Consensus statements for the diagnosis of mild traumatic brain injury and clinical integration of blood-based biomarkers in the Asia-Pacific region: a modified Delphi study

Abstract

Background

Timely and accurate diagnosis of mild traumatic brain injury (mTBI) remains challenging in acute care. In the Asia-Pacific (APAC) region, marked heterogeneity in healthcare infrastructure, computed tomography (CT) utilization, and diagnostic pathways underscores the need for practical, standardized approaches to assessment. Blood-based biomarkers, particularly glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), have shown promising diagnostic performance and have been incorporated into clinical pathways in other regions. However, their role in APAC emergency care workflows has not been systematically addressed. This study aimed to develop expert consensus on the definition, diagnosis, and clinical integration of these biomarkers into mTBI assessment across APAC.

Methods

A structured modified Delphi process was employed, involving ten expert panelists representing emergency medicine, neurosurgery, and neurology from APAC countries including Australia, India, Indonesia, the Philippines, Singapore, Taiwan, and Thailand. A targeted literature review informed the development of 34 preliminary statements, consolidated into 11 statements covering mTBI definition, diagnostic approach, and biomarker integration. Panelists rated each statement using a 4-point Likert scale across two anonymous online voting rounds, with consensus defined as ≥ 70% agreement. Voting results were reviewed at a face-to-face meeting in Bangkok in May 2025, where statements were refined before Round 2 voting.

Results

All 11 final consensus statements achieved agreement ratings of 90% to 100% following Round 2 voting. Seven statements reached 100% agreement and four achieved 90% agreement. Statements addressed definitions of TBI and mTBI, the adjunctive diagnostic role of GFAP and UCH-L1 within a 12-hour post-injury window, their utility in diagnostically challenging subgroups such as anticoagulated and intoxicated patients, and the continued primacy of clinical assessment and local imaging pathways in guiding triage, imaging, discharge, and follow-up decisions.

Conclusions

This modified Delphi study produced 11 high-consensus statements that provide a regional framework for the diagnosis of mTBI and for integration of GFAP and UCH-L1 into biomarker-supported assessment pathways across APAC. These biomarkers may help reduce avoidable CT imaging and support triage in selected patients when used as adjuncts to clinical assessment and established imaging decision-making. The statements are intended to support locally adapted protocols and future APAC-specific implementation and validation studies.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s12245-026-01292-0.

Background

Timely and accurate diagnosis of mild traumatic brain injury (mTBI) remains challenging, particularly in the setting of acute care [1]. There is a lack of objective tests with sufficient diagnostic performance. Standardized brief symptom evaluation and computerized neurocognitive tools have been developed to support rapid screening for mTBI but remain uncommonly available and psychosocial factors complicate their interpretation [2]. Neuropsychological testing has identified reduced processing speed and attention as key early markers of mTBI but are limited in their use acutely due to expertise and time requirements [3].

In the Asia-Pacific region (APAC), the epidemiology of TBI exhibits considerable variability. Reports of incidence are highly heterogeneous, and quoted rates span from 264 per 100,000 population in Indonesia to as high as 455 per 100,000 in India, reflecting diverse epidemiological and healthcare factors across these countries [4]. Incidence rates in Australia, the Philippines, and Singapore fall within a narrower range, approximately 275–285 per 100,000 population, indicating comparable public health burdens despite differences in healthcare infrastructure and preventive measures [5, 6].

The Glasgow Coma Scale (GCS) continues to serve as the primary tool for the initial triage of patients with TBI, with CT being commonly used to exclude or define severity of TBI [7]. However, the utilization of GCS and computed tomography (CT) imaging varies across countries in APAC, reflecting differences in healthcare infrastructure, clinical protocols, and resource availability [8]. While some nations adopt a conservative approach to imaging based on GCS thresholds, others employ more liberal CT use, even in cases classified as mTBI, to mitigate the risk of missed diagnoses. In some settings, CT scans are over-utilized, particularly in low-risk cases, while in resource-limited environments, they may be underused [9]. These practice gaps underscore the need for objective and standardized diagnostic tools to support clinical decision-making. At present, there is no single CT decision rule or imaging protocol used uniformly across the APAC region. Instead, local practice is shaped by a combination of international decision rules, institutional protocols, resource availability, and medicolegal context. This heterogeneity reinforces the need for any biomarker-based approach to be integrated within, rather than replace, existing local imaging pathways.

Blood-based biomarkers represent promising tools that might assist mTBI diagnosis through quantification of proteins associated with astroglial injury (e.g., glial fibrillary acidic protein [GFAP]; S100 calcium-binding protein B [S100B]), neuronal injury (e.g., ubiquitin carboxy-terminal hydrolase L1 [UCH-L1]), axonal injury (e.g., neurofilament light chain, tau, spectrin breakdown products), and inflammatory responses [10, 11]. Although much of the current biomarker literature has emerged from North America and Europe, APAC-based work has also contributed to this field. For example, a New Zealand study evaluating S100B in emergency care settings provides important context for biomarker-supported triage in APAC populations and highlight the need for further regional validation [12].

