Clinical Effectiveness of a Blood-Based Biomarker in Patients with Mild Traumatic Brain Injury

Abstract

Objectives

Mild traumatic brain injury (mTBI) is among the most prevalent neurological conditions worldwide. Its diagnosis predominantly depends on computed tomography (CT) imaging, despite the majority of scans yielding negative results, leading to unnecessary resource utilization and avoidable radiation exposure. This study aims to investigate the potential of glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) as serum biomarkers for ruling out clinically significant intracranial injuries.

Materials and Methods

This prospective cohort study enrolled adult patients (aged >18 years) presenting to the emergency department with nonpenetrating mTBI between October 2023 and October 2024. All participants underwent brain CT imaging and venous blood sampling for quantification of GFAP and UCH-L1. Diagnostic performance metrics, including sensitivity, specificity, positive predictive value, and negative predictive value, were calculated to assess biomarker accuracy in detecting intracranial abnormalities.

Results

A total of 123 patients were enrolled, with a mean age of 70 years. The predominant mechanism of injury was a ground-level fall. The combined use of GFAP and UCH-L1 demonstrated excellent sensitivity (100%; 95% CI: 89.1–100%) and negative predictive value (100%; 95% CI: 76.8–100%) for detecting intracranial injury. However, specificity was low (15.4%; 95% CI: 8.7–24.5%), indicating limited ability to rule in pathology based on biomarker elevation alone.

Conclusion

This study demonstrates the high sensitivity and negative predictive value of GFAP and UCH-L1 as a combined biomarker test for evaluating moderate- and high-risk mTBI. Patients with a negative biomarker result may safely forgo head CT, thereby reducing unnecessary radiation exposure and avoiding unwarranted CT utilization. Nevertheless, practical challenges remain before routine clinical adoption is feasible. Future cost analyses will be essential to determine the economic viability of these biomarkers, particularly in resource-limited settings.

Keywords

traumatic brain injury - mild traumatic brain injury - serum biomarkers - head CT scan - ubiquitin C-terminal hydrolase-L1 - glial fibrillary acidic protein

Introduction

Traumatic brain injury (TBI) remains a major public health concern both globally and in Thailand, with mild TBI (mTBI) accounting for the majority of emergency department visits.[1] [2] [3] Although head computed tomography (CT) is the standard diagnostic modality for detecting intracranial injuries, its routine use has been increasingly scrutinized due to concerns over radiation exposure,[4] [5] resource utilization, and financial burden on patients and healthcare systems—especially given that intracranial abnormalities are detected in fewer than 10% of mTBI cases.[6] [7] [8] Moreover, CT availability is often limited in rural settings, necessitating transfers to secondary or tertiary care centers and further straining resources.

In response, blood-based biomarkers have emerged as promising tools to reduce unnecessary CT imaging. Among the earliest studied was S100 calcium-binding protein B (S100B), though its clinical adoption has been limited due to several drawbacks.[9] [10] [11] More recent evidence highlights glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) as more reliable indicators for ruling out intracranial injury following TBI—data that supported their FDA clearance in 2018.[12] [13]

Despite growing international interest, no data currently exist within the Thai clinical context. To address this gap, we conducted a prospective clinical trial to evaluate the diagnostic performance of combined serum GFAP and UCH-L1 in detecting intracranial injuries on CT among patients presenting with mTBI.

Materials and Methods

Study Design and Participants

This prospective cohort study enrolled adult patients aged 18 years and older with Glasgow Coma Scale (GCS) 13 to 15 from nonpenetrating head injury presenting in the Emergency Department of King Chulalongkorn Memorial Hospital, which is a tertiary center in Bangkok, Thailand. This study was approved by the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University. All participants were eligible if they had a noncontrast CT scan and a blood drawn within 12 hours of injury. They were excluded if they (1) were pregnant; (2) had unstable vital signs; (3) had active brain disease; (4) had an uncertain time of injury.

