Relationship of admission blood proteomic biomarkers levels to lesion type and lesion burden in traumatic brain injury: A CENTER-TBI study

CENTER TBI Participants and Investigators, Daniel P. Whitehouse, Miguel Monteiro, Endre Czeiter, Thijs Vande Vyvere, Fernanda Valerio, Zheng Ye, Krisztina Amrein, Konstantinos Kamnitsas, Haiyan Xu, Zhihui Yang, Jan Verheyden, Tilak Das, Evgenios N. Kornaropoulos, Ewout Steyerberg, Andrew I.R. Maas, Kevin K.W. Wang, András Büki, Ben Glocker, David K. MenonVirginia F.J. Newcombe*

*Corresponding author for this work

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Abstract

Background: We aimed to understand the relationship between serum biomarker concentration and lesion type and volume found on computed tomography (CT) following all severities of TBI. Methods: Concentrations of six serum biomarkers (GFAP, NFL, NSE, S100B, t-tau and UCH-L1) were measured in samples obtained <24 hours post-injury from 2869 patients with all severities of TBI, enrolled in the CENTER-TBI prospective cohort study (NCT02210221). Imaging phenotypes were defined as intraparenchymal haemorrhage (IPH), oedema, subdural haematoma (SDH), extradural haematoma (EDH), traumatic subarachnoid haemorrhage (tSAH), diffuse axonal injury (DAI), and intraventricular haemorrhage (IVH). Multivariable polynomial regression was performed to examine the association between biomarker levels and both distinct lesion types and lesion volumes. Hierarchical clustering was used to explore imaging phenotypes; and principal component analysis and k-means clustering of acute biomarker concentrations to explore patterns of biomarker clustering. Findings: 2869 patient were included, 68% (n=1946) male with a median age of 49 years (range 2-96). All severities of TBI (mild, moderate and severe) were included for analysis with majority (n=1946, 68%) having a mild injury (GCS 13-15). Patients with severe diffuse injury (Marshall III/IV) showed significantly higher levels of all measured biomarkers, with the exception of NFL, than patients with focal mass lesions (Marshall grades V/VI). Patients with either DAI+IVH or SDH+IPH+tSAH, had significantly higher biomarker concentrations than patients with EDH. Higher biomarker concentrations were associated with greater volume of IPH (GFAP, S100B, t-tau;adj r2 range:0·48-0·49; p<0·05), oedema (GFAP, NFL, NSE, t-tau, UCH-L1;adj r2 range:0·44-0·44; p<0·01), IVH (S100B;adj r2 range:0.48-0.49; p<0.05), Unsupervised k-means biomarker clustering revealed two clusters explaining 83·9% of variance, with phenotyping characteristics related to clinical injury severity. Interpretation: Interpretation: Biomarker concentration within 24 hours of TBI is primarily related to severity of injury and intracranial disease burden, rather than pathoanatomical type of injury. Funding: CENTER-TBI is funded by the European Union 7th Framework programme (EC grant 602150).

Original languageEnglish
Article number103777
JournalEBioMedicine
Volume75
Early online date24 Dec 2021
DOIs
Publication statusPublished - 1 Jan 2022

Bibliographical note

Funding Information:
The CENTER-TBI study was supported by the European Union 7th Framework Programme (EC grant 602150), with additional project support from OneMind, Hannelore Kohl Foundation, NeuroTrauma Sciences and Integra Neurosciences. Development of the BLAST-CT algorithm was supported by the European Research Council Horizon 2020 (EC grant 757173). Individual sources of funding were the Engineering and Physical Sciences Research Council (EP/R511547/1, to BG, KK), the National Institute for Health Research UK (DKM), and the Academy of Medical Sciences/The Health Foundation (VFJN).

Funding Information:
DKM reports: grants from the European Union (EU), the National Institute for Health Research UK supporting the submitted work; grants from GlaxoSmithKline Ltd and Lantmannen AB, consulting fees from Calico LLC, GlaxoSmithKline Ltd, Lantmannen AB and NeuroTrauma Sciences LLC, and personal fees from Integra Neurosciences outside the submitted work. BG has received grants from European Commission and UK Research and Innovation Engineering and Physical Sciences Research Council, during the conduct of this study; and is Scientific Advisor for Kheiron Medical Technologies, Advisor and Scientific Lead of the HeartFlow-Imperial Research Team, outside the submitted work. MM reports a ERC grant agreement and consultancy fees from Triradiate Industries, outside the submitted work. ES reports a FP7 grant from the EU supporting the submitted work, and royalties for the book “Clinical Prediction Models” published by Springer. AIRM reports a FP7 grant from the EU supporting the submitted work, and grants from NeuroTrauma Sciences, Hannelore Kohl Foundation, and IntegraLife Sciences, personal fees from PresSura Neuro as DSMB chairman outside of the submitted work. KKWW reports a FP7 grant from the EU supporting the submitted work, and as a shareholder of Gryphon Bio, Inc. VFJN reports an Academy of Medical Sciences/The Health Foundation Clinician Scientist Fellowship, during the conduct of this study; a grant from Roche Pharmaceuticals, and honorarium for talks from Neurodiem, outside the submitted work. All other authors declare no competing interests.

Publisher Copyright:
© 2021

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