Performance of the IMPACT and CRASH prognostic models for traumatic brain injury in a contemporary multicenter cohort: a TRACK-TBI study.

OBJECTIVE: The International Mission on Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (IMPACT) and Corticosteroid Randomization After Significant Head Injury (CRASH) prognostic models for mortality and outcome after traumatic brain injury (TBI) were developed using data from 1984 to 2004. This study examined IMPACT and CRASH model performances in a contemporary cohort of US patients. METHODS: The prospective 18-center Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study (enrollment years 2014-2018) enrolled subjects aged ≥ 17 years who presented to level I trauma centers and received head CT within 24 hours of TBI. Data were extracted from the subjects who met the model criteria (for IMPACT, Glasgow Coma Scale [GCS] score 3-12 with 6-month Glasgow Outcome Scale-Extended [GOSE] data [n = 441]; for CRASH, GCS score 3-14 with 2-week mortality data and 6-month GOSE data [n = 831]). Analyses were conducted in the overall cohort and stratified on the basis of TBI severity (severe/moderate/mild TBI defined as GCS score 3-8/9-12/13-14), age (17-64 years or ≥ 65 years), and the 5 top enrolling sites. Unfavorable outcome was defined as GOSE score 1-4. Original IMPACT and CRASH model coefficients were applied, and model performances were assessed by calibration (intercept [< 0 indicated overprediction; > 0 indicated underprediction] and slope) and discrimination (c-statistic). RESULTS: Overall, the IMPACT models overpredicted mortality (intercept -0.79 [95% CI -1.05 to -0.53], slope 1.37 [1.05-1.69]) and acceptably predicted unfavorable outcome (intercept 0.07 [-0.14 to 0.29], slope 1.19 [0.96-1.42]), with good discrimination (c-statistics 0.84 and 0.83, respectively). The CRASH models overpredicted mortality (intercept -1.06 [-1.36 to -0.75], slope 0.96 [0.79-1.14]) and unfavorable outcome (intercept -0.60 [-0.78 to -0.41], slope 1.20 [1.03-1.37]), with good discrimination (c-statistics 0.92 and 0.88, respectively). IMPACT overpredicted mortality and acceptably predicted unfavorable outcome in the severe and moderate TBI subgroups, with good discrimination (c-statistic ≥ 0.81). CRASH overpredicted mortality in the severe and moderate TBI subgroups and acceptably predicted mortality in the mild TBI subgroup, with good discrimination (c-statistic ≥ 0.86); unfavorable outcome was overpredicted in the severe and mild TBI subgroups with adequate discrimination (c-statistic ≥ 0.78), whereas calibration was nonlinear in the moderate TBI subgroup. In subjects ≥ 65 years of age, the models performed variably (IMPACT-mortality, intercept 0.28, slope 0.68, and c-statistic 0.68; CRASH-unfavorable outcome, intercept -0.97, slope 1.32, and c-statistic 0.88; nonlinear calibration for IMPACT-unfavorable outcome and CRASH-mortality). Model performance differences were observed across the top enrolling sites for mortality and unfavorable outcome. CONCLUSIONS: The IMPACT and CRASH models adequately discriminated mortality and unfavorable outcome. Observed overestimations of mortality and unfavorable outcome underscore the need to update prognostic models to incorporate contemporary changes in TBI management and case-mix. Investigations to elucidate the relationships between increased survival, outcome, treatment intensity, and site-specific practices will be relevant to improve models in specific TBI subpopulations (e.g., older adults), which may benefit from the inclusion of blood-based biomarkers, neuroimaging features, and treatment data.

MaPPeRTrac: A Massively Parallel, Portable, and Reproducible Tractography Pipeline.

Large-scale diffusion MRI tractography remains a significant challenge. Users must orchestrate a complex sequence of instructions that requires many software packages with complex dependencies and high computational costs. We developed MaPPeRTrac, an edge-centric tractography pipeline that simplifies and accelerates this process in a wide range of high-performance computing (HPC) environments. It fully automates either probabilistic or deterministic tractography, starting from a subject's magnetic resonance imaging (MRI) data, including structural and diffusion MRI images, to the edge density image (EDI) of their structural connectomes. Dependencies are containerized with Singularity (now called Apptainer) and decoupled from code to enable rapid prototyping and modification. Data derivatives are organized with the Brain Imaging Data Structure (BIDS) to ensure that they are findable, accessible, interoperable, and reusable following FAIR principles. The pipeline takes full advantage of HPC resources using the Parsl parallel programming framework, resulting in the creation of connectome datasets of unprecedented size. MaPPeRTrac is publicly available and tested on commercial and scientific hardware, so it can accelerate brain connectome research for a broader user community. MaPPeRTrac is available at: https://github.com/LLNL/mappertrac .

Isolated Traumatic Subarachnoid Hemorrhage on Head Computed Tomography Scan May Not Be Isolated: A TRACK-TBI Study.