Procedures

Neurological examination and GCS score were evaluated by an emergency physician. The criteria for performing a CT scan were based on the clinical practice guidelines for traumatic brain injury issued by the Royal College of Neurological Surgeons of Thailand in 2019.

After the inclusion criteria were met and informed consent was obtained from the patient or legal representative, venous blood sampling was collected by nursing staff in the emergency department at the same time as the blood draw for basic biochemical tests. Three milliliters of blood sample were collected in a separate tube for use in the study. Blood samples were stored at −80°C within 1 hour of collection and subsequently processed on a weekly schedule to optimize study costs. This approach has been demonstrated to maintain the integrity of initial biomarker levels.[12] [14]

The quantitative analysis of GFAP and UCH-L1 was performed weekly using the Abbott Alinity system. The Alinity i TBI test is a panel of in vitro diagnostic chemiluminescent microparticle immunoassays used for the quantitative measurements of GFAP and UCH-L1 in plasma and serum, and provides a semiquantitative interpretation of test results derived from a combination of these measurements. The GFAP and UCH-L1 results are reported separately, and the Alinity i platform software provides a TBI interpretation relative to the prespecified cutoff values of 35 pg/mL for GFAP and 400 pg/mL for UCH-L1. The reportable interval for each assay extends from the limit of detection to the upper limit of quantitation. The reportable interval for GFAP is 3.2 to 42,000 pg/mL, and for UCH-L1 is 18.3 to 25,000 pg/mL. Using a prespecified cut-off value, the test was defined as positive if either GFAP or UCH-L1 was positive or both markers were positive. Laboratory personnel were blinded from clinical data. At present, this test remains investigational in Thailand; therefore, biomarker results were not disclosed to the treating physicians.

A brain CT was performed at an emergency department. All head CT scans were independently reviewed by experienced neuroradiologists who were blinded to clinical information and biomarker results. The CT results were taken from the final verified reports generated with the current standard radiology reporting practices. CT-positive was defined as the presence of one or more of the following injuries: acute epidural hematoma, subdural hematoma, intraparenchymal hematoma, intraventricular hemorrhage, brain edema, indeterminate extra-axial hemorrhage (cases in which the precise location, epidural or subdural, cannot be clearly determined), or skull fractures. Solitary scalp hematoma was not included as a positive result. The primary outcomes were sensitivity, specificity, negative predictive value (NPV), and the sensitivity of the UCH-L1 and GFAP test results for CT-positive injuries.

Statistical Analysis

A sample size of at least 100 eligible patients was determined for this pilot study based on the limited availability of test kits. Descriptive statistics were used to summarize baseline characteristics. Categorical variables were compared using the Chi-square test. Continuous variables were analyzed using the independent t-test or the Mann–Whitney U-test, as appropriate. Diagnostic performance was assessed by calculating sensitivity, specificity, positive predictive value (PPV), and NPV to evaluate agreement. All statistical tests were two-tailed, and a p-value less than 0.05 was considered statistically significant. All analyses were performed using Stata version 17.0 (StataCorp LLC, College Station, Texas, United States).

Role of Sponsor

Abbott Laboratories Limited (Sligo, Ireland) supported all the Alinity i TBI test kits in this study but had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Results

Between December 2023 and October 2024, a total of 150 patients were enrolled for serum biomarker analysis and underwent head CT scans. The median time from injury to blood sample collection was 3 hours and 48 minutes. Twenty-seven patients were excluded due to sample collection occurring more than 12 hours postinjury, resulting in a final cohort of 123 patients.

Of these, 116 patients (94.3%) presented with a GCS of 15. The cohort included 58 male patients (47.2%), with a mean age of 70.2 years. Thirty-seven patients (30.1%) were receiving antiplatelet therapy, and 15 patients (12.2%) were on anticoagulants. Ground-level falls represented the predominant mechanism of injury, occurring in 74.8% of cases. CT revealed positive findings in 32 patients (26%). Detailed demographic and clinical data are summarized in [Table 1].

