Comparing blood biomarkers to clinical decision rules to select patients suspected of traumatic brain injury for head computed tomography.

INTRODUCTION: Traumatic brain injury (TBI) is a major public health concern in the U.S. Recommendations for patients admitted in the emergency department (ED) to receive head computed tomography (CT) scan are currently guided by various clinical decision rules. OBJECTIVE: To compare how a blood biomarker approach compares with clinical decision rules in terms of predicting a positive head CT in adult patients suspected of TBI. METHODS: We retrospectively identified patients transported to our emergency department and underwent a noncontrast head CT due to suspicion of TBI and who had blood samples available. Published thresholds for serum and plasma glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1), and serum S100ß were used to make CT recommendations. These blood biomarker-based recommendations were compared to those achieved under widely used clinical head CT decision rules (Canadian, New Orleans, NEXUS II, and ACEP Clinical Policy). RESULTS: Our study included 463 patients, of which 122 (26.3%) had one or more abnormalities presenting on head CT. Individual blood biomarkers achieved high negative predictive value (NPV) for abnormal head CT findings (88%-98%), although positive predictive value (PPV) was consistently low (25%-42%). A composite biomarker-based decision rule (GFAP+UCH-L1)'s NPV of 100% and PPV of 29% were comparable or better than those achieved under the clinical decision rules. CONCLUSION: Blood biomarkers perform at least as well as clinical rules in terms of selecting TBI patients for head CT and may be easier to implement in the clinical setting. A prospective study is necessary to validate this approach.

Association between Blood and Computed Tomographic Imaging Biomarkers in a Cohort of Mild Traumatic Brain Injury Patients.

The objective of this work was to analyze the relationships between traumatic brain injury (TBI) on computed tomographic (CT) imaging and blood concentration of glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), and S100B. This prospective cohort study involved 644 TBI patients referred to Stanford Hospital's Emergency Department between November 2015 and April 2017. Plasma and serum samples of 462 patients were analyzed for levels of GFAP, UCH-L1, and S100B. Glial neuronal ratio (GNR) was calculated as the ratio between GFAP and UCH-L1 concentrations. Admission head CT scans were reviewed for TBI imaging common data elements, and performance of biomarkers for identifying TBI was assessed via area under the receiver operating characteristic curve (ROC). We also dichotomized biomarkers at established thresholds and estimated standard measures of classification accuracy. We assessed the ability of GFAP, UCH-L1, and GNR to discriminate small and large/diffuse lesions based on CT imaging using an ROC analysis. In our cohort of mostly mild TBI patients, GFAP was significantly more accurate in detecting all types of acute brain injuries than UCH-L1 in terms of area under the curve (AUC) values (p < 0.001), and also compared with S100B (p < 0.001). UCH-L1 and S100B had similar performance (comparable AUC values, p = 0.342). Sensitivity exceeded 0.8 for each biomarker across all different types of TBI injuries, and no significant differences were observed by type of injury. There was a significant difference between GFAP and GNR in distinguishing between small lesions and large/diffuse lesions in all injuries (p = 0.004, p = 0.007). In conclusion, GFAP, UCH-L1, and S100B show high sensitivity and negative predictive values for all types of TBI lesions on head CT. A combination of negative blood biomarkers (GFAP and UCH-L1) in a patient suspected of TBI may be used to safely obviate the need for a head CT scan. GFAP is a promising indicator to discriminate between small and large/diffuse TBI lesions.

Biomarkers May Predict Unfavorable Neurological Outcome after Mild Traumatic Brain Injury.

The objective of this study was to determine if initial or repeat measurements of serum concentrations of glial fibrillary acidic protein (GFAP) or ubiquitin C-terminal hydrolase L1 (UCH-L1) are predictive of an acute unfavorable neurological outcome in patients who present to the emergency department (ED) with brain injury and an initial Glasgow Coma Scale Score (GCS) of 14-15. This multi-center observational trial included brain-injured adults presenting to the ED, receiving a head computed tomography (CT) and venipuncture for biomarker concentration measurements within 6 h of injury. Subjects had repeat serum sampling and GCS scores every 4 h for the first 24 h, if available for assessment. We analyzed blood samples using an enzyme-linked immunosorbent assay approved by the Food and Drug Administration (FDA). Wilcoxin two-sample test was used to compare initial and repeat serum concentrations for both biomarkers between CT-positive patients who did not have an acute unfavorable neurological outcome and those patients who did. A total of 145 enrolled subjects had adequate data for analysis; 69 were CT-positive, 74 were CT-negative, and 2 were CT-inconclusive. Five subjects developed an acute unfavorable neurological outcome, defined as need for intracranial pressure monitoring, craniotomy, persistent neurological deficits, or death resulting from brain injury. Initial median serum concentrations of GFAP and UCH-L1 (obtained <6 h from injury) were significantly greater in CT-positive patients who had an acute unfavorable neurological outcome than in CT-positive patients who did not (GFAP: 5237 pg/mL [IQR 4511, 8180] versus 283.5 pg/mL [IQR 107, 1123]; p = 0.026; UCH-L1: 3329 pg/mL [QR 1423, 5010] versus 679.5 pg/mL [IQR 363, 1100] p = 0.014). Repeat serum testing (6- < 12 h from injury) showed that UCH-L1 serum concentration, but not GFAP, was also significantly greater in the acute unfavorable neurological outcome group than in those without an unfavorable outcome: 1088 pg/mL versus 374 pg/mL; p = 0.041.

Predictive Performance of Traumatic Brain Injury Biomarkers in High-Risk Elderly Patients.

BACKGROUND: Serum glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal esterase L1 (UCH-L1) have recently received US Food and Drug Administration approval for prediction of abnormal computed tomography (CT) in mild traumatic brain injury patients (mTBI). However, their performance in elderly patients has not been characterized. METHODS: We performed a posthoc analysis using the A Prospective Clinical Evaluation of Biomarkers of Traumatic Brain Injury (ALERT-TBI) study data. Previously recorded patient variables and serum values of GFAP and UCH-L1 from mTBI patients were partitioned at 65 years of age (herein referred to as ≥65, high-risk; <65, low-risk). We sought to assess the influence of age on predictive performance, sensitivity, and negative predictive value (NPV) of serum UCH-L1 and GFAP to predict intracranial injury by CT. RESULTS: Elderly mTBI patients constituted 25.7% of the patient cohort (n = 504/1959). Sensitivity and NPV of GFAP/UCH-L1 were 100%, with no significant difference from younger patients (P = 0.5525 and P > 0.9999, respectively). Specificity was significantly lower in elderly patients (0.131 vs 0.442; P < 0.0001) and decreased stepwise with older age. Compared to younger patients, elderly mTBI patients without abnormal (i.e., normal) CT findings also had a significantly higher GFAP (38.6 vs 16.2 pg/mL; P < 0.0001) and UCH-L1 (347.4 vs 232.1 pg/mL; P < 0.0001). CONCLUSIONS: Sensitivity and NPV to predict intracranial injury by CT was nearly identical between younger and elderly mTBI patients. Decrements in specificity and increased serum values suggest that special deference may be warranted for elderly patients.

Stability of Blood Biomarkers of Traumatic Brain Injury.

Blood biomarker tests were recently approved for clinical diagnosis of traumatic brain injury (TBI), yet there are still fundamental questions that need attention. One such question is the stability of putative biomarkers in blood over the course of several days after injury if the sample is unable to be processed into serum or plasma and stored at low temperatures. Blood may not be able to be stored at ultra-low temperatures in austere combat or sports environments. In this prospective study of 20 adult patients with positive head computed tomography imaging findings, the stability of three biomarkers (glial fibrillary acidic protein [GFAP], ubiquitin C-terminal hydrolase-L1 [UCH-L1], and S100 calcium binding protein B [S100B]) in whole blood and in serum stored at 4-5°C was evaluated over the course of 72 h after blood collection. The amount of time whole blood and serum were refrigerated had no significant effect on GFAP concentration in plasma obtained from whole blood and in serum (p = 0.6256 and p = 0.3687, respectively), UCH-L1 concentration in plasma obtained from whole blood and in serum (p = 0.0611 and p = 0.5189, respectively), and S100B concentration in serum (p = 0.4663). Concentration levels of GFAP, UCH-L1, and S100B in blood collected from patients with TBI were found to be stable at 4-5°C for at least 3 days after blood draw. This study suggests that the levels of the three diagnostic markers above are still valid for diagnostic TBI tests if the sample is stored in 4-5°C refrigerated conditions.