Isolated traumatic subarachnoid hemorrhage (tSAH) after traumatic brain injury (TBI) on head computed tomography (CT) scan is often regarded as a "mild" injury, with reduced need for additional workup. However, tSAH is also a predictor of incomplete recovery and unfavorable outcome. This study aimed to evaluate the characteristics of CT-occult intracranial injuries on brain magnetic resonance imaging (MRI) scan in TBI patients with emergency department (ED) arrival Glasgow Coma Scale (GCS) score 13-15 and isolated tSAH on CT. The prospective, 18-center Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study (TRACK-TBI; enrollment years 2014-2019) enrolled participants who presented to the ED and received a clinically-indicated head CT within 24 hours (h) of TBI. A subset of TRACK-TBI participants underwent venipuncture within 24h for plasma glial fibrillary acidic protein (GFAP) analysis, and research MRI at 2-weeks post-injury. In the current study, TRACK-TBI participants aged ≥17 years with ED arrival GCS 13-15, isolated tSAH on initial head CT, plasma GFAP level, and 2-week MRI data were analyzed. In 57 participants, median age was 46.0 years [quartile 1 to 3 (Q1-Q3): 34-57] and 52.6% were male. At ED disposition, 12.3% were discharged home, 61.4% were admitted to hospital ward, and 26.3% to intensive care unit. MRI identified CT-occult traumatic intracranial lesions in 45.6% (26 of 57 participants; 1 additional lesion type: 31.6%; 2 additional lesion types: 14.0%); of these 26 participants with CT-occult intracranial lesions, 65.4% had axonal injury, 42.3% had subdural hematoma, and 23.1% had intracerebral contusion. GFAP levels were higher in participants with CT-occult MRI lesions compared to without (median: 630.6 pg/ml, Q1-Q3: [172.4-941.2] vs. 226.4 [105.8-436.1], p=0.049), and were associated with axonal injury (no: median 226.7 pg/ml [109.6-435.1], yes: 828.6 pg/ml [204.0-1194.3], p=0.009). Our results indicate that isolated tSAH on head CT is often not the sole intracranial traumatic injury in GCS 13-15 TBI. Forty-six percent of patients in our cohort (26 of 57 participants) had additional CT-occult traumatic lesions on MRI. Plasma GFAP may be an important biomarker for the identification of additional CT-occult injuries, including axonal injury. These findings should be interpreted cautiously given our modest sample size and await validation from larger studies.

Diagnostic Utility of Glial Fibrillary Acidic Protein Beyond 12 Hours After Traumatic Brain Injury: A TRACK-TBI Study.

Blood levels of glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1) within 12h of suspected traumatic brain injury (TBI) have been approved by the Food and Drug administration to aid in determining the need for a brain computed tomography (CT) scan. The current study aimed to determine whether this context of use can be expanded beyond 12h post-TBI in patients presenting with Glasgow Coma Scale (GCS) 13-15. The prospective, 18-center Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study enrolled TBI participants aged ≥17 years who presented to a United States Level 1 trauma center and received a clinically indicated brain CT scan within 24h post-injury, a blood draw within 24h and at 14 days for biomarker analysis. Data from participants with emergency department arrival GCS 13-15 and biomarker values at days 1 and 14 were extracted for the primary analysis. A subgroup of hospitalized participants with serial biomarkers at days 1, 3, 5, and 14 were analyzed, including plasma GFAP and UCH-L1, and serum neuron-specific enolase (NSE) and S100 calcium-binding protein B (S100B). The primary analysis compared biomarker values dichotomized by head CT results (CT+/CT-). Area under receiver-operating characteristic curve (AUC) was used to determine diagnostic accuracy. The overall cohort included 1142 participants with initial GCS 13-15, with mean age 39.8 years, 65% male, and 73% Caucasian. The GFAP provided good discrimination in the overall cohort at days 1 (AUC = 0.82) and 14 (AUC = 0.72), and in the hospitalized subgroup at days 1 (AUC = 0.84), 3 (AUC = 0.88), 5 (AUC = 0.82), and 14 (AUC = 0.74). The UCH-L1, NSE, and S100B did not perform well (AUC = 0.51-0.57 across time points). This study demonstrates the utility of GFAP to aid in decision-making for diagnostic brain CT imaging beyond the 12h time frame in patients with TBI who have a GCS 13-15.

Data-driven distillation and precision prognosis in traumatic brain injury with interpretable machine learning.

Traumatic brain injury (TBI) affects how the brain functions in the short and long term. Resulting patient outcomes across physical, cognitive, and psychological domains are complex and often difficult to predict. Major challenges to developing personalized treatment for TBI include distilling large quantities of complex data and increasing the precision with which patient outcome prediction (prognoses) can be rendered. We developed and applied interpretable machine learning methods to TBI patient data. We show that complex data describing TBI patients' intake characteristics and outcome phenotypes can be distilled to smaller sets of clinically interpretable latent factors. We demonstrate that 19 clusters of TBI outcomes can be predicted from intake data, a ~ 6× improvement in precision over clinical standards. Finally, we show that 36% of the outcome variance across patients can be predicted. These results demonstrate the importance of interpretable machine learning applied to deeply characterized patients for data-driven distillation and precision prognosis.