GFAP is an intermediate filament protein specific to astrocytes, released into biofluids following astroglial injury or necrosis, while UCH-L1 is a neuron-specific enzyme involved in ubiquitin-mediated protein degradation and released after neuronal injury. The translational foundation for these biomarkers was significantly advanced by Wang, Kobeissy and colleagues, who demonstrated that GFAP and UCH-L1 are released in proportion to injury severity and correlate with neuroimaging findings and clinical outcomes [13, 14]. Wang’s and Kobeissy’s work established that GFAP and UCH-L1 measure distinct molecular events and that their combined measurement improves diagnostic and prognostic accuracy for TBI compared to either marker alone. This mechanistic distinction is supported by weak correlation between their levels in TBI patients, underscoring their complementary value [15]. Clinically, these biomarkers have undergone large-scale validation in prospective cohorts, including TRACK-TBI, for prediction of intracranial injury and subsequent outcomes [16].

By contrast, other emerging and complementary biomarkers, including tau, phosphorylated tau, neurofilament light, and inflammatory biomarkers, remain of considerable scientific interest but have not yet reached the same level of validation or near-term clinical deployability in acute mTBI assessment [10, 11]. S100B has been incorporated into some guidelines and has important historical and practical relevance, but its shorter testing window and lower neuro-specificity compared with GFAP and UCH-L1 may limit broader applicability in some acute care settings [17–19].

Measures of S100B, and GFAP and UCH-L1 combinations are now approved for clinical use as highly sensitive predictors of intracranial bleeding post-TBI in Scandinavia and France [17, 18]. In addition, some classification accuracy with biomarkers has been reported in smaller studies of mTBI in the emergency department (ED) and sport [19]. However, most validation evidence and regulatory adoption have emerged outside APAC, and translation into APAC emergency care requires consideration of heterogeneous resources, workflows, and reimbursement, and that biomarkers should be considered adjuncts to clinical assessment and established neuroimaging decision-making. Recent international guidance has also supported structured approaches to biomarker-informed mTBI assessment. In addition to French and Scandinavian recommendations, newer European consensus efforts, including a recent Spanish consensus, have similarly emphasized the need to reduce unnecessary CT imaging while preserving patient safety and adapting recommendations to local system constraints [20]. Positioning the present APAC consensus within this broader international landscape highlights both convergence in core principles and the importance of regional implementation strategies.

Despite this progress, several key gaps must be addressed before biomarkers can be implemented within clinical practice. Findings from other settings may lack generalizability to ED care, where there is a wide range of pathophysiology and comorbidities [21]. Hospital-based studies may conflate TBI severities or CT-negative and CT-positive mTBI, and sport-related concussion cohort studies do not capture the heterogeneity in patient demographics and injury mechanisms present at EDs [22]. Biomarker candidates have divergent and dynamic temporal profiles, and results from samples at various time points postinjury may not reflect classification performance in an ED setting [23]. Additionally, while loss of consciousness for 30 min or less and posttraumatic amnesia within 24 h are strong indicators of mTBI, their association with biomarkers is poorly characterized [24].

The present consensus was designed to support the definition, diagnosis, and early assessment of mTBI, particularly through the potential clinical integration of blood-based biomarkers, rather than to serve as a comprehensive guideline for all aspects of acute and longitudinal mTBI management. The overarching aim of this study was to provide direction to support objective assessment and decision-making in emergency and neurology care settings across APAC. A panel of multidisciplinary clinicians convened to establish a unified approach to TBI management, focusing on the clinical integration of blood-based biomarkers in mTBI through a structured modified Delphi process.

Methods

Design

We employed a structured modified Delphi method to establish expert consensus on the clinical integration of blood-based biomarkers in the management of mTBI across APAC (Fig. 1). The Delphi method was first developed by the RAND Corporation in 1948 [25]. It is a structured and iterative process used to acquire knowledge and opinions from experts on a selected topic. The major advantages of using the Delphi method are that a wide range of views can be obtained, which enables the collation of international opinions while being cost-effective and eliminating the need to travel. It also provides a platform for experts to revise their initial opinions based on the feedback from the group, fostering convergence and consensus-building. The consensus development process followed a structured, transparent, and explicit approach using the modified Delphi technique [26]. This approach was selected to systematically solicit expert opinions, assess levels of agreement, and refine statements concerning the incorporation of blood-based biomarkers into mTBI management.

Fig. 1.

Modified Delphi study design

Data extraction and statement development

A targeted literature review was conducted to identify existing definitions, diagnostic pathways, and evidence on blood-based biomarkers for mTBI in acute care. Based on this.

review and steering group discussions, an initial set of 34 preliminary statements was drafted to cover key domains including definition, burden, diagnostic assessment, biomarker use, and clinical decision-making (Supplementary Table 1). Because the purpose of this consensus was to address biomarkers that are closest to current clinical implementation, the Delphi discussions focused primarily on GFAP and UCH-L1, which currently have the strongest validation and greatest translational readiness in adult mTBI assessment. Other promising biomarkers were acknowledged but were not the primary focus of statement development. Likewise, comprehensive treatment and rehabilitation issues in mTBI were considered beyond the intended scope of this Delphi. The preliminary statements were reviewed for redundancy and clarity and consolidated into 11 statements for Round 1 voting (Fig. 1). The drafting and consolidation were performed by the manuscript steering group prior to Round 1 voting. The consolidated 11 statements and the strength of evidence are listed in Supplementary Table 2.

