An outlier analysis for acute blood biomarkers of moderate and severe traumatic brain injury

Abstract

Blood biomarkers have been studied to improve the clinical assessment and prognostication of patients with moderate– severe traumatic brain injury (mo/sTBI). To assess their clinical usability, one needs to know potential factors that might cause outlier values and affect clinical decision-making. In a prospective study we recruited patients with mo/sTBI (n = 85) and measured the blood levels of eight protein brain pathophysiology biomarkers, including glial fibrillary acidic protein (GFAP), S100 calcium-binding protein B (S100B), neurofilament light (NF-L), heart-type fatty acid-binding protein (H-FABP), interleukin-10 (IL-10), total tau (T-tau), amyloid β40 (Aβ40) and amyloid β42 (Aβ42), within 24h of admission. Similar analyses were conducted for controls (n = 40) with an acute orthopedic injury without any head trauma. The patients with TBI were divided into subgroups of normal vs. abnormal (n = 9/76) head computed tomography (CT) and favorable (Glasgow Outcome Scale Extended = GOSE 5-8) vs. unfavorable (GOSE < 5) (n = 38/42, 5 missing) outcome. Outliers were sought individually from all subgroups and the whole TBI patient population. Biomarker levels outside Q1 −1.5 IQR or Q3 +1.5 IQR were considered as outliers. The medical records of each outlier patient were reviewed in a team meeting to determine possible reasons for outlier values. A total of 29 patients (34%) combined from all subgroups and 12 patients (30%) among the controls showed outlier values for one or more of the eight biomarkers. 9 patients with TBI and 5 control patients had outlier values in more than one biomarker (up to 4). All outlier values were higher than Q3 +1.5 IQR. A logical explanation was found for almost all cases, except the amyloid proteins. Explanations for outlier values included extremely severe injury, especially for GFAP and S100B. In case of H-FABP and IL-10 the explanation was extracranial injuries (thoracic injuries for H-FABP and multi-trauma for IL-10), in some cases these also associated with abnormally high S100B. Timing of sampling and demographic factors such as age and pre-existing neurological conditions (esp. for T-tau), explained some of the abnormally high values especially for NF-L. Similar explanations also emerged in controls, where the outlier values were caused especially by pre-existing neurological diseases. To utilize blood-based biomarkers in clinical assessment of mo/sTBI, very severe or fatal TBIs, various extracranial injuries, timing of sampling and demographic factors such as age and pre-existing systemic or neurological conditions must be taken into consideration. Very high levels seem to be often associated with poor prognosis and mortality (GFAP and S100B).