Clinical Outcomes After Traumatic Brain Injury and Exposure to Extracranial Surgery: A TRACK-TBI Study.

Importance: Traumatic brain injury (TBI) is associated with persistent functional and cognitive deficits, which may be susceptible to secondary insults. The implications of exposure to surgery and anesthesia after TBI warrant investigation, given that surgery has been associated with neurocognitive disorders. Objective: To examine whether exposure to extracranial (EC) surgery and anesthesia is related to worse functional and cognitive outcomes after TBI. Design, Setting, and Participants: This study was a retrospective, secondary analysis of data from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study, a prospective cohort study that assessed longitudinal outcomes of participants enrolled at 18 level I US trauma centers between February 1, 2014, and August 31, 2018. Participants were 17 years or older, presented within 24 hours of trauma, were admitted to an inpatient unit from the emergency department, had known Glasgow Coma Scale (GCS) and head computed tomography (CT) status, and did not undergo cranial surgery. This analysis was conducted between January 2, 2020, and August 8, 2023. Exposure: Participants who underwent EC surgery during the index admission were compared with participants with no surgery in groups with a peripheral orthopedic injury or a TBI and were classified as having uncomplicated mild TBI (GCS score of 13-15 and negative CT results [CT- mTBI]), complicated mild TBI (GCS score of 13-15 and positive CT results [CT+ mTBI]), or moderate to severe TBI (GCS score of 3-12 [m/sTBI]). Main Outcomes and Measures: The primary outcomes were functional limitations quantified by the Glasgow Outcome Scale-Extended for all injuries (GOSE-ALL) and brain injury (GOSE-TBI) and neurocognitive outcomes at 2 weeks and 6 months after injury. Results: A total of 1835 participants (mean [SD] age, 42.2 [17.8] years; 1279 [70%] male; 299 Black, 1412 White, and 96 other) were analyzed, including 1349 nonsurgical participants and 486 participants undergoing EC surgery. The participants undergoing EC surgery across all TBI severities had significantly worse GOSE-ALL scores at 2 weeks and 6 months compared with their nonsurgical counterparts. At 6 months after injury, m/sTBI and CT+ mTBI participants who underwent EC surgery had significantly worse GOSE-TBI scores (B = -1.11 [95% CI, -1.53 to -0.68] in participants with m/sTBI and -0.39 [95% CI, -0.77 to -0.01] in participants with CT+ mTBI) and performed worse on the Trail Making Test Part B (B = 30.1 [95% CI, 11.9-48.2] in participants with m/sTBI and 26.3 [95% CI, 11.3-41.2] in participants with CT+ mTBI). Conclusions and Relevance: This study found that exposure to EC surgery and anesthesia was associated with adverse functional outcomes and impaired executive function after TBI. This unfavorable association warrants further investigation of the potential mechanisms and clinical implications that could inform decisions regarding the timing of surgical interventions in patients after TBI.

Association of Early Dexmedetomidine Utilization With Clinical and Functional Outcomes Following Moderate-Severe Traumatic Brain Injury: A Transforming Clinical Research and Knowledge in Traumatic Brain Injury Study.

OBJECTIVE: To examine early sedation patterns, as well as the association of dexmedetomidine exposure, with clinical and functional outcomes among mechanically ventilated patients with moderate-severe traumatic brain injury (msTBI). DESIGN: Retrospective cohort study with prospectively collected data. SETTING: Eighteen Level-1 Trauma Centers, United States. PATIENTS: Adult (age > 17) patients with msTBI (as defined by Glasgow Coma Scale < 13) who required mechanical ventilation from the Transforming Clinical Research and Knowledge in TBI (TRACK-TBI) study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Using propensity-weighted models, we examined the association of early dexmedetomidine exposure (within the first 5 d of ICU admission) with the primary outcome of 6-month Glasgow Outcomes Scale Extended (GOS-E) and the following secondary outcomes: length of hospital stay, hospital mortality, 6-month Disability Rating Scale (DRS), and 6-month mortality. The study population included 352 subjects who required mechanical ventilation within 24 hours of admission. The initial sedative medication was propofol for 240 patients (68%), midazolam for 59 patients (17%), ketamine for 6 patients (2%), dexmedetomidine for 3 patients (1%), and 43 patients (12%) never received continuous sedation. Early dexmedetomidine was administered in 77 of the patients (22%), usually as a second-line agent. Compared with unexposed patients, early dexmedetomidine exposure was not associated with better 6-month GOS-E (weighted odds ratio [OR] = 1.48; 95% CI, 0.98-2.25). Early dexmedetomidine exposure was associated with lower DRS (weighted OR = -3.04; 95% CI, -5.88 to -0.21). In patients requiring ICP monitoring within the first 24 hours of admission, early dexmedetomidine exposure was associated with higher 6-month GOS-E score (OR 2.17; 95% CI, 1.24-3.80), lower DRS score (adjusted mean difference, -5.81; 95% CI, -9.38 to 2.25), and reduced length of hospital stay (hazard ratio = 1.50; 95% CI, 1.02-2.20). CONCLUSION: Variation exists in early sedation choice among mechanically ventilated patients with msTBI. Early dexmedetomidine exposure was not associated with improved 6-month functional outcomes in the entire population, although may have clinical benefit in patients with indications for ICP monitoring.