Delphi panelists

To develop the consensus, ten expert panelists from multiple specialties and countries across APAC with clinical experience in managing TBI were identified and invited to participate. The countries were chosen based on current capacity to test for biomarkers of TBI (Fig. 2). Panelists were purposively selected to ensure representation of acute mTBI decision-makers across the APAC region and included clinicians from emergency medicine, neurosurgery, and neurology. Eligibility criteria included: (i) current clinical practice in an acute care setting managing adult TBI/mTBI; (ii) familiarity with CT-based triage and local pathways; and (iii) ability to participate in two online survey rounds and a consensus meeting. Invitations were issued to achieve geographic diversity across APAC healthcare systems and resource contexts. All invited panelists who accepted participated in rounds 1 and 2.

Fig. 2.

Geographical representation of the panel

The formal consensus process was conducted through two online surveys and a face-to-face meeting. The online survey forms were distributed to the panelists for self-completion. Each panelist rated the proposed statements using a 4-point Likert scale, where 0 represented “strongly disagree,” 1 “disagree,” 2 “agree,” and 3 “strongly agree.” To minimise bias and prevent dominance by any individual, the ratings were submitted anonymously. Statements achieving a predetermined level of 70% or more agreement (i.e., ratings of “agree” or “strongly agree”) were considered to have reached “consensus agreement.” Conversely, statements with 30% or less agreement were categorized as having “consensus disagreement,” while those falling between these thresholds were classified as having “no consensus.” The strength of recommendation for each statement was determined by the median rating across the ten panelists, with a median score of 3 indicating the highest level of recommendation and 0 the lowest. The primary outcomes were statement-level consensus (percentage agreement) and strength of recommendation (median Likert rating).

Abbott Laboratories provided financial support for the consensus process, and IQVIA provided operational coordination, including survey administration, anonymization and aggregation of voting responses, and meeting logistics. Neither Abbott Laboratories nor IQVIA participated in statement voting, consensus determination, or manuscript drafting. Anonymous voting and predefined agreement thresholds were used to reduce the risk of undue influence.

The aggregated consensus rating results were presented at the one-and-a-half-day face-to-face meeting held from 7 to 8 May 2025. During the meeting, statements that received “no consensus” or “consensus disagreement” were discussed further, along with those that had achieved “consensus agreement” but were considered by the panel to require wording revisions for greater precision and appropriateness. Following the meeting, the revised statements were redistributed to the panelists for a second round of voting via an online survey to reassess their level of agreement. During day 1 of the meeting, panelists presented their local management of TBI. Following round 2 of voting further discussions were held on possible challenges to adoption and future directions of blood-based biomarkers for mTBI in APAC.

Ethics statement

In accordance with the Declaration of Helsinki, the study protocol was reviewed and approved by the Monash University Human Research and Ethics Committee (Project ID 49108). Participation in the panel implied consent, and all panelists were co-investigators of the study.

Results

Panel selection

Ten experts were invited, all of whom agreed to participate. The final expert panel comprised five emergency physicians, four neurosurgeons, and one neurologist representing Australia, India (two), Indonesia, the Philippines, Singapore, Taiwan, and Thailand (three) (Fig. 2). All ten experts participated in rounds 1 and 2 of the voting process. Six of the panelists attended the face-to-face meeting in Bangkok, Thailand on 7 and 8 May 2025, while the remaining four attended via live video conference.

Consensus statements with agreement rating and strength of recommendation

A total of 11 consensus statements were presented to the panel of experts for the first round of voting (Table 1). All statements achieved at least 90% agreement rating, and most responses fell within the 2 “agree” and 3 “strongly agree” categories for strength of recommendation. Minor areas of disagreement were primarily related to specific wording or scope, rather than disagreement with the underlying concepts. All comments and suggestions were documented to guide further refinement during the in-person discussion.

Table 1.

