A genome-wide association study of outcome from traumatic brain injury.

BACKGROUND: Factors 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. METHODS: We 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. FINDINGS: The 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). INTERPRETATION: While 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. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Association Between TBI-Related Hearing Impairment and Cognition: A TRACK-TBI Study.

OBJECTIVE: To examine the association between hearing impairment and cognitive function after traumatic brain injury (TBI). SETTING: A total of 18 level I trauma centers throughout the United States in the T ransforming R esearch a nd C linical K nowledge in TBI (TRACK-TBI) study. PARTICIPANTS: From February 2014 to June 2018, a total of 2697 participants with TBI were enrolled in TRACK-TBI. Key eligibility criteria included external force trauma to the head, presentation to a participating level I trauma center, and receipt of a clinically indicated head computed tomographic (CT) scan within 24 hours of injury. A total of 1267 participants were evaluated in the study, with 216 participants with hearing impairment and 1051 participants without hearing impairment. Those with missing or unknown hearing status or cognitive assessment were excluded from analysis. DESIGN: Prospective, observational cohort study. MAIN MEASURES: Hearing impairment at 2 weeks post-TBI was based on self-report. Participants who indicated worse hearing in one or both ears were defined as having hearing impairment, whereas those who denied worse hearing in either ear were defined as not having hearing impairment and served as the reference group. Cognitive outcomes at 6 months post-TBI included executive functioning and processing speed, as measured by the Trail Making Test (TMT) B/A and the Wechsler Adult Intelligence Scale, Fourth Edition, Processing Speed Index subscale (WAIS-IV PSI), respectively. RESULTS: TBI-related hearing impairment had a small but significantly greater TMT B/A ratio than without TBI-related hearing impairment: mean difference ( B ) = 0.25; 95% CI, 0.07 to 0.43; P = .005. No significant mean differences on WAIS-IV PSI scores were found between participants with and without TBI-related hearing impairment: B = 0.36; 95% CI, -2.07 to 2.60; P = .825. CONCLUSION: We conclude that TBI-related hearing impairment at 6 months postinjury was significantly associated with worse executive functioning but not cognitive processing speed.

FAIR Data Reuse in Traumatic Brain Injury: Exploring Inflammation and Age as Moderators of Recovery in the TRACK-TBI Pilot.

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.

An update on diagnostic and prognostic biomarkers for traumatic brain injury.

INTRODUCTION: Traumatic 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.

The diagnostic values of UCH-L1 in traumatic brain injury: A meta-analysis.

Traumatic brain injury (TBI) is a major health concern. The purpose of this study is to identify the diagnostic accuracy of ubiquitin C-terminal hydrolase-L1 (UCH-L1)-a protein biomarker-in comparison with CT-scan findings post-TBI. Accordingly, we conducted a systematic review of eligible studies and assessed the risk of bias according to the QUADAS-2 checklist. A total of 13 reports from 10 original studies were included. Based on our analysis, serum UCH-L1 has a high accuracy in predicting CT findings in mild to moderate TBI. Based on the QUADAS-2 checklist, this result has a high risk of bias affecting its applicability. The plasma level of UCH-L1 has moderate accuracy in predicting CT findings when assessed in all GCS levels. This result has a low risk of bias and low concerns regarding applicability. Pooled analysis suggests that the plasma/serum UCH-L1 level has high accuracy in predicting CT findings in a wide range of GCS in patients with TBI. This result has a high risk of bias and high concern about its applicability. The heterogeneity in approaching TBI biomarker interferes with drawing a definitive conclusion. Therefore, although UCH-L1 is a promising blood-based diagnostic biomarker for TBI, but due to differences in reported diagnostic accuracy, further studies are needed to recommend UCH-L1 as an alternative to CT scanning.

Prehospital Intubation is Associated with Favorable Outcomes and Lower Mortality in ProTECT III.

OBJECTIVE: Traumatic 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. METHODS: ProTECT 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. RESULTS: Favorable 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). CONCLUSIONS: In 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.

Continuous muscle tissue oxygenation in critically injured patients: a prospective observational study.

BACKGROUND: Despite normalization of vital signs, critically injured patients may remain in a state of occult underresuscitation that sets the stage for sepsis, organ failure, and death. A continuous, sensitive, and accurate measure of resuscitation after injury remains elusive. METHODS: In this pilot study, we evaluated the ability of two continuous measures of peripheral tissue oxygenation in their ability to detect hypoperfusion: the Licox polarographic tissue oxygen monitor (PmO2) and the InSpectra near-infrared spectrometer (StO2). We hypothesized that deltoid muscle tissue oxygenation measurements could detect patients in "occult shock" who are at increased risk for post-injury complications. The study was designed to (1) define values for PmO2 and StO2 in patients who by all standard measures appeared to be clinically resuscitated; (2) evaluate the relationship between PmO2, StO2 and other physiologic variables including mean arterial pressure (MAP), lactate and base deficit (BD); and (3) examine the relationship between early low tissue oxygen values and the subsequent development of infections and organ dysfunction. Licox probes were inserted into the deltoid muscle of critically injured patients after initial surgical and radiologic interventions, and transcutaneous StO2 monitors were applied over the same muscle bed. PmO2, StO2, and standard physiologic data were collected continuously using a multimodal bioinformatics system. RESULTS: Twenty-eight critically injured patients were enrolled in this study at admission to the intensive care unit (ICU). For patients who appeared to be well resuscitated (defined as MAP > or = 70 mm Hg, heart rate [HR] < or = 110 bpm, BD > or = -2, and partial pressure of arterial oxygen (PaO2) = 80 and 150 mm Hg), the mean PmO2 was 34 +/- 11 mm Hg and StO2 was 63 +/- 27%. There was a strong relationship between PmO2 and BD (p < 0.001) but no significant relationship between StO2 and BD. The relationship between PmO2 and StO2 was weak but statistically significant. Early low values of both PmO2 and StO2 identified patients at risk for infectious complications or multiple organ failure (MOF). In patients who were well resuscitated by standard continuous parameters (HR and MAP), low PmO2 during the first 24 hours after admission (PmO2 < or = 25 for at least 2 hours) was strongly associated with the development of infectious complications (Odds Ratio = 16.5, 95% CI 1.49 to 183, p = 0.02). CONCLUSIONS: PmO2 is a responsive, reliable and continuous monitor of changes in base deficit. Initial low values for either PmO2 or StO2 were associated with post-injury complications. PmO2 monitoring may be useful in identifying patients in the state of occult underresuscitation who remain at risk for developing infection and MOF.