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BackgroundFactors such as age, pre-injury health, and injury severity, account for less than 35% of outcome variability in traumatic brain injury (TBI). While some residual outcome variability may be attributable to genetic factors, published candidate gene association studies have often been underpowered and subject to publication bias.MethodsWe performed the first genome- and transcriptome-wide association studies (GWAS, TWAS) of genetic effects on outcome in TBI. The study population consisted of 5268 patients from prospective European and US studies, who attended hospital within 24 h of TBI, and satisfied local protocols for computed tomography.FindingsThe estimated heritability of TBI outcome was 0·26. GWAS revealed no genetic variants with genome-wide significance (p < 5 × 10-8), but identified 83 variants in 13 independent loci which met a lower pre-specified sub-genomic statistical threshold (p < 10-5). Similarly, none of the genes tested in TWAS met tissue-wide significance. An exploratory analysis of 75 published candidate variants associated with 28 genes revealed one replicable variant (rs1800450 in the MBL2 gene) which retained significance after correction for multiple comparison (p = 5·24 × 10-4).InterpretationWhile multiple novel loci reached less stringent thresholds, none achieved genome-wide significance. The overall heritability estimate, however, is consistent with the hypothesis that common genetic variation substantially contributes to inter-individual variability in TBI outcome. The meta-analytic approach to the GWAS and the availability of summary data allows for a continuous extension with additional cohorts as data becomes available.FundingA full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

The guiding principle for data stewardship dictates that data be FAIR: findable, accessible, interoperable, and reusable. Data reuse allows researchers to probe data that may have been originally collected for other scientific purposes in order to gain novel insights. The current study reuses the Transforming Research and Clinical Knowledge for Traumatic Brain Injury (TRACK-TBI) Pilot dataset to build upon prior findings and ask new scientific questions. Specifically, we have previously used a multivariate analytics approach to multianalyte serum protein data from the TRACK-TBI Pilot dataset to show that an inflammatory ensemble of biomarkers can predict functional outcome at 3 and 6 months post-TBI. We and others have shown that there are quantitative and qualitative changes in inflammation that come with age, but little is known about how this interaction affects recovery from TBI. Here we replicate the prior proteomics findings with improved missing value analyses and non-linear principal component analysis and then expand upon this work to determine whether age moderates the effect of inflammation on recovery. We show that increased age correlates with worse functional recovery on the Glasgow Outcome Scale-Extended (GOS-E) as well as increased inflammatory signature. We then explore the interaction between age and inflammation on recovery, which suggests that inflammation has a more detrimental effect on recovery for older TBI patients.

IntroductionTraumatic brain injury (TBI) is a major worldwide neurological disorder of epidemic proportions. To date, there are still no FDA-approved therapies to treat any forms of TBI. Encouragingly, there are emerging data showing that biofluid-based TBI biomarker tests have the potential to diagnose the presence of TBI of different severities including concussion, and to predict outcome. Areas covered: The authors provide an update on the current knowledge of TBI biomarkers, including protein biomarkers for neuronal cell body injury (UCH-L1, NSE), astroglial injury (GFAP, S100B), neuronal cell death (αII-spectrin breakdown products), axonal injury (NF proteins), white matter injury (MBP), post-injury neurodegeneration (total Tau and phospho-Tau), post-injury autoimmune response (brain antigen-targeting autoantibodies), and other emerging non-protein biomarkers. The authors discuss biomarker evidence in TBI diagnosis, outcome prognosis and possible identification of post-TBI neurodegernative diseases (e.g. chronic traumatic encephalopathy and Alzheimer's disease), and as theranostic tools in pre-clinical and clinical settings. Expert commentary: A spectrum of biomarkers is now at or near the stage of formal clinical validation of their diagnostic and prognostic utilities in the management of TBI of varied severities including concussions. TBI biomarkers could serve as a theranostic tool in facilitating drug development and treatment monitoring.

ObjectiveTraumatic brain injury (TBI) causes more than 2.5 million emergency department visits, hospitalizations, or deaths annually. Prehospital endotracheal intubation has been associated with poor outcomes in patients with TBI in several retrospective observational studies. We evaluated the relationship between prehospital intubation, functional outcomes, and mortality using high quality data on clinical practice collected prospectively during a randomized multicenter clinical trial.MethodsProTECT III was a multicenter randomized, double-blind, placebo-controlled trial of early administration of progesterone in 882 patients with acute moderate to severe nonpenetrating TBI. Patients were excluded if they had an index GCS of 3 and nonreactive pupils, those with withdrawal of life support on arrival, and if they had documented prolonged hypotension and/or hypoxia. Prehospital intubation was performed as per local clinical protocol in each participating EMS system. Models for favorable outcome and mortality included prehospital intubation, method of transport, index GCS, age, race, and ethnicity as independent variables. Significance was set at α = 0.05. Favorable outcome was defined by a stratified dichotomy of the GOS-E scores in which the definition of favorable outcome depended on the severity of the initial injury.ResultsFavorable outcome was more frequent in the 349 subjects with prehospital intubation (57.3%) than in the other 533 patients (46.0%, p = 0.003). Mortality was also lower in the prehospital intubation group (13.8% v. 19.5%, p = 0.03). Logistic regression analysis of prehospital intubation and mortality, adjusted for index GCS, showed that odds of dying for those with prehospital intubation were 47% lower than for those that were not intubated (OR = 0.53, 95% CI = 0.36-0.78). 279 patients with prehospital intubation were transported by air. Modeling transport method and mortality, adjusted for index GCS, showed increased odds of dying in those transported by ground compared to those transported by air (OR = 2.10, 95% CI = 1.40-3.15). Decreased odds of dying trended among those with prehospital intubation adjusted for transport method, index GCS score at randomization, age, and race/ethnicity (OR = 0.70, 95% CI = 0.37-1.31).ConclusionsIn this study that excluded moribund patients, prehospital intubation was performed primarily in patients transported by air. Prehospital intubation and air medical transport together were associated with favorable outcomes and lower mortality. Prehospital intubation was not associated with increased morbidity or mortality regardless of transport method or severity of injury.