Results from first round of voting

Statement	Original statements	Percentage agreement
1	Traumatic brain injury is defined as an alteration in brain function, or other evidence of brain pathology, caused by an external force. This alteration may encompass a decreased level of consciousness, post-traumatic amnesia, neurological deficits, alterations in mental status, or laboratory-confirmed evidence of brain injury, particularly in individuals with a suspected diagnosis of traumatic brain injury.	100%
2	Traumatic brain injury is a common presentation in emergency departments across the Asia-Pacific region, with a prevalence of 438 per 100,000 population. In the absence of a standardized regional protocol, country- or institution-specific guidelines should be evidence-based and adapted to local healthcare infrastructure and resource availability.	100%
3	Mild traumatic brain injury is defined as a traumatically induced disruption of brain function, evidenced by at least one of the following: loss of consciousness for 30 min or less, post-traumatic amnesia lasting less than 24 h, altered mental state at the time of injury, or focal neurological deficits. It is further characterized by a Glasgow Coma Scale score of 13 to 15, measured 30 min post-injury. Elevated blood biomarkers of intracranial injury are increasingly recognized as valuable tools for triage and early diagnosis in mild traumatic brain injury. As such, blood-based biomarkers may complement clinical and imaging findings, particularly in cases of either suspected or complicated mild traumatic brain injury.	100%
4	A diagnosis of traumatic brain injury may be supported by diagnostic tests, including visual, neuroradiologic, or laboratory confirmation of structural or functional damage to the brain. Traditionally diagnosed using clinical criteria, traumatic brain injury diagnosis is now increasingly supported by advances in imaging and laboratory techniques — which offer greater sensitivity in detecting subtle or delayed brain injuries, especially in mild cases.	90%
5	While computed tomography scans remain the standard for detecting intracranial lesions in moderate to severe traumatic brain injury, their use in mild traumatic brain injury is often inconsistent and may result in unnecessary imaging despite the availability of clinical tools such as the Glasgow Coma Scale and Canadian Computed Tomography Head Rule. To improve diagnostic accuracy and reduce avoidable computed tomography use, incorporation of blood-based biomarkers in the assessment of mild traumatic brain injury is recommended.	90%
6	Accurate assessment of mild traumatic brain injury is critical. Growing evidence suggests that early evaluation using blood-based biomarkers such as glial fibrillary acidic protein and ubiquitin carboxy-terminal hydrolase L1 may aid in the assessment of mild traumatic brain injury patients, help identify those at risk, guide clinical monitoring, and inform timely management to reduce the risk for short and longer-term complications.	100%
7	Glial fibrillary acidic protein and ubiquitin carboxy-terminal hydrolase L1, measured within 12 h post-injury — with some evidence supporting their use up to 24 h — can aid in assessing mild traumatic brain injury by serving as an additional triage tool to guide neuroimaging decisions. Glial fibrillary acidic protein levels below 35 pg/mL and ubiquitin carboxy-terminal hydrolase L1 below 400 pg/mL indicate a negative result and can rule out the need for brain computed tomography with a sensitivity of 96.7% and negative predictive value of 99.4%. Elevated levels of either glial fibrillary acidic protein and ubiquitin carboxy-terminal hydrolase L1 above the defined cut-offs indicate a positive result and neuroimaging should be considered to enhance diagnostic accuracy.	100%
8	S100B is a blood-based biomarker that has been included in Scandinavian guidelines to be measured within 6 h of trauma in select mTBI patients (Glasgow Coma Scale 14 without risk factors* or Glasgow Coma Scale 15 with loss of consciousness or 2 or more episodes of vomiting); if levels are below 0.10 mcg/L, brain computed tomography may be omitted, and the patient considered for discharge. However, Food and Drug Administration-approved glial fibrillary acidic protein and ubiquitin carboxy-terminal hydrolase L1offer additional benefit of greater neuro-specificity and longer testing window.	100%
9	Glial fibrillary acidic protein and ubiquitin carboxy-terminal hydrolase L1 are effective in ruling out delayed intracranial injury in anticoagulated patients. Glial fibrillary acidic protein and ubiquitin carboxy-terminal hydrolase L1 retain diagnostic accuracy even in the presence of elevated blood alcohol levels, supporting their use — particularly in uncooperative or intoxicated patients — as an adjunct to clinical decision rules to reduce unnecessary brain computed tomography imaging.	90%
10	Blood-based biomarkers should be used as an aid to diagnosis and do not supersede clinical decision-making and determining the need for imaging or further intervention. Asymptomatic, alert, and neurologically normal patients with normal biomarkers levels may be safely observed and discharged if stable. Patients with neurological risk factors (e.g., abnormal computed tomography, skull fracture, severe headache) should be admitted or transferred for further evaluation.	90%
11	Clinical assessment in traumatic brain injury plays a critical role to guide triage, confirm diagnosis, initiate timely interventions (e.g., biomarkers, computed tomography, magnetic resonance imaging), optimize resuscitation, minimise secondary complications, allocate patients to appropriate clinical management pathways (e.g., discharge from the emergency department, or admission to a hospital ward or intensive care unit), and ensure appropriate follow-up.	100%

Upon modification of the original statements after discussion among the panel of experts, the final consensus statements were re-voted in Round 2. These statements primarily addressed the definition and diagnosis of mTBI, the adjunctive role of blood-based biomarkers in early assessment, and the place of clinical judgment within imaging, discharge, and follow-up decision-making. All statements attained agreement ratings ranging from 90% to 100% and median strengths of recommendation between 2 and 3 indicating “agree” and “strongly agree”, respectively (Table 2). Seven statements (1, 2, 3, 6, 7, 8, and 11) achieved agreement ratings of 100% while the remaining four statements (4, 5, 9, and 10) received agreement ratings of 90%. In terms of strength of recommendation, five statements (1, 2, 3, 4, and 11) had a median of 3 “strongly agree” and the remaining six statements (5, 6, 7, 8, 9, and 10) had median of 2 “agree”.

