Correlation of Blood Biomarkers and Biomarker Panels with Traumatic Findings on Computed Tomography after Traumatic Brain Injury

Abstract

The aim of the study was to examine the ability of eight protein biomarkers and their combinations in discriminating computed tomography (CT)-negative and CT-positive patients with traumatic brain injury (TBI), utilizing highly sensitive immunoassays in a well-characterized cohort. Blood samples were obtained from 160 patients with acute TBI within 24 h of admission. Levels of β-amyloid isoforms 1-40 (Aβ40) and 1-42 (Aβ42), glial fibrillary acidic protein (GFAP), heart fatty-acid binding protein (H-FABP), interleukin 10 (IL-10), neurofilament light (NF-L), S100 calcium-binding protein B (S100B), and tau were measured. Patients were divided into CT-negative (n = 65) and CT-positive (n = 95), and analyses were conducted separately for TBIs of all severities (Glasgow Coma Scale [GCS] score 3-15) and mild TBIs (mTBIs; GCS 13-15). NF-L, GFAP, and tau were the best in discriminating CT-negative and CT-positive patients, both in patients with mTBI and with all severities. In patients with all severities, area under the curve of the receiver operating characteristic (AUC) was 0.822, 0.817, and 0.781 for GFAP, NF-L, and tau, respectively. In patients with mTBI, AUC was 0.720, 0.689, and 0.676, for GFAP, tau, and NF-L, respectively. The best panel of three biomarkers for discriminating CT-negative and CT-positive patients in the group of all severities was a combination of GFAP+H-FABP+IL-10, with a sensitivity of 100% and specificity of 38.5%. In patients with mTBI, the best panel of three biomarkers was H-FABP+S100B+tau, with a sensitivity of 100% and specificity of 46.4%. Panels of biomarkers outperform individual biomarkers in separating CT-negative and CT-positive patients. Panels consisted mainly of different biomarkers than those that performed best as an individual biomarker.

Keywords: biomarkers; computed tomography; traumatic brain injury.

Conflict of interest statement

Jussi P. Posti has no competing financial interests. JPP has received speaker's fees from Orion corporation and Finnish Medical Association.

Riikka S.K. Takala has no competing financial interests. RSKT has received speakers' fees from Abbott, Fresenius-Kabi, Orion corporation and UCB, conference funding from Pfizer and Steripolar and is stockholder of Orion.

Janek Frantzén is a Member of Board at Bonalive Ltd., JF has received travel support from Abbot, Teva, and Medtronic. He has received speaker's fees from Teva, Medtronic and Bonalive Ltd.

David K. Menon reports collaborative research or consultancy agreements with GlaxoSmithKline Ltd; Ornim Medical; Shire Medical; Calico Inc; Pfizer Ltd; Pressura Ltd; Glide Pharma Ltd; NeuroTraumaSciences LLC; Lantasman AB.

Kevin Hrusovsky is an employee and stockholder at Quanterix Corp.

David H. Wilson is an employee and stockholder at Quanterix Corp.

Henrik Zetterberg has served at advisory boards for Roche Diagnostics, Wave, Samumed and CogRx, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg.

Kaj Blennow has served as a consultant or at advisory boards for Alzheon, BioArctic, Biogen, Eli Lilly, Fujirebio Europe, IBL International, Merck, Novartis, Pfizer, and Roche Diagnostics, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg.

For the other authors, no competing financial interests exist.

Figures

FIG. 1.

Ability of the individual biomarkers in discriminating computed tomography (CT)-negative and CT-positive patients with traumatic brain injuries of all severities. Within each receiver operating characteristics curve, the uppermost value in parentheses are specificity at 100% sensitivity, the centermost values are specificity at sensitivity set the range of 90–100%, and the undermost values are specificity and sensitivity from Youden's index; a value before parentheses is a cut-off value of a protein at a particular specificity/sensitivity; all cut off values are presented in pg/mL except H-FABF in ng/mL; AUC, area under receiver operating characteristic curve; Aβ40, β-Amyloid isoform 1–40; Aβ42 β-Amyloid isoform 1–42; GFAP, glial fibrillary acidic protein; H-FABP, heart fatty-acid binding protein; IL-10, interleukin 10; NF-L neurofilament light; S100B, S100 calcium-binding protein B.

FIG. 2.

Ability of the individual biomarkers in discriminating computed tomography (CT)-negative and CT-positive patients with mild traumatic brain injury. Within each receiver operating characteristics curve, the uppermost value in parentheses are specificity at 100% sensitivity, the centermost values are specificity at sensitivity set the range of 90–100%, and the undermost values are specificity and sensitivity from Youden's index (exception: Aβ40 same dot for 100% and 90–100%); a value before parentheses is a cut-off value of a protein at a particular specificity/sensitivity; all cut off values are presented in pg/mL except H-FABF in ng/mL; AUC, area under receiver operating characteristic curve; Aβ40, β-Amyloid isoform 1–40; Aβ42 β-Amyloid isoform 1–42; GFAP, glial fibrillary acidic protein; H-FABP, heart fatty-acid binding protein; IL-10, interleukin 10; NF-L neurofilament light; S100B, S100 calcium-binding protein B.

FIG. 3.

Ability of the individual biomarkers in discriminating computed tomography (CT)-negative and CT-positive patients with isolated traumatic brain injuries of all severities. Within each receiver operating characteristics curve, the uppermost value in parentheses are specificity at 100% sensitivity, the centermost values are specificity at sensitivity set the range of 90–100%, and the undermost values are specificity and sensitivity from Youden's index (exceptions: same dot for S100B 100% and 90–100%, Aβ42 100% and 90–100%, Aβ40 100% and 90–100%); a value before parentheses is a cut-off value of a protein at a particular specificity/sensitivity; all cut off values are presented in pg/mL except H-FABF in ng/mL; AUC, area under receiver operating characteristic curve; Aβ40, β-Amyloid isoform 1–40; Aβ42 β-Amyloid isoform 1–42; GFAP, glial fibrillary acidic protein; H-FABP, heart fatty-acid binding protein; IL-10, interleukin 10; NF-L neurofilament light; S100B, S100 calcium-binding protein B.

FIG. 4.

Ability of the individual biomarkers in discriminating computed tomography (CT)-negative and CT-positive patients with isolated mild TBI. Within each receiver operating characteristics curve, the uppermost value in parentheses are specificity at 100% sensitivity, the centermost values are specificity at sensitivity set the range of 90–100%, and the undermost values are specificity and sensitivity from Youden's index (exceptions: same dot for S100B 90–100% as Youden's Index, Aβ40 100% and 90–100%, GFAP 90–100% as Youden's Index); a value before parentheses is a cut-off value of a protein at a particular specificity/sensitivity; all cut off values are presented in pg/mL except H-FABF in ng/mL; AUC, area under receiver operating characteristic curve; Aβ40, β-Amyloid isoform 1–40; Aβ42 β-Amyloid isoform 1–42; GFAP, glial fibrillary acidic protein; H-FABP, heart fatty-acid binding protein; IL-10, interleukin 10; NF-L neurofilament light; S100B, S100 calcium-binding protein B.