Association of Early Beta-Blocker Exposure and Functional Outcomes in Critically Ill Patients With Moderate to Severe Traumatic Brain Injury: A Transforming Clinical Research and Knowledge in Traumatic Brain Injury Study.

OBJECTIVES: We aimed to 1) describe patterns of beta-blocker utilization among critically ill patients following moderate-severe traumatic brain injury (TBI) and 2) examine the association of early beta-blocker exposure with functional and clinical outcomes following injury. DESIGN: Retrospective cohort study. SETTING: ICUs at 18 level I, U.S. trauma centers in the Transforming Clinical Research and Knowledge in TBI (TRACK-TBI) study. PATIENTS: Greater than or equal to 17 years enrolled in the TRACK-TBI study with moderate-severe TBI (Glasgow Coma Scale of <13) were admitted to the ICU after a blunt TBI. INTERVENTIONS: None. MEASUREMENTS: Primary exposure was a beta blocker during the first 7 days in the ICU, with a primary outcome of 6-month Glasgow Outcome Scale-Extended (GOSE). Secondary outcomes included: length of hospital stay, in-hospital mortality, 6-month and 12-month mortality, 12-month GOSE score, and 6-month and 12-month measures of disability, well-being, quality of life, and life satisfaction. MAIN RESULTS: Of the 450 eligible participants, 57 (13%) received early beta blockers (BB+ group). The BB+ group was on average older, more likely to be on a preinjury beta blocker, and more likely to have a history of hypertension. In the BB+ group, 34 participants (60%) received metoprolol only, 19 participants (33%) received propranolol only, 3 participants (5%) received both, and 1 participant (2%) received atenolol only. In multivariable regression, there was no difference in the odds of a higher GOSE score at 6 months between the BB+ group and BB- group (odds ratio = 0.86; 95% CI, 0.48-1.53). There was no association between BB exposure and secondary outcomes. CONCLUSIONS: About one-sixth of subjects in our study received early beta blockers, and within this group, dose, and timing of beta-blocker administration varied substantially. No significant differences in GOSE score at 6 months were demonstrated, although our ability to draw conclusions is limited by overall low total doses administered compared with prior studies.

Longitudinal Recovery Following Repetitive Traumatic Brain Injury.

Importance: One traumatic brain injury (TBI) increases the risk of subsequent TBIs. Research on longitudinal outcomes of civilian repetitive TBIs is limited. Objective: To investigate associations between sustaining 1 or more TBIs (ie, postindex TBIs) after study enrollment (ie, index TBIs) and multidimensional outcomes at 1 year and 3 to 7 years. Design, Setting, and Participants: This cohort study included participants presenting to emergency departments enrolled within 24 hours of TBI in the prospective, 18-center Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study (enrollment years, February 2014 to July 2020). Participants who completed outcome assessments at 1 year and 3 to 7 years were included. Data were analyzed from September 2022 to August 2023. Exposures: Postindex TBI(s). Main Outcomes and Measures: Demographic and clinical factors, prior TBI (ie, preindex TBI), and functional (Glasgow Outcome Scale-Extended [GOSE]), postconcussive (Rivermead Post-Concussion Symptoms Questionnaire [RPQ]), psychological distress (Brief Symptom Inventory-18 [BSI-18]), depressive (Patient Health Questionnaire-9 [PHQ-9]), posttraumatic stress disorder (PTSD; PTSD Checklist for DSM-5 [PCL-5]), and health-related quality-of-life (Quality of Life After Brain Injury-Overall Scale [QOLIBRI-OS]) outcomes were assessed. Adjusted mean differences (aMDs) and adjusted relative risks are reported with 95% CIs. Results: Of 2417 TRACK-TBI participants, 1572 completed the outcomes assessment at 1 year (1049 [66.7%] male; mean [SD] age, 41.6 [17.5] years) and 1084 completed the outcomes assessment at 3 to 7 years (714 [65.9%] male; mean [SD] age, 40.6 [17.0] years). At 1 year, a total of 60 participants (4%) were Asian, 255 (16%) were Black, 1213 (77%) were White, 39 (2%) were another race, and 5 (0.3%) had unknown race. At 3 to 7 years, 39 (4%) were Asian, 149 (14%) were Black, 868 (80%) were White, 26 (2%) had another race, and 2 (0.2%) had unknown race. A total of 50 (3.2%) and 132 (12.2%) reported 1 or more postindex TBIs at 1 year and 3 to 7 years, respectively. Risk factors for postindex TBI were psychiatric history, preindex TBI, and extracranial injury severity. At 1 year, compared with those without postindex TBI, participants with postindex TBI had worse functional recovery (GOSE score of 8: adjusted relative risk, 0.57; 95% CI, 0.34-0.96) and health-related quality of life (QOLIBRI-OS: aMD, -15.9; 95% CI, -22.6 to -9.1), and greater postconcussive symptoms (RPQ: aMD, 8.1; 95% CI, 4.2-11.9), psychological distress symptoms (BSI-18: aMD, 5.3; 95% CI, 2.1-8.6), depression symptoms (PHQ-9: aMD, 3.0; 95% CI, 1.5-4.4), and PTSD symptoms (PCL-5: aMD, 7.8; 95% CI, 3.2-12.4). At 3 to 7 years, these associations remained statistically significant. Multiple (2 or more) postindex TBIs were associated with poorer outcomes across all domains. Conclusions and Relevance: In this cohort study of patients with acute TBI, postindex TBI was associated with worse symptomatology across outcome domains at 1 year and 3 to 7 years postinjury, and there was a dose-dependent response with multiple postindex TBIs. These results underscore the critical need to provide TBI prevention, education, counseling, and follow-up care to at-risk patients.