Table 2.

Concepts, final consensus statements, agreement and strength of recommendation

Statement	Concepts	Final consensus statements	Percentage agreement	Median strength of recommendation
1	Definition of traumatic brain injury	Traumatic brain injury is defined as an alteration in brain function, or other evidence of brain pathology, caused by an external force. This alteration may encompass a decreased level of consciousness, post-traumatic amnesia, neurological deficits, alterations in mental status, radiological or laboratory evidence of brain injury.	100%	Strongly agree
2	High burden of traumatic brain injury in the Asia-Pacific region	Traumatic brain injury poses a substantial burden on emergency departments and is a leading cause of morbidity and mortality across the Asia-Pacific region. Country- or institution-specific guidelines should be evidence-based and adapted to local healthcare infrastructure and resource availability.	100%	Strongly agree
3	Definition of mild traumatic brain injury	Mild traumatic brain injury is defined as a traumatically induced disruption of brain function, evidenced by at least one of the following: loss of consciousness for 30 min or less, post-traumatic amnesia lasting less than 24 h, altered mental state at the time of injury, or focal neurological deficits. It is further characterized by a Glasgow Coma Scale score of 13 to 15, measured 30 min post-injury.	100%	Strongly agree
4	Diagnosis of mild traumatic brain injury	Traditionally diagnosed using clinical criteria, advances in imaging and laboratory techniques are increasingly recognized as valuable tools for triage and early diagnosis in mild traumatic brain injury. As such, blood-based biomarkers complement clinical and imaging decision-making, particularly in cases of either suspected or complicated mild traumatic brain injury.	90%	Strongly agree
5	Diagnosis of mild traumatic brain injury	The use of computed tomography scans in mild traumatic brain injury is often inconsistent and may result in unnecessary imaging. To improve diagnostic accuracy and reduce avoidable computed tomography use, incorporation of blood-based biomarkers in the assessment of mild traumatic brain injury should be considered.	90%	Agree
6	Early assessment using blood-based biomarkers	Growing evidence suggests that early evaluation using blood-based biomarkers such as glial fibrillary acidic protein and ubiquitin carboxy-terminal hydrolase L1 may aid in the assessment of mild traumatic brain injury patients, help identify those at risk, guide clinical monitoring, and inform timely management to reduce the risk for short and longer-term complications.	100%	Agree
7	Glial fibrillary acidic protein and ubiquitin carboxy-terminal hydrolase L1 as triage tools	Glial fibrillary acidic protein and ubiquitin carboxy-terminal hydrolase L1, measured within 12 h post-injury can aid in assessing mild traumatic brain injury by serving as an additional triage tool to guide neuroimaging decisions. Glial fibrillary acidic protein and ubiquitin carboxy-terminal hydrolase L1 levels below the defined cut-offs indicate a negative result and can rule out the need for brain computed tomography with likelihood ratio of less than 0.1 for a negative test. Neuroimaging may be considered in patients with levels of either glial fibrillary acidic protein or ubiquitin carboxy-terminal hydrolase L1 above the defined cut-offs.	100%	Agree
8	S100B versus glial fibrillary acidic protein and ubiquitin carboxy-terminal hydrolase L1	S100B is a blood-based biomarker that has been included in some guidelines to be measured within 3–6 h of trauma in select mild traumatic brain injury patients. However, Food and Drug Administration-approved glial fibrillary acidic protein and ubiquitin carboxy-terminal hydrolase L1 may offer additional benefit of greater neuro-specificity and longer testing window.	100%	Agree
9	Improve mild traumatic brain injury assessment in intoxicated patients and those on anticoagulant or antiplatelet therapy	Glial fibrillary acidic protein and ubiquitin carboxy-terminal hydrolase L1 retain diagnostic accuracy in the presence of elevated blood alcohol levels, supporting their use in patients who are difficult to assess. Glial fibrillary acidic protein and ubiquitin carboxy-terminal hydrolase L1 are also effective in patients on anticoagulant or antiplatelet therapy.	90%	Agree
10	Blood-based biomarkers supporting clinical decision-making	Blood-based biomarkers should be considered as an aid to diagnosis, without superseding clinical decision-making in determining the need for imaging or further intervention. Asymptomatic, alert, and neurologically normal patients with normal biomarkers levels may be discharged.	90%	Agree
11	Role of clinical assessment in traumatic brain injury	Clinical assessment in traumatic brain injury plays a critical role in guiding triage, confirming diagnosis, initiating timely interventions, optimizing resuscitation, minimizing secondary complications, allocating patients to appropriate clinical management pathways, and ensuring appropriate discharge and follow-up.	100%	Strongly agree

Discussion

Definitions and burden

The expert panel was unanimous in supporting standardized definitions of TBI and mTBI as well as recognizing the substantial burden these conditions pose across the APAC region. Alignment around shared terminology is important because consistent diagnostic language improves communication across specialties, facilitates case identification for research and surveillance, and supports the development of locally relevant clinical pathways. Distinguishing mTBI within the broader TBI spectrum remains especially important in patients who may lack obvious structural abnormalities yet still require careful assessment, follow-up, and safety-netting.

