Comparative Diagnostic Accuracy of S100B, GFAP, and UCH-L1 for Predicting Neurosurgical Intervention in Traumatic Brain Injury: A Scoping Review Protocol

Traumatic brain injury (TBI) is a major global health burden, with millions of emergency department visits annually. A critical clinical challenge is determining which patients with mild-to-moderate TBI require neurosurgical intervention. Current practice relies heavily on CT imaging, which is resource-intensive, costly, and exposes patients to ionising radiation. Blood-based biomarkers have emerged as potential triage tools to complement or reduce reliance on CT, with three candidates—S100B, GFAP, and UCH-L1—receiving regulatory approval in Europe and the United States. Despite growing literature, the evidence base has notable limitations. First, most meta-analyses use CT positivity as the primary outcome, which does not directly reflect neurosurgical need. Second, biomarker performance is biologically influenced by age, yet few studies stratify results across paediatric, adult, and elderly populations. Third, sex-specific differences in biomarker release and diagnostic accuracy remain largely unexplored, despite plausible biological mechanisms and emerging evidence in concussion research. This scoping review will systematically map the existing evidence on the diagnostic accuracy of S100B, GFAP, and UCH-L1 for predicting neurosurgical intervention in TBI. Using the PCC framework, we will include studies across all ages and settings, focusing on neurosurgical outcomes as the primary endpoint, while also capturing secondary outcomes such as CT positivity, clinically important TBI composites, functional outcomes, and mortality. The purpose of this project is to provide a comprehensive overview of the current evidence landscape, identify the extent to which age and sex stratification have been addressed, and highlight head-to-head comparisons of biomarkers where available. Expected outcomes include: - A mapped summary of studies reporting biomarker accuracy for neurosurgical intervention. - Documentation of whether and how age and sex differences are considered. - Identification of evidence gaps and methodological limitations. - A proposed research agenda to guide future primary studies and meta-analyses. By clarifying what is known and unknown, this review will inform clinicians, researchers, and policymakers about the readiness of blood-based biomarkers for clinical triage in TBI, and provide a foundation for more targeted systematic reviews and evidence-based practice.