Association Between Insomnia and Mental Health and Neurocognitive Outcomes Following Traumatic Brain Injury.

We previously described five trajectories of insomnia (each defined by a distinct pattern of insomnia severity over 12 months following traumatic brain injury [TBI]). Our objective in the present study was to estimate the association between insomnia trajectory status and trajectories of mental health and neurocognitive outcomes during the 12 months after TBI. In this study, participants included N = 2022 adults from the Federal Inter-agency Traumatic Brain Injury Repository database and Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. The following outcome measures were assessed serially at 2 weeks, and 3, 6, and 12 months post-injury: Insomnia Severity Index, Patient Health Questionnaire, Post-Traumatic Stress Disorder (PTSD) Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), Patient Reported Outcomes Measurement Information System-Pain, and Quality of Life After Brain Injury-Overall Scale. Neurocognitive performance was assessed at 2 weeks, and 6 and 12 months using the Wechsler Adult Intelligence Scales Processing Speed Index and the Trails Making Test Parts A and B. Results indicated that greater insomnia severity was associated with greater abnormality in mental health, quality of life, and neuropsychological testing outcomes. The pattern of insomnia over time tracked the temporal pattern of all these outcomes for all but a very small number of participants. Notably, severe insomnia at 3 or 6 months post-TBI was a risk factor for poor recovery at 12 months post-injury. In conclusion, in this well-characterized sample of individuals with TBI, insomnia severity generally tracked severity of depression, pain, PTSD, quality of life, and neurocognitive outcomes over 12 months post-injury. More intensive sleep assessment is needed to elucidate the nature of these relationships and to help inform best strategies for intervention.

Predicting Functional Dependency in Patients with Disorders of Consciousness: A TBI-Model Systems and TRACK-TBI Study.

OBJECTIVE: It is not currently possible to predict long-term functional dependency in patients with disorders of consciousness (DoC) after traumatic brain injury (TBI). Our objective was to fit and externally validate a prediction model for 1-year dependency in patients with DoC ≥ 2 weeks after TBI. METHODS: We included adults with TBI enrolled in TBI Model Systems (TBI-MS) or Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) studies who were not following commands at rehabilitation admission or 2 weeks post-injury, respectively. We fit a logistic regression model in TBI-MS and validated it in TRACK-TBI. The primary outcome was death or dependency at 1 year post-injury, defined using the Disability Rating Scale. RESULTS: In the TBI-MS Discovery Sample, 1,960 participants (mean age 40 [18] years, 76% male, 68% white) met inclusion criteria, and 406 (27%) were dependent 1 year post-injury. In a TBI-MS held out cohort, the dependency prediction model's area under the receiver operating characteristic curve was 0.79 (95% CI 0.74-0.85), positive predictive value was 53% and negative predictive value was 86%. In the TRACK-TBI external validation (n = 124, age 40 [16] years, 77% male, 81% white), the area under the receiver operating characteristic curve was 0.66 (0.53, 0.79), equivalent to the standard IMPACTcore + CT score (p = 0.8). INTERPRETATION: We developed a 1-year dependency prediction model using the largest existing cohort of patients with DoC after TBI. The sensitivity and negative predictive values were greater than specificity and positive predictive values. Accuracy was diminished in an external sample, but equivalent to the IMPACT model. Further research is needed to improve dependency prediction in patients with DoC after TBI. ANN NEUROL 2023;94:1008-1023.

Integrating, Harmonizing, and Curating Studies With High-Frequency and Hourly Physiological Data: Proof of Concept from Seven Traumatic Brain Injury Data Sets.

Research in severe traumatic brain injury (TBI) has historically been limited by studies with relatively small sample sizes that result in low power to detect small, yet clinically meaningful outcomes. Data sharing and integration from existing sources hold promise to yield larger more robust sample sizes that improve the potential signal and generalizability of important research questions. However, curation and harmonization of data of different types and of disparate provenance is challenging. We report our approach and experience integrating multiple TBI data sets containing collected physiological data, including both expected and unexpected challenges encountered in the integration process. Our harmonized data set included data on 1536 patients from the Citicoline Brain Injury Treatment Trial (COBRIT), Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial (EPO Severe TBI), BEST-TRIP, Progesterone for the Treatment of Traumatic Brain Injury III Clinical Trial (ProTECT III), Transforming Research and Clinical Knowledge in Traumatic brain Injury (TRACK-TBI), Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase-II (BOOST-2), and Ben Taub General Hospital (BTGH) Research Database studies. We conclude with process recommendations for data acquisition for future prospective studies to aid integration of these data with existing studies. These recommendations include using common data elements whenever possible, a standardized recording system for labeling and timing of high-frequency physiological data, and secondary use of studies in systems such as Federal Interagency Traumatic Brain Injury Research Informatics System (FITBIR), to engage investigators who collected the original data.