Diagnosis and biomarker-supported triage

The panel agreed that although mTBI remains primarily a clinical diagnosis, advances in imaging and laboratory techniques are increasingly valuable in supporting early assessment and triage. This view is consistent with emerging international guidance, including French, Scandinavian, and more recent European consensus efforts, which support structured use of blood-based biomarkers in selected patients to reduce unnecessary CT imaging while maintaining safety [17, 18, 20]. Similarly, the American Congress of Rehabilitation Medicine includes the evaluation of blood biomarkers indicative of intracranial injury as part of the supportive evidence for diagnosing brain injury [27].

Within this evolving diagnostic landscape, GFAP and UCH-L1 were prioritized because they currently have the strongest evidence base and greatest near-term clinical readiness for adult mTBI assessment [16, 28, 29]. Evidence from prospective studies and meta-analyses suggests that, when measured within an appropriate time window after injury, these biomarkers may help identify patients at low likelihood of intracranial injury and support decisions regarding neuroimaging [28, 29]. Their utility may be particularly relevant in settings where CT use is inconsistent, overused in low-risk patients, or constrained by access.

At the same time, these biomarkers should not be interpreted as standalone replacements for clinical assessment or imaging. Rather, they are best understood as adjunctive tools that may refine triage in selected patients, especially where diagnostic uncertainty exists. This is particularly relevant in APAC, where there is no single imaging rule used uniformly across the region and where institutional protocols, workforce patterns, and resource constraints vary substantially. On an operational level, patients who have clear indications for CT would still be imaged, while those who can be confidently ruled out of having acute traumatic lesions would be excluded clinically. There are many patients who then fall in a “grey zone”, where there is uncertainty on potential value of imaging. Where imaging is readily available, most such patients are investigated with CT, and this is the population where biomarkers could be of benefit. We postulate that in this population of low pre-test probability and negative biomarkers, CT can be avoided.

S100B has a meaningful role in some existing guidelines and remains relevant as a comparator biomarker, particularly given its prior integration into Scandinavian pathways [12, 17]. However, its shorter testing window and lower neuro-specificity may limit its flexibility in some emergency care settings [17–19, 28]. Other markers, including tau, phosphorylated tau, neurofilament light, and inflammatory biomarkers, may ultimately prove valuable for prognosis, persistent symptoms, and biological subtyping of brain injury, but currently require further validation before routine incorporation into acute ED workflows [10, 11].

A recent systematic review and meta-analysis of 16 studies showed that combined measurement of GFAP and UCH-L1 could exclude intracranial injury after mTBI in adult patients with 100% sensitivity and negative predictive value [29]. The combined results of these studies indicate likelihood ratio below 0·1 for negative tests, which is considered to provide strong evidence to rule out the diagnosis of intracranial injury [30].

In terms of regulatory and clinical use guidance, GFAP and UCH-L1 have been approved as diagnostic aids for adult patients with suspected mild TBI [31]. Their use is indicated in patients aged 18 years and older presenting with a GCS score of 13 to 15 within 12 h of injury. Unlike S100B, the levels of GFAP and UCH-L1 are not significantly affected by extracranial injuries, which enhances their specificity for brain injury. This makes them particularly valuable in complex clinical situations where decisions regarding CT imaging are not straightforward, allowing for improved diagnostic accuracy while reducing unnecessary imaging. In their systematic review and meta-analysis, Puravet and colleagues suggested that the combined GFAP and UCH-L1 levels below specified thresholds could theoretically reduce the number of head CT scans by almost one-third [29].

It was agreed that GFAP and UCH-L1 retain diagnostic accuracy in patients receiving anticoagulant or antiplatelet therapy, as well as in those who are intoxicated. The TRACK-TBI study, which investigated the impact of blood alcohol levels on the diagnostic performance of these biomarkers, found that even moderate (81–300 mg/dL) and high (> 300 mg/dL) alcohol levels did not reduce their accuracy in predicting traumatic brain injury [32]. Additionally, a prospective observational study in anticoagulated patients with mild head injury (GCS 14–15) demonstrated that GFAP and UCH-L1 maintained high negative predictive value when measured within 12 h of injury [33]. These findings suggest that the use of blood-based biomarkers could help reduce unnecessary head CT scans in this high-risk population without compromising on safety.

Clinical decision-making, discharge, and follow-up

The panel strongly agreed that blood-based biomarkers should support, rather than supersede, clinical decision-making. Patients with high-risk features, clear indications for urgent CT, progressive neurological symptoms, or other clinical concerns should proceed directly to imaging and/or specialist review irrespective of biomarker status. Conversely, in clinically appropriate low-risk patients within the validated biomarker testing window, normal biomarker results may support a decision to defer CT and consider discharge, provided that the patient is neurologically normal, clinically stable, and managed according to local observation, discharge, and follow-up protocols.

