The prognostic value of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) as day-of-injury predictors of functional outcome after traumatic brain injury is not ...well understood. GFAP is a protein found in glial cells and UCH-L1 is found in neurons, and these biomarkers have been cleared to aid in decision making regarding whether brain CT should be performed after traumatic brain injury. We aimed to quantify their prognostic accuracy and investigate whether these biomarkers contribute novel prognostic information to existing clinical models.
We enrolled patients from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) observational cohort study. TRACK-TBI includes patients 17 years and older who are evaluated for TBI at 18 US level 1 trauma centres. All patients receive head CT at evaluation, have adequate visual acuity and hearing preinjury, and are fluent in either English or Spanish. In our analysis, we included participants aged 17–90 years who had day-of-injury plasma samples for measurement of GFAP and UCH-L1 and completed 6-month assessments for outcome due to traumatic brain injury with the Glasgow Outcome Scale–Extended (GOSE-TBI). Biomarkers were analysed as continuous variables and in quintiles. This study is registered with ClinicalTrials.gov, NCT02119182.
We enrolled 2552 patients from Feb 26, 2014, to Aug 8, 2018. Of the 1696 participants with brain injury and data available at baseline and at 6 months who were included in the analysis, 120 (7·1%) died (GOSE-TBI=1), 235 (13·9%) had an unfavourable outcome (ie, GOSE-TBI ≤4), 1135 (66·9%) had incomplete recovery (ie, GOSE-TBI <8), and 561 (33·1%) recovered fully (ie, GOSE-TBI=8). The area under the curve (AUC) of GFAP for predicting death at 6 months in all patients was 0·87 (95% CI 0·83–0·91), for unfavourable outcome was 0·86 (0·83–0·89), and for incomplete recovery was 0·62 (0·59–0·64). The corresponding AUCs for UCH-L1 were 0·89 (95% CI 0·86–0·92) for predicting death, 0·86 (0·84–0·89) for unfavourable outcome, and 0·61 (0·59–0·64) for incomplete recovery at 6 months. AUCs were higher for participants with traumatic brain injury and Glasgow Coma Scale (GCS) score of 3–12 than for those with GCS score of 13–15. Among participants with GCS score of 3–12 (n=353), adding GFAP and UCH-L1 (alone or combined) to each of the three International Mission for Prognosis and Analysis of Clinical Trials in traumatic brain injury models significantly increased their AUCs for predicting death (AUC range 0·90–0·94) and unfavourable outcome (AUC range 0·83–0·89). However, among participants with GCS score of 13–15 (n=1297), adding GFAP and UCH-L1 to the UPFRONT study model modestly increased the AUC for predicting incomplete recovery (AUC range 0·69–0·69, p=0·025).
In addition to their known diagnostic value, day-of-injury GFAP and UCH-L1 plasma concentrations have good to excellent prognostic value for predicting death and unfavourable outcome, but not for predicting incomplete recovery at 6 months. These biomarkers contribute the most prognostic information for participants presenting with a GCS score of 3–12.
US National Institutes of Health, National Institute of Neurologic Disorders and Stroke, US Department of Defense, One Mind, US Army Medical Research and Development Command.
Mild Traumatic Brain Injury (mTBI), or concussion, is a major public health concern. There is controversy in the literature regarding the true incidence of postconcussion syndrome (PCS), with the ...constellation of physical, cognitive, emotional, and sleep symptoms after mTBI. In the current study, we report on the incidence and evolution of PCS symptoms and patient outcomes after mTBI at 3, 6, and 12 months in a large, prospective cohort of mTBI patients. Participants were identified as part of the prospective, multi-center Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study. The study population was mTBI patients (Glasgow Coma Scale score of 13-15) presenting to the emergency department, including patients with a negative head computed tomography discharged to home without admission to hospital; 375 mTBI subjects were included in the analysis. At both 6 and 12 months after mTBI, 82% (n=250 of 305 and n=163 of 199, respectively) of patients reported at least one PCS symptom. Further, 44.5 and 40.3% of patients had significantly reduced Satisfaction With Life scores at 6 and 12 months, respectively. At 3 months after injury, 33% of the mTBI subjects were functionally impaired (Glasgow Outcome Scale-Extended score ≤6); 22.4% of the mTBI subjects available for follow-up were still below full functional status at 1 year after injury. The term "mild" continues to be a misnomer for this patient population and underscores the critical need for evolving classification strategies for TBI for targeted therapy.
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.
Brain lesions are subtle or absent in most patients with mild traumatic brain injury (mTBI) and the standard clinical criteria are not reliable for predicting long-term outcome. This study ...investigates resting-state functional MRI (rsfMRI) to assess semiacute alterations in brain connectivity and its relationship with outcome measures assessed 6 months after injury. Seventy-five mTBI patients were recruited as part of the prospective multicenter Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) pilot study and compared with matched 47 healthy subjects. Patients were classified following radiological criteria: CT/MRI positive, evidence of lesions; CT/MRI negative, without evidence of brain lesions. rsfMRI data were acquired and then processed using probabilistic independent component analysis. We compared the functional connectivity of the resting-state networks (RSNs) between patients and controls, as well as group differences in the interactions between RSNs, and related both to cognitive and behavioral performance at 6 months post-injury. Alterations were found in the spatial maps of the RSNs between mTBI patients and healthy controls in networks involved in behavioral and cognition processes. These alterations were predictive of mTBI patients' outcomes at 6 months post-injury. Moreover, different patterns of reduced network interactions were found between the CT/MRI positive and CT/MRI negative patients and the control group. These rsfMRI results demonstrate that even mTBI patients not showing brain lesions on conventional CT/MRI scans can have alterations of functional connectivity at the semiacute stage that help explain their outcomes. These results suggest rsfMRI as a sensitive biomarker both for early diagnosis and for prediction of the cognitive and behavioral performance of these patients.