Functional Recovery, Symptoms, and Quality of Life 1 to 5 Years After Traumatic Brain Injury.

Importance: Many level I trauma center patients experience clinical sequelae at 1 year following traumatic brain injury (TBI). Longer-term outcome data are needed to develop better monitoring and rehabilitation services. Objective: To examine functional recovery, TBI-related symptoms, and quality of life from 1 to 5 years postinjury. Design, Setting, and Participants: This cohort study enrolled trauma patients across 18 US level I trauma centers between 2014 and 2018. Eligible participants were enrolled within 24 hours of injury and followed up to 5 years postinjury. Data were analyzed January 2023. Exposures: Mild TBI (mTBI), moderate-severe TBI (msTBI), or orthopedic traumatic controls (OTC). Main Outcomes and Measures: Functional independence (Glasgow Outcome Scale-Extended [GOSE] score 5 or higher), complete functional recovery (GOSE score, 8), better (ie, lower) TBI-related symptom burden (Rivermead Post Concussion Symptoms Questionnaire score of 15 or lower), and better (ie, higher) health-related quality of life (Quality of Life After Brain Injury Scale-Overall Scale score 52 or higher); mortality was analyzed as a secondary outcome. Results: A total 1196 patients were included in analysis (mean [SD] age, 40.8 [16.9] years; 781 [65%] male; 158 [13%] Black, 965 [81%] White). mTBI and OTC groups demonstrated stable, high rates of functional independence (98% to 100% across time). While odds of independence were lower among msTBI survivors, the majority were independent at 1 year (72%), and this proportion increased over time (80% at 5 years; group × year, P = .005; independence per year: odds ratio [OR] for msTBI, 1.28; 95% CI, 1.03-1.58; OR for mTBI, 0.81; 95% CI, 0.64-1.03). For other outcomes, group differences at 1 year remained stable over time (group × year, P ≥ .44). Odds of complete functional recovery remained lower for persons with mTBI vs OTC (OR, 0.39; 95% CI, 0.28-0.56) and lower for msTBI vs mTBI (OR, 0.34; 95% CI, 0.24-0.48). Odds of better TBI-related symptom burden and quality of life were similar for both TBI subgroups and lower than OTCs. Mortality between 1 and 5 years was higher for msTBI (5.5%) than mTBI (1.5%) and OTC (0.7%; P = .02). Conclusions and Relevance: In this cohort study, patients with previous msTBI displayed increased independence over 5 years; msTBI was also associated with increased mortality. These findings, in combination with the persistently elevated rates of unfavorable outcomes in mTBI vs controls imply that more monitoring and rehabilitation are needed for TBI.

Predicting Functional Dependency in Patients with Disorders of Consciousness: A TBI-Model Systems and TRACK-TBI Study.

Importance: There are currently no models that predict long-term functional dependency in patients with disorders of consciousness (DoC) after traumatic brain injury (TBI). Objective: Fit, test, and externally validate a prediction model for 1-year dependency in patients with DoC 2 or more weeks after TBI. Design: Secondary analysis of patients enrolled in TBI Model Systems (TBI-MS, 1988-2020, Discovery Sample) or Transforming Research and Clinical Knowledge in TBI (TRACK-TBI, 2013-2018, Validation Sample) and followed 1-year post-injury. Setting: Multi-center study at USA rehabilitation hospitals (TBI-MS) and acute care hospitals (TRACK-TBI). Participants: Adults with TBI who were not following commands at rehabilitation admission (TBI-MS; days post-injury vary) or 2-weeks post-injury (TRACK-TBI). Exposures: In the TBI-MS database (model fitting and testing), we screened demographic, radiological, clinical variables, and Disability Rating Scale (DRS) item scores for association with the primary outcome. Main Outcome: The primary outcome was death or complete functional dependency at 1-year post-injury, defined using a DRS-based binary measure (DRS Depend ), indicating need for assistance with all activities and concomitant cognitive impairment. Results: In the TBI-MS Discovery Sample, 1,960 subjects (mean age 40 [18] years, 76% male, 68% white) met inclusion criteria and 406 (27%) were dependent at 1-year post-injury. A dependency prediction model had an area under the receiver operating characteristic curve (AUROC) of 0.79 [0.74, 0.85], positive predictive value of 53%, and negative predictive value of 86% for dependency in a held-out TBI-MS Testing cohort. Within the TRACK-TBI external validation sample (N=124, age 40 [16], 77% male, 81% white), a model modified to remove variables not collected in TRACK-TBI, had an AUROC of 0.66 [0.53, 0.79], equivalent to the gold-standard IMPACT core+CT score (0.68; 95% AUROC difference CI: -0.2 to 0.2, p=0.8). Conclusions and Relevance: We used the largest existing cohort of patients with DoC after TBI to develop, test and externally validate a prediction model of 1-year dependency. The model’s sensitivity and negative predictive value were greater than specificity and positive predictive value. Accuracy was diminished in an external sample, but equivalent to the best-available models. Further research is needed to improve dependency prediction in patients with DoC after TBI.