Table 1 Demographic data

	Total	CT result		p-Value
		Positive	Negative
	n = 123	n = 32	n = 91
Age, mean ± SD	70.2 ± 19.2	66.7 ± 22.7	71.5 ± 17.7	0.222
Sex
Female	65 (52.8)	10 (31.3)	55 (60.4)	0.004[a]
Male	58 (47.2)	22 (68.8)	36 (39.6)
Drug/alcohol intoxication	5 (4.1)	2 (6.3)	3 (3.3)	0.467
Antiplatelet	37 (30.1)	6 (18.8)	31 (34.1)	0.104
Anticoagulant	15 (12.2)	2 (6.3)	13 (14.3)	0.232
GCS
15	116 (94.3)	28 (87.5)	88 (96.7)	0.053
13–14	7 (5.7)	4 (12.5)	3 (3.3)
Loss of consciousness	33 (26.8)	9 (28.1)	24 (26.4)	0.847
Posttraumatic amnesia	10 (8.1)	7 (21.9)	3 (3.3)	0.001[a]
Headache	14 (11.4)	6 (18.8)	8 (8.8)	0.127
Vomiting	5 (4.1)	3 (9.4)	2 (2.2)	0.077
Hospitalized	85 (69.1)	28 (87.5)	57 (62.6)	0.009[a]
Mechanism of injury, n (%)
Fall on ground level	92 (74.8)	21 (65.6)	71 (78)	0.598
Fall from height	13 (10.6)	4 (12.5)	9 (9.9)
Motor vehicle accident	12 (9.8)	5 (15.6)	7 (7.7)
Auto-pedestrian accident	2 (1.6)	1 (3.1)	1 (1.1)
Others	4 (2.4)	1 (3.1)	3 (3.3)
GFAP (pg/mL), median (IQR)	71.57 (39.22, 117.55)	201.77 (76.87, 842.96)	61.62 (29.42, 97.7)	<0.001[a]
Positive	95 (77.2)	32 (100)	63 (69.2)	<0.001[a]
Negative	28 (22.8)	0 (0)	28 (30.8)
UCH-L1 (pg/mL), median (IQR)	442.94 (286.24, 706.02)	607.83 (387.63, 1,545.11)	420.02 (263.61, 639.84)	0.003[a]
Positive	73 (59.3)	23 (71.9)	50 (54.9)	0.094
Negative	50 (40.7)	9 (28.1)	41 (45.1)

Abbreviations: GCS, Glasgow Coma Scale; GFAP, glial fibrillary acidic protein; UCH-L1, ubiquitin C-terminal hydrolase-L1.

Notes: p-Value by chi-square test and independent t-test or Mann–Whitney test. Data are n (%), mean (SD, range), and median (IQR), unless stated otherwise.

^a P<0.05

The most frequent CT findings among TBI cases were subarachnoid hemorrhage and subdural hematoma. Additional radiological findings are summarized in [Table 2]. One patient (0.8%) required neurosurgical intervention for an indeterminate extra-axial hemorrhage.

Table 2 Type of injury

CT results	n (%)
Intracerebral hemorrhage	8 (7)
Subarachnoid hemorrhage	10 (8)
Acute subdural hematoma	11 (9)
Indeterminate extra-axial hemorrhage	5 (4)
Epidural hematoma	4 (3)
Skull fracture	3 (2)
Brain edema	1 (1)

Among patients with TBI, 109 (88.6%) yielded a positive biomarker test result, while 14 (11.4%) tested negative. The overall test sensitivity was 100% (95% CI: 89.1–100), with an NPV of 100% (95% CI: 76.8–100). Detailed performance metrics and statistical analyses for each biomarker are provided in [Table 3].