Traumatic brain injury (TBI) is among the leading causes of death and disability worldwide, with enormous negative social and economic impacts. The heterogeneity of TBI combined with the lack of ...precise outcome measures have been central to the discouraging results from clinical trials. Current approaches to the characterization of disease severity and outcome have not changed in more than three decades. This prospective multicenter observational pilot study aimed to validate the feasibility of implementing the TBI Common Data Elements (TBI-CDEs). A total of 650 subjects who underwent computed tomography (CT) scans in the emergency department within 24 h of injury were enrolled at three level I trauma centers and one rehabilitation center. The TBI-CDE components collected included: 1) demographic, social and clinical data; 2) biospecimens from blood drawn for genetic and proteomic biomarker analyses; 3) neuroimaging studies at 2 weeks using 3T magnetic resonance imaging (MRI); and 4) outcome assessments at 3 and 6 months. We describe how the infrastructure was established for building data repositories for clinical data, plasma biomarkers, genetics, neuroimaging, and multidimensional outcome measures to create a high quality and accessible information commons for TBI research. Risk factors for poor follow-up, TBI-CDE limitations, and implementation strategies are described. Having demonstrated the feasibility of implementing the TBI-CDEs through successful recruitment and multidimensional data collection, we aim to expand to additional study sites. Furthermore, interested researchers will be provided early access to the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) data set for collaborative opportunities to more precisely characterize TBI and improve the design of future clinical treatment trials. (ClinicalTrials.gov Identifier NCT01565551.).
Concussion is a significant public health problem that is receiving increased attention from physicians, the media, and the public. Recent studies suggest that persistent symptoms after ...concussion/mild traumatic brain injury (mTBI) may arise from structural or metabolic alterations in the brain, despite normal conventional neuroimaging studies. New, advanced neuroimaging techniques show promise in refining diagnosis and outcome prediction in concussion/mTBI. Here, we review some of these techniques, including diffusion tensor imaging, task-based and resting-state functional magnetic resonance imaging, as well as positron emission tomography, H magnetic resonance spectroscopy, and perfusion imaging. Although further validation is needed through large prospective studies that correlate these techniques with patient outcome, it is likely that the definitions of pathoanatomic lesions, and a better understanding of their relationship to symptoms and prognosis, will continue to evolve as neuroimaging techniques continue to progress.
ABBREVIATIONS:BOLD, blood oxygen level-dependentDMN, default mode networkFA, fractional anisotropyF-FDG,F-fluorodeoxyglucosefMRI, function magnetic resonance imagingGOS-E, extended Glasgow Outcome ScaleGCS, Glasgow Coma ScaleLOC, loss of consciousnessMD, mean diffusivityMRS, magnetic resonance spectroscopymTBI, mild traumatic brain injuryNAA, N-acetylaspartateROI, region of interestrs, resting stateSPECT, single-photon emission computed tomography
Although the majority of patients with mild traumatic brain injury (mTBI) recover completely, some still suffer from disabling ailments at 3 or 6 months. We validated existing prognostic models for ...mTBI and explored predictors of poor outcome after mTBI. We selected patients with mTBI from TRACK-TBI Pilot, an unselected observational cohort of TBI patients from three centers in the United States. We validated two prognostic models for the Glasgow Outcome Scale Extended (GOS-E) at 6 months after injury. One model was based on the CRASH study data and another from Nijmegen, The Netherlands. Possible predictors of 3- and 6-month GOS-E were analyzed with univariate and multi-variable proportional odds regression models. Of the 386 of 485 patients included in the study (median age, 44 years; interquartile range, 27-58), 75% (n=290) presented with a Glasgow Coma Score (GCS) of 15. In this mTBI population, both previously developed models had a poor performance (area under the receiver operating characteristic curve, 0.49-0.56). In multivariable analyses, the strongest predictors of lower 3- and 6-month GOS-E were older age, pre-existing psychiatric conditions, and lower education. Injury caused by assault, extracranial injuries, and lower GCS were also predictive of lower GOS-E. Existing models for mTBI performed unsatisfactorily. Our study shows that, for mTBI, different predictors are relevant as for moderate and severe TBI. These include age, pre-existing psychiatric conditions, and lower education. Development of a valid prediction model for mTBI patients requires further research efforts.
Over 70% of traumatic brain injuries (TBI) are classified as mild (mTBI), which present heterogeneously. Associations between pre-injury comorbidities and outcomes are not well-understood, and ...understanding their status as risk factors may improve mTBI management and prognostication.
mTBI subjects (GCS 13-15) from TRACK-TBI Pilot completing 3- and 6-month functional Glasgow Outcome Scale-Extended (GOSE) and post-concussive outcomes Acute Concussion Evaluation (ACE) physical/cognitive/sleep/emotional subdomains were extracted. Pre-injury comorbidities >10% incidence were included in regressions for functional disability (GOSE ≤ 6) and post-concussive symptoms by subdomain. Odds ratios (OR) and mean differences (B) were reported. Significance was assessed at
< 0.0083 (Bonferroni correction).
In 260 subjects sustaining blunt mTBI, mean age was 44.0-years and 70.4% were male. Baseline comorbidities >10% incidence included psychiatric-30.0%, cardiac (hypertension)