Neuroinflammatory Biomarkers for Traumatic Brain Injury Diagnosis and Prognosis: A TRACK-TBI Pilot Study.

The relationship between systemic inflammation and secondary injury in traumatic brain injury (TBI) is complex. We investigated associations between inflammatory markers and clinical confirmation of TBI diagnosis and prognosis. The prospective TRACK-TBI Pilot (Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot) study enrolled TBI patients triaged to head computed tomography (CT) and received blood draw within 24 h of injury. Healthy controls (HCs) and orthopedic controls (OCs) were included. Thirty-one inflammatory markers were analyzed from plasma. Area under the receiver operating characteristic curve (AUC) was used to evaluate discriminatory ability. AUC >0.7 was considered acceptable. Criteria included: TBI diagnosis (vs. OC/HC); moderate/severe vs. mild TBI (Glasgow Coma Scale; GCS); radiographic TBI (CT positive vs. CT negative); 3- and 6-month Glasgow Outcome Scale-Extended (GOSE) dichotomized to death/greater relative disability versus less relative disability (GOSE 1-4/5-8); and incomplete versus full recovery (GOSE <8/ = 8). One-hundred sixty TBI subjects, 28 OCs, and 18 HCs were included. Markers discriminating TBI/OC: HMGB-1 (AUC = 0.835), IL-1b (0.795), IL-16 (0.784), IL-7 (0.742), and TARC (0.731). Markers discriminating GCS 3-12/13-15: IL-6 (AUC = 0.747), CRP (0.726), IL-15 (0.720), and SAA (0.716). Markers discriminating CT positive/CT negative: SAA (AUC = 0.767), IL-6 (0.757), CRP (0.733), and IL-15 (0.724). At 3 months, IL-15 (AUC = 0.738) and IL-2 (0.705) discriminated GOSE 5-8/1-4. At 6 months, IL-15 discriminated GOSE 1-4/5-8 (AUC = 0.704) and GOSE <8/ = 8 (0.711); SAA discriminated GOSE 1-4/5-8 (0.704). We identified a profile of acute circulating inflammatory proteins with potential relevance for TBI diagnosis, severity differentiation, and prognosis. IL-15 and serum amyloid A are priority markers with acceptable discrimination across multiple diagnostic and outcome categories. Validation in larger prospective cohorts is needed. ClinicalTrials.gov Registration: NCT01565551.

Polygenic risk for mental disorders as predictors of posttraumatic stress disorder after mild traumatic brain injury.

Many patients with mild traumatic brain injury (mTBI) are at risk for mental health problems such as posttraumatic stress disorder (PTSD). The objective of this study was to determine whether the polygenic risk for PTSD (or for related mental health disorders or traits including major depressive disorder [MDD] and neuroticism [NEU]) was associated with an increased likelihood of PTSD in the aftermath of mTBI. We used data from individuals of European ancestry with mTBI enrolled in TRACK-TBI (n = 714), a prospective longitudinal study of level 1 trauma center patients. One hundred and sixteen mTBI patients (16.3%) had probable PTSD (PCL-5 score ≥33) at 6 months post-injury. We used summary statistics from recent GWAS studies of PTSD, MDD, and NEU to generate polygenic risk scores (PRS) for individuals in our sample. A multivariable model that included age, sex, pre-injury history of mental disorder, and cause of injury explained 7% of the variance in the PTSD outcome; the addition of the PTSD-PRS (and five ancestral principal components) significantly increased the variance explained to 11%. The adjusted odds of PTSD in the uppermost PTSD-PRS quintile was nearly four times higher (aOR = 3.71, 95% CI 1.80-7.65) than in the lowest PTSD-PRS quintile. There was no evidence of a statistically significant interaction between PTSD-PRS and prior history of mental disorder, indicating that PTSD-PRS had similar predictive utility among those with and without pre-injury psychiatric illness. When added to the model, neither MDD-PRS nor NEU-PRS were significantly associated with the PTSD outcome. These findings show that the risk for PTSD in the context of mTBI is, in part, genetically influenced. They also raise the possibility that an individual's PRS could be clinically actionable if used-possibly with other non-genetic predictors-to signal the need for enhanced follow-up and early intervention; this precision medicine approach needs to be prospectively studied.

Feasibility and Utility of a Flexible Outcome Assessment Battery for Longitudinal Traumatic Brain Injury Research: A TRACK-TBI Study.

