Defining paediatric reference intervals for a biomarker-based traumatic brain injury test

Problem addressed Over one million people attend UK emergency departments (ED) annually with mild traumatic brain injury (mTBI). Paediatrics (<16 years old) account for 33-50% of these attendances (1). Only 5-10% of children who undergo a CT-scan for mTBI will show intracranial lesions (ICLs) (2). ICLs can cause serious complications and require fast diagnosis. However, CT imaging is expensive, time-consuming and involves radiation exposure. Deciding when to scan or monitor a child with a mTBI remains a challenge for clinicians. Innovation Biomarkers released into the blood following a mTBI have shown high sensitivity in predicting the absence of ICLs on CT scans (3). The BioMérieux VIDAS®TBI (GFAP, UCH-L1) test is an automated, quantitative, enzyme-linked immunofluorescent assay for the measurement of serum biomarkers, GFAP and UCH-L1, that provides results within 40 minutes and is suitable for clinical use. The VIDAS®TBI test obtained a CE Mark in September 2023 to aid in determining the need for a CT scan in adults with suspected mTBI. A negative interpretation of VIDAS®TBI test is associated with the absence of acute ICLs visualized on a head CT scan. As this innovation advances TBI diagnosis, a form of acquired brain injury, it aligns with the scope of this call. Evidence to date UCH-L1 and GFAP, in combination, have shown high sensitivity and negative predictive value for ruling out the need for a CT scan in large adult cohorts with mTBI presenting at emergency departments (4,5). While data on GFAP and UCH-L1 in paediatrics with mTBI is limited, both biomarkers are raised in children with ICLs on a CT scan (6-8). No paediatric reference intervals have been established for UCH-L1, and only one study has evaluated GFAP in a healthy Danish paediatric cohort. In line with other brain biomarkers, GFAP levels were found to be strongly age-dependent in the healthy Danish pediatric cohort (9). Both GFAP and UCH-L1 serum levels have been shown to change with age in adults (5). Decision thresholds for using the BioMérieux VIDAS®TBI assay to rule out the need for CT scan will very likely need to be age-based in paediatrics. Establishing platform-specific age-dependent reference intervals in paediatrics will therefore be crucial for the approval of the assays for use in children and in interpreting the results of ongoing diagnostic accuracy trials in children with head injuries. PPI input and stakeholder engagement Prior to designing this study we sought support from BioMérieux who have provided a letter confirming that they will provide assays at no cost and that this research will inform future commercialisation plans for GFAP and UCH-L1 in children. In addition, 30 parents, children and young people were consulted; there was unanimous agreement that they would be happy to have reliable blood tests done to rule out the need for CT scans following a head injury. 87% also felt that, when possible, stored blood samples should be used to establish typical test values in healthy children instead of taking fresh blood samples from healthy children as this involved additional painful procedures.