This distinction is important because the present consensus is not intended to function as a self-contained discharge rule. Biomarker results should be interpreted in conjunction with symptom burden, examination findings, injury mechanism, anticoagulant or antiplatelet use, intoxication status, social circumstances, and the availability of follow-up. We have added a simple clinical algorithm for biomarker integration in mTBI triage (Fig. 3).

Fig. 3.

Suggested workflow for integrating GFAP and UCH-L1 into adult mTBI assessment. CT: computed tomography; GCS: Glasgow Coma Scale; GFAP: glial fibrillary acidic protein; UCH-L1: ubiquitin carboxy-terminal hydrolase L1

Limitations

This study reports expert consensus derived from a modified Delphi process and is therefore not data-generating. The statements reflect expert interpretation of the existing literature and do not constitute prospective validation of biomarker-guided pathways in APAC settings. The panel size was modest (n = 10) and, although geographically diverse, may not fully represent the breadth of practice environments across APAC, particularly rural, lower-resource, or non-tertiary settings.

A further limitation is that the evidence base for biomarker use in hyperacute presentations remains less mature than for some later sampling windows. Although available data support use of GFAP and UCH-L1 within a 12-hour post-injury window, relatively fewer studies have evaluated very early post-injury sampling in unselected, real-world ED populations. Some evidence is also derived from broader TBI cohorts, mixed-severity populations, or study settings that may not fully reflect routine emergency care workflows.

Panel membership consisted of clinicians from emergency medicine, neurosurgery, neurology and did not include basic scientists, laboratory medicine specialists, statisticians, methodologists, patients, or public representatives. Future work would benefit from broader stakeholder representation, especially when implementation, reimbursement, and patient-centered outcomes are concerned.

Finally, the Delphi process was supported by industry funding and operational coordination, which may introduce a perceived risk of bias. To mitigate this, voting was anonymous, predefined consensus thresholds were used, and neither Abbott Laboratories nor IQVIA participated in statement voting, consensus determination, or manuscript drafting. Relevant competing interests are fully disclosed in Acknowledgments and Declaration of Interests.

Implementation considerations

For implementation in APAC emergency care, biomarker-supported triage should be embedded into existing clinical decision workflows rather than used as a standalone diagnostic pathway [34]. Patients with suspected mTBI should first undergo structured clinical assessment, including Glasgow Coma Scale scoring, neurological examination, and application of locally adopted CT decision rules where available. Patients with immediate indications for CT or neurosurgical evaluation should proceed directly to imaging and specialist care. In clinically stable patients who fall within the validated biomarker testing window and do not have mandatory imaging indications, GFAP and UCH-L1 may be considered as adjunctive tests to support imaging decisions (Fig. 3).

Negative biomarker results may support deferral of CT in selected low-risk patients, whereas positive results should prompt consideration of neuroimaging in conjunction with the overall clinical picture. Local protocols should define eligibility criteria, timing of blood sampling, pathways for repeat assessment in the event of symptom progression, and the minimum discharge requirements for patients in whom CT is deferred. In this way, biomarker testing may help standardize care without displacing clinical judgment.

Implementation should also consider operational realities, including assay turnaround time, sample handling, quality control, staffing, training, and governance for audit and safety monitoring. Depending on the local system, central laboratory testing may not be faster than CT-based pathways, and the practical advantage of biomarkers may therefore vary between institutions. Future implementation studies in APAC should evaluate not only diagnostic performance but also service-level outcomes such as CT utilization, ED length of stay, patient flow, revisit rates, and downstream costs.

While there may be an upfront expenditure to set up platforms for biomarker testing, it is possible that the costs of CT scanning and delays to patient disposition may offset these costs. Emerging economic analyses suggest that biomarker-guided strategies may improve ED efficiency and reduce time to disposition in selected mTBI populations, in addition to lowering unnecessary imaging and radiation exposure [35]. However, such benefits must be interpreted considering local reimbursement structures, platform costs, and workflow constraints.

Possible challenges to adoption of blood-based biomarkers in the Asia-Pacific region

Several challenges may hinder the adoption of blood-based biomarkers for mTBI in APAC. First, clinical and cultural barriers remain important. In many settings, clinicians continue to rely on CT imaging for diagnostic certainty, particularly where defensive medicine, patient expectations, or medicolegal concerns favor imaging-based reassurance [36]. Limited familiarity with biomarker interpretation may further reduce confidence in adopting biomarker-supported pathways.

Second, health system readiness and infrastructure constraints are likely to influence feasibility. Laboratory capacity, sample transport systems, turnaround times, and point-of-care availability vary markedly across the region. In some institutions, CT may remain more practical than laboratory testing despite the theoretical appeal of biomarker-supported triage. Pre-analytical variability, delayed processing, and inconsistent access to point-of-care instruments may all affect the reliability and usefulness of testing.

Third, financial barriers may be substantial. In several settings, CT is subsidized or routinely covered, whereas biomarker testing may require out-of-pocket payment or may not yet be reimbursed. In addition to the cost per assay, implementation requires instrument procurement, maintenance, calibration, quality assurance, staff training, and dependable supply chains. These requirements may limit scalability and risk widening inequity if biomarker testing is available only in better-resourced centers.

