Blood-Based Protein Biomarkers for the Management of Traumatic Brain Injuries in Adults Presenting to Emergency Departments with Mild Brain Injury: A Living Systematic Review and Meta-Analysis

Abstract

Accurate diagnosis of traumatic brain injury (TBI) is critical to effective management and intervention, but can be challenging in patients with mild TBI. A substantial number of studies have reported the use of circulating biomarkers as signatures for TBI, capable of improving diagnostic accuracy and clinical decision making beyond current practice standards. We performed a systematic review and meta-analysis to comprehensively and critically evaluate the existing body of evidence for the use of blood protein biomarkers (S100 calcium binding protein B [S100B], glial fibrillary acidic protein [GFAP], neuron specific enolase [NSE], ubiquitin C-terminal hydrolase-L1 [UCH-L1]. tau, and neurofilament proteins) for diagnosis of intracranial lesions on CT following mild TBI. Effects of potential confounding factors and differential diagnostic performance of the included markers were explored. Further, appropriateness of study design, analysis, quality, and demonstration of clinical utility were assessed. Studies published up to October 2016 were identified through searches of MEDLINE^®, Embase, EBM Reviews, the Cochrane Library, World Health Organization (WHO), International Clinical Trials Registry Platform (ICTRP), and clinicaltrials.gov. Following screening of the identified articles, 26 were selected as relevant. We found that measurement of S100B can help informed decision making in the emergency department, possibly reducing resource use; however, there is insufficient evidence that any of the other markers is ready for clinical application. Our work pointed out serious problems in the design, analysis, and reporting of many of the studies, and identified substantial heterogeneity and research gaps. These findings emphasize the importance of methodologically rigorous studies focused on a biomarker's intended use, and defining standardized, validated, and reproducible approaches. The living nature of this systematic review, which will summarize key updated information as it becomes available, can inform and guide future implementation of biomarkers in the clinical arena.

Keywords: TBI; biomarkers; diagnosis; living systematic review; meta-analysis.

FIG. 1.

Study flow diagram.

FIG. 2.

(A) Risk of bias and applicability concerns graph. Review authors' judgments about each domain presented as percentages across included studies. (B) Risk of bias and applicability concerns summary. Review authors' judgments about each domain for each included study.

FIG. 3.

Forest plot showing individual sensitivity and specificity of circulating S100 calcium binding protein B (S100B), glial fibrillary acidic protein (GFAP), neuron specific enolase (NSE), and ubiquitin C-terminal hydrolase-L1 (UCH-L1) for detection of intracranial lesions on CT. Horizontal lines represent 95% confidence intervals. TP, true positive; FP, false positive; FN, false negative; TN, true negative.

FIG. 4.

(A, B) Summary receiver operating characteristic (ROC) plots for S100 calcium binding protein B (S100B) and glial fibrillary acidic protein (GFAP) for detection of CT abnormalities. (C, D) Study estimates of sensitivity and specificity with 95% confidence intervals plotted in ROC space for neuron specific enolase (NSE), and ubiquitin C-terminal hydrolase-L1 (UCH-L1) for detection of CT abnormalities. Each square represents an individual study; the size of the symbol is proportional to the number of patients in each study. The hierarchical summary ROC (HSROC) model was used to estimate a summary curve using Proc NLMIXED in SAS.

FIG. 5.

Summary receiver operating characteristics plot of sensitivity and specificity of S100 calcium binding protein B (S100B) at a 0.10–0.11μg/L cutoff value for detecting intracranial lesions on CT. Each circle represents an individual study; size of the symbol reflects the number of patients in the studies; red solid spot in the middle is summary sensitivity and specificity; inner ellipse represents 95% confidence region, and outer ellipse represents 95% prediction region.

FIG. 6.

Summary of evidence for the use of blood S100 calcium binding protein B (S100B) protein concentrations (0.10–0.11μg/L cutoff) to diagnose brain injury as assessed by CT scan in patients with mild traumatic brain injury (mTBI).