The effects of traumatic brain injury (TBI) are difficult to measure in longitudinal cohort studies, because disparate pre-injury characteristics and injury mechanisms produce variable impairment profiles and recovery trajectories. In preparation for the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study, which followed patients with injuries ranging from uncomplicated mild TBI to coma, we designed a multi-dimensional Flexible outcome Assessment Battery (FAB). The FAB relies on a decision-making algorithm that assigns participants to a Comprehensive (CAB) or Abbreviated Assessment Battery (AAB) and guides test selection across all phases of recovery. To assess feasibility of the FAB, we calculated the proportion of participants followed at 2 weeks (2w) and at 3, 6, and 12 months (3m, 6m, 12m) post-injury who completed the FAB and received valid scores. We evaluated utility of the FAB by examining differences in 6m and 12m Glasgow Outcome Scale-Extended (GOSE) scores between participant subgroups derived from the FAB-enabled versus traditional approach to outcome assessment applied at 2w. Among participants followed at 2w (n = 2094), 3m (n = 1871), 6m (n = 1736), and 12m (n = 1607) post-injury, 95-99% received valid completion scores on the FAB, in full or in part, either in person or by telephone. Level of function assessed by the FAB-enabled approach at 2w was associated with 6m and 12m GOSE scores (proportional odds p < 0.001). These findings suggest that the participant classification methodology afforded by the FAB may enable more effective data collection to improve detection of natural history changes and TBI treatment effects.

Association of Brain Injury Biomarkers and Circulatory Shock Following Moderate-Severe Traumatic Brain Injury: A TRACK-TBI Study.

INTRODUCTION: Early circulatory shock following traumatic brain injury (TBI) is a multifactorial process; however, the impact of brain injury biomarkers on the risk of shock has not been evaluated. We examined the association between neuronal injury biomarker levels and the development of circulatory shock following moderate-severe TBI. METHODS: In this retrospective cohort study, we examined adults with moderate-severe TBI (Glasgow Coma Scale score <13) enrolled in the TRACK-TBI study, an 18-center prospective TBI cohort study. The exposures were day-1 levels of neuronal injury biomarkers (glial fibrillary acidic protein, ubiquitin C-terminal hydrolase-L1 [UCH-L1], S100 calcium-binding protein B [S100B], neuron-specific enolase), and of an inflammatory biomarker (high-sensitivity C-reactive protein). The primary outcome was the development of circulatory shock, defined as cardiovascular Sequential Organ Failure Assessment Score ≥2 within 72 hours of admission. Association between day-1 biomarker levels and the development of circulatory shock was assessed with regression analysis. RESULTS: The study included 392 subjects, with a mean age of 40 years; 314 (80%) were male and 165 (42%) developed circulatory shock. Median (interquartile range) day-1 levels of UCH-L1 (994.8 [518.7 to 1988.2] pg/mL vs. 548.1 [280.2 to 1151.9] pg/mL; P <0.0001) and S100B (0.47 µg/mL [0.25 to 0.88] vs. 0.27 [0.16 to 0.46] µg/mL; P <0.0001) were elevated in those who developed early circulatory shock compared with those who did not. In multivariable regression, there were associations between levels of both UCH-L1 (odds ratio, 1.63 [95% confidence interval, 1.25-2.12]; P <0.0005) and S100B (odds ratio, 1.73 [95% confidence interval 1.27-2.36]; P <0.0005) with the development of circulatory shock. CONCLUSION: Neuronal injury biomarkers may provide the improved mechanistic understanding and possibly early identification of patients at risk for early circulatory shock following moderate-severe TBI.

Emotional Resilience Predicts Preserved White Matter Microstructure Following Mild Traumatic Brain Injury.

BACKGROUND: Adult patients with mild traumatic brain injury (mTBI) exhibit distinct phenotypes of emotional and cognitive functioning identified by latent profile analysis of clinical neuropsychological assessments. When discerned early after injury, these latent clinical profiles have been found to improve prediction of long-term outcomes from mTBI. The present study hypothesized that white matter (WM) microstructure is better preserved in an emotionally resilient mTBI phenotype compared with a neuropsychiatrically distressed mTBI phenotype. METHODS: The present study used diffusion magnetic resonance imaging to investigate and compare WM microstructure in major association, projection, and commissural tracts between the two phenotypes and over time. Diffusion magnetic resonance images from 172 patients with mTBI were analyzed to compute individual diffusion tensor imaging maps at 2 weeks and 6 months after injury. RESULTS: By comparing the diffusion tensor imaging parameters between the two phenotypes at global, regional, and voxel levels, emotionally resilient patients were shown to have higher axial diffusivity compared with neuropsychiatrically distressed patients early after mTBI. Longitudinal analysis revealed greater compromise of WM microstructure in neuropsychiatrically distressed patients, with greater decrease of global axial diffusivity and more widespread decrease of regional axial diffusivity during the first 6 months after injury compared with emotionally resilient patients. CONCLUSIONS: These results provide neuroimaging evidence of WM microstructural differences underpinning mTBI phenotypes identified from neuropsychological assessments and show differing longitudinal trajectories of these biological effects. These findings suggest that diffusion magnetic resonance imaging can provide short- and long-term imaging biomarkers of resilience.