Finally, local evidence and policy support remain limited. Regulatory approvals, reimbursement pathways, and inclusion in national guidelines differ across APAC. Without stronger local validation data and implementation studies, clinicians and policymakers may remain hesitant to depart from imaging-centered practice.

Future directions

The expert panel identified several clinical scenarios in which blood-based biomarkers may provide substantial future value. Pediatric and pregnant patients were highlighted because reducing radiation exposure is especially desirable in these groups, although dedicated validation studies are needed before routine use can be recommended [37]. The panel also noted potential roles for biomarkers in post-discharge planning, follow-up, and risk stratification, particularly in identifying patients who may benefit from closer monitoring despite an initially reassuring evaluation.

The importance of further research into the long-term outcomes of biomarker-positive, CT-negative patients was emphasized. Future biomarker research should also extend beyond GFAP and UCH-L1 alone. Although these biomarkers currently have the strongest support for near-term implementation, a broader biomarker panel may ultimately be needed to improve prognostication, detect evolving injury patterns, and characterize neuroinflammatory or neurodegenerative trajectories after mTBI. Biomarkers such as S100B, tau, phosphorylated tau, neurofilament light, and inflammatory mediators remain important areas for future investigation. Ongoing studies on prognostic applications were also recognized, with biomarkers seen as useful tools for identifying high-risk patients who may benefit from closer monitoring or earlier interventions, particularly in previously undiagnosed cognitive impairment or neurogenerative disorders [38, 39].

From a translational perspective, greater attention should be paid to accessibility and affordability. Lower-cost technologies, including simplified point-of-care platforms and lateral flow devices, may eventually improve access in lower-resource settings, but these approaches will require robust analytical and clinical validation before widespread adoption.

Clarification was also made regarding potential applications of biomarkers in stroke populations. Although current evidence does not support routine use of GFAP and UCH-L1 as first-line triage tools in acute stroke pathways, this is an evolving area of investigation, including in relation to large-vessel occlusion and reperfusion-related decision-making [40]. At present, imaging remains indispensable in time-critical stroke care, but future studies may better define complementary roles for biomarkers in selected stroke scenarios.

Overall, the next phase of work in APAC should include prospective implementation studies, locally relevant health economic evaluations, and validation across diverse healthcare environments, including lower-resource and decentralized systems.

Conclusions

The integration of blood-based biomarkers into the assessment pathway for mTBI may support clinical decision-making, reduce avoidable imaging, and improve triage in selected APAC emergency care settings when used as adjuncts to structured clinical assessment and established imaging pathways. Their potential value may be greatest in diagnostically challenging scenarios, such as anticoagulant use, intoxication, or unclear neurological status. These consensus statements are intended to support the definition, diagnosis, and biomarker-supported assessment of mTBI rather than provide a comprehensive management guideline. They provide a baseline for locally adapted protocols and future APAC-specific implementation and validation studies.

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

APAC

Asia-Pacific

CT

Computed tomography

ED

Emergency department

FDA

Food and Drug Administration

GCS

Glasgow Coma Scale

GFAP

Glial fibrillary acidic protein

ICU

Intensive care unit

MRI

Magnetic resonance imaging

mTBI

Mild traumatic brain injury

NSE

Neuron-specific enolase

S100B

S100 calcium-binding protein B

SBDPs

Spectrin breakdown products

TBI

Traumatic brain injury

UCH-L1

Ubiquitin carboxy-terminal hydrolase L1

Author contributions

W.S.K.: contributed to the conceptualization, data curation, formal analysis, investigation, methodology, project administration, supervision, validation, visualization, writing of the original draft and review and editing of the draft. K.V., M.J., K.M., K.C., Y.P., R.A.Z., J.A.C., and D.S.: contributed to the conceptualization, data curation, methodology, validation and review and edition of the final draft. B.M.: contributed to the conceptualization, data curation, formal analysis, methodology, project administration, supervision, validation, writing of the original draft and review and editing of the draft.

Funding

This study was supported by Abbott Laboratories.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

In accordance with the Declaration of Helsinki, the study protocol was reviewed and approved by the Monash University Human Research and Ethics Committee (Project ID 49108). Participation in the panel implied consent, and all panelists were co-investigators of the study.

Consent for publication

Not applicable.

Competing interests

W.S.K., K.V., K.M., and R.A.Z. received honoraria from Abbott Laboratories for their participation as expert panelists in this modified Delphi consensus process. All delegates were offered compensation for their time as expert panelists (not manuscript drafting) at an approved hourly rate; individual payments ranged from USD 0 to USD 2,400, with a total compensation amount of < USD 15,000 across all delegates. B.M. is an investigator on a research grant from Abbott Laboratories related to blood biomarkers for traumatic brain injury; the grant was paid to Monash University. The other authors declare no competing interests. All relevant financial relationships were disclosed before the consensus process, and voting was conducted anonymously using predefined consensus thresholds.