Relationship of admission blood proteomic biomarkers levels to lesion type and lesion burden in traumatic brain injury: A CENTER-TBI study
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. Menon,
Virginia F.J. Newcombe
Affiliations
Daniel P. Whitehouse
University Division of Anaesthesia, Department of Medicine, University of Cambridge, UK
Miguel Monteiro
Biomedical Image Analysis Group, Department of Computing, Imperial College, London, UK
Endre Czeiter
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; Pécs, Hungary
Thijs Vande Vyvere
Research and Development, Icometrix, Leuven, Belgium; Department of Radiology, Antwerp University Hospital and University of Antwerp, Wilrijkstraat 10, 2650, Edegem, Belgium
Fernanda Valerio
University Division of Anaesthesia, Department of Medicine, University of Cambridge, UK
Zheng Ye
University Division of Anaesthesia, Department of Medicine, University of Cambridge, UK
Krisztina Amrein
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
Konstantinos Kamnitsas
Biomedical Image Analysis Group, Department of Computing, Imperial College, London, UK
Haiyan Xu
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
Zhihui Yang
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
Jan Verheyden
Research and Development, Icometrix, Leuven, Belgium
Tilak Das
Department of Radiology, Addenbrooke's Hospital, Cambridge, UK
Evgenios N. Kornaropoulos
University Division of Anaesthesia, Department of Medicine, University of Cambridge, UK
Ewout Steyerberg
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
Andrew I.R. Maas
Department of Neurosurgery, Antwerp University Hospital and University of Antwerp, Wijlrijkstraat 10, 2650 Edegem, Belgium
Kevin K.W. Wang
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
András Büki
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
Ben Glocker
Biomedical Image Analysis Group, Department of Computing, Imperial College, London, UK
David K. Menon
University Division of Anaesthesia, Department of Medicine, University of Cambridge, UK
Virginia F.J. Newcombe
University Division of Anaesthesia, Department of Medicine, University of Cambridge, UK; Corresponding author.
Summary: 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).
