yang¹⁰, Andrew I R Maas¹¹, Kevin K W Wang¹², András Büki²; CENTER-TBI Participants and Investigators

Affiliations

¹ Department of Neurosurgery, Medical School, University of Pécs, Rét u. 2, H-7623 Pécs, Hungary; Neurotrauma Research Group, Szentágothai Research Centre, University of Pécs, Ifjúság útja 20, H-7624 Pécs, Hungary; MTA-PTE Clinical Neuroscience MR Research Group, Rét u. 2, H-7623 Pécs, Hungary. Electronic address: endre.czeiter@gmail.com.
² Department of Neurosurgery, Medical School, University of Pécs, Rét u. 2, H-7623 Pécs, Hungary; Neurotrauma Research Group, Szentágothai Research Centre, University of Pécs, Ifjúság útja 20, H-7624 Pécs, Hungary.
³ Center for Medical Decision Making, Department of Public Health, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, Netherlands.
⁴ Centre for Urgent and emergency care REsearch (CURE), Health Services Research Section, School of Health and Related Research (ScHARR), University of Sheffield, S1 4DA, UK; Emergency Department, Salford Royal Hospital, Stott Ln, Salford M6 8HD, UK.
⁵ Division of Anaesthesia, University of Cambridge, Box 93, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
⁶ Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Via Consolare Valeria n. 1, 98125 Messina, Italy.
⁷ Center for Medical Decision Making, Department of Public Health, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, Netherlands; Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, Netherlands.
⁸ Research and Development, Icometrix, Kolonel Begaultlaan 1b/12, 3012 Leuven, Belgium; Department of Radiology, Antwerp University Hospital and University of Antwerp, Wijlrijkstraat 10, 2650 Edegem, Belgium.
⁹ Research and Development, Icometrix, Kolonel Begaultlaan 1b/12, 3012 Leuven, Belgium.
¹⁰ Program for Neurotrauma, Neuroproteomics and Biomarker Research, Departments of Emergency Medicine, Psychiatry and Neuroscience, University of Florida, McKnight Brain Institute, L4-100L 1149 South Newell Drive, Gainesville, FL 32611, USA.
¹¹ Department of Neurosurgery, Antwerp University Hospital and University of Antwerp, Wijlrijkstraat 10, 2650 Edegem, Belgium.
¹² Program for Neurotrauma, Neuroproteomics and Biomarker Research, Departments of Emergency Medicine, Psychiatry and Neuroscience, University of Florida, McKnight Brain Institute, L4-100L 1149 South Newell Drive, Gainesville, FL 32611, USA; Brain Rehabilitation Research Center, Malcom Randall Veterans Affairs Medical Center (VAMC), 1601 SW Archer Rd. Gainesville, FL 32608, USA.

Abstract

Background: Serum biomarkers may inform and improve care in traumatic brain injury (TBI). We aimed to correlate serum biomarkers with clinical severity, care path and imaging abnormalities in TBI, and explore their incremental value over clinical characteristics in predicting computed tomographic (CT) abnormalities.

Methods: We analyzed six serum biomarkers (S100B, NSE, GFAP, UCH-L1, NFL and t-tau) obtained <24 h post-injury from 2867 patients with any severity of TBI in the Collaborative European NeuroTrauma Effectiveness Research (CENTER-TBI) Core Study, a prospective, multicenter, cohort study. Univariable and multivariable logistic regression analyses were performed. Discrimination was assessed by the area under the receiver operating characteristic curve (AUC) with 95% confidence intervals.

Findings: All biomarkers scaled with clinical severity and care path (ER only, ward admission, or ICU), and with presence of CT abnormalities. GFAP achieved the highest discrimination for predicting CT abnormalities (AUC 0•89 [95%CI: 0•87-0•90]), with a 99% likelihood of better discriminating CT-positive patients than clinical characteristics used in contemporary decision rules. In patients with mild TBI, GFAP also showed incremental diagnostic value: discrimination increased from 0•84 [95%CI: 0•83-0•86] to 0•89 [95%CI: 0•87-0•90] when GFAP was included. Results were consistent across strata, and injury severity. Combinations of biomarkers did not improve discrimination compared to GFAP alone.

Interpretation: Currently available biomarkers reflect injury severity, and serum GFAP, measured within 24 h after injury, outperforms clinical characteristics in predicting CT abnormalities. Our results support the further development of serum GFAP assays towards implementation in clinical practice, for which robust clinical assay platforms are required.

Funding: CENTER-TBI study was supported by the European Union 7th Framework program (EC grant 602150).

Keywords: Biomarkers; Clinical decision rule; Computerized tomography; Diagnostic; GFAP; Injury severity; Serum; Traumatic brain injury.

Publication types

Clinical Trial
Multicenter Study

MeSH terms

Aged
Aged, 80 and over
Area Under Curve
Biomarkers / blood*
Brain Injuries, Traumatic / blood
Brain Injuries, Traumatic / diagnostic imaging*
Female
Glial Fibrillary Acidic Protein / blood*
Humans
Male
Neurofilament Proteins / blood
Patient Admission
Patient Care Planning
Prospective Studies
ROC Curve
S100 Calcium Binding Protein beta Subunit / blood
Severity of Illness Index
Tomography, X-Ray Computed / methods*
Ubiquitin Thiolesterase / blood
tau Proteins / blood

Substances

Biomarkers
GFAP protein, human
Glial Fibrillary Acidic Protein
MAPT protein, human
Neurofilament Proteins
S100 Calcium Binding Protein beta Subunit
S100B protein, human
UCHL1 protein, human
neurofilament protein L
tau Proteins
Ubiquitin Thiolesterase