Table 3 Diagnostic test results

	Sensitivity (95% CI)	Specificity (95% CI)	PPV (95% CI)	NPV (95% CI)
Test	100 (89.1–100)	15.4 (8.7–24.5)	29.4 (21.0–38.9)	100 (76.8–100)
GFAP	100 (89.3–100)	30.8 (21.5–41.3)	33.7 (24.3–441)	100 (87.7–100)
UCH-L1	71.9 (53.3–86.3)	45.1 (34.6–55.8)	31.5 (21.1–43.4)	82 (68.2–91.4)

Abbreviations: NPV, negative predictive value; PPV, positive predictive value.

Discussion

The study was conducted in the context of the Clinical Practice Guidelines for Traumatic Brain Injury issued by the Royal College of Neurological Surgeons of Thailand. According to these guidelines, head CT is not indicated for low-risk mTBI patients; moderate-risk patients may require a head CT or hospital admission at the physician's discretion; and high-risk patients are required to undergo CT. Thus, low-risk mTBI patients were not included as head CT was not performed in this group. Consequently, this study focused on moderate- and high-risk mTBI patients to evaluate whether biomarkers could guide more judicious CT utilization.

Although the biomarkers demonstrated a relatively high false-positive rate and low specificity, this did not result in increased CT utilization, as patients in this cohort were already required to undergo CT scan (or hospital admission) based on clinical criteria. In contrast, the very high NPV indicates that patients with a negative biomarker result may safely forgo head CT, which represents the true clinical utility of these biomarkers. This is particularly relevant for reducing unnecessary radiation exposure, avoiding unwarranted CT utilization, and reducing the need to transfer patients from facilities without CT scanners to centers where such imaging is available. It should be noted, however, that the proportion of negative biomarker results varies across studies.[12] [14] [15]

When compared with the ALERT-TBI and i-STAT studies, several distinctions emerge. The mean patient age in this cohort was 70.2 years, significantly higher than the 48.8 and 49.1 years reported in ALERT-TBI and i-STAT, respectively.[12] [14] Most injuries in this study resulted from falls, with fewer than 10% attributed to motor vehicle accidents. In contrast, previous studies reported ∼50% fall-related injuries and 30% due to traffic accidents. These findings are likely attributable to variations across geographic settings, influenced by factors such as urban versus rural environments, national and regional differences, and socioeconomic conditions.[16] [17] [18] [19] [20] The population in this study likely reflects mTBI cases in a large metropolitan center, where traffic accidents are less prevalent and falls, either at construction sites or among the elderly, constitute the major mechanisms of injury. Nevertheless, the cohort examined here provides valuable insight into biomarker performance in an aging population with distinct injury mechanisms, an aspect that has not been previously described. Moreover, the rate of positive CT findings was 26%, markedly higher than the 5.9 to 10.8% reported in earlier studies.[12] [14] [20] [21] These differences likely reflect a higher proportion of older individuals, who carry an increased risk of positive head CT findings following mTBI (see [Table 4]).[22] [23] [24] [25]

Table 4 Summary of previous studies on UCH-L1 and GFAP

Author, year	n	Age (y), mean	GCS	Mechanism		Time to blood draw (h)	Cut off		Test value, mean/median		Combined test					CT positive rate (%)	Manageable lesion (%)
				Fall (%)	MVA (%)		UCH-L1 (pg/mL)	GFAP (pg/mL)	UCH-L1 (pg/mL)	GFAP (pg/mL)	Sens.	Spec.	PPV	NPV	Negative rate (%)
Bazarian et al, 2018[12]	1,920	48.8	14–15	51	31	3.2	327	22	270.1	24.1	97.3	36.7	8.8	99.5	34.0	5.9	0.25
Bazarian et al, 2021[14]	1,901	49.1	13–15	51.9	30.8	3.1	360	30	209.1	36.0	95.8	40.4	9.8	99.3	38.1	6.3	0.26
Wichmann et al, 2025[15]	105	46.1	14–15	27.6	38.1	0.9	400	35	–	–	100.0	22.9	20.2	100.0	–	16.2	–
This study, 2025	123	70.2	13–15	85.4	10	3.8	400	35	442.9	71.6	100.0	16.5	29.6	100.0	11.4	26	0.8

Abbreviations: GCS, Glasgow Coma Scale; MVA, motor vehicle accident; NPV, negative predictive value; PPV, positive predictive value; sens., sensitivity; spec., specificity.

Additionally, to the best of our knowledge, this study is the first to separately report sensitivity, specificity, NPV, and PPV for both biomarkers. Although the rationale for combining biomarkers is to enhance temporal coverage, given that UCH-L1 peaks earlier in the acute phase than GFAP, our study demonstrated that GFAP achieved superior sensitivity and NPV compared with UCH-L1 alone, while performing equivalently to the combined biomarker approach. Furthermore, GFAP has consistently outperformed UCH-L1 in sensitivity, specificity, and AUC across multiple studies.[26] [27] [28] These results align with those of Papa et al, who reported that GFAP yielded higher AUC values for detecting intracranial lesions than UCH-L1 at all time points up to 168 hours postinjury, and comparable AUCs to the combined test.[29]

Despite the diagnostic promise of biomarkers, several practical limitations deserve further discussion. First, in cases of multiorgan trauma, these biomarkers play a limited role as the patients often require CT imaging of other organs regardless of biomarker results.

Second, rapid turnaround time is critical in TBI management. The turnaround time for these biomarkers is approximately 4 hours, which may exceed that required to obtain a CT scan in many emergency departments,[30] [31] thereby limiting their routine use. The i-STAT platform, which delivers results in ∼15 minutes, may help address this challenge.

Third, the number of biomarker tests required to avoid a single unnecessary CT scan warrants consideration. In this study, 14 CT scans could have been avoided among 123 patients, equating to 8.8 tests per one CT avoided. This contrasts with 2.9 and 2.6 tests per CT avoided in the ALERT-TBI and i-STAT studies, respectively. These differences are likely attributable to variation in cutoff values and patient populations.

Fourth, from an economic perspective, many uncertainties remain, including assay costs, operational expenses, direct and indirect costs associated with CT reduction, broader healthcare system expenditures, and willingness-to-pay thresholds. Cost analysis, therefore, represents an essential consideration before these biomarkers can be widely adopted, particularly in resource-limited settings.

This study has several limitations. It was conducted at a single tertiary-care center, which may restrict the generalizability of the findings. The sample size is small due to the pilot nature of the study. Moreover, most patients with mTBI were elderly individuals who had sustained falls, potentially limiting applicability to other populations. Future research should aim to include larger, more diverse patient cohorts to improve generalizability.

Conclusion

This study demonstrates the high sensitivity and NPV of GFAP and UCH-L1 as a combined biomarker test for evaluating moderate- and high-risk mTBI. Patients with a negative biomarker result may safely forgo head CT, thereby reducing unnecessary radiation exposure and avoiding unwarranted CT utilization. Nevertheless, practical challenges remain before routine clinical adoption is feasible. Future cost analyses will be essential to determine the economic viability of these biomarkers, particularly in resource-limited settings.

Conflict of Interest

None declared.

Authors' Contributions

K.L. contributed to conceptualization, methodology, data curation, formal analysis, project administration, and resources, and was responsible for writing the original draft as well as writing, reviewing, and editing the manuscript, including review of the submitted version. K.M. contributed to conceptualization, methodology, data curation, project administration, and resources, and reviewed the submitted version. K.B. contributed to conceptualization, supervision, formal analysis, and project administration, and was involved in writing, reviewing, and editing the manuscript, as well as reviewing the submitted version.

Ethical Approval

The Institutional Review Board of the Faculty of Medicine, Chulalongkorn University, has approved this study in compliance with the international guidelines for human research protection as Declaration of Helsinki, The Belmont Report, CIOMS Guideline, and International Conference on Harmonization in Good Clinical Practice (ICH-GCP) with IRB number 0246/66, COA 615/2023, 599/2024.

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Publication History

Article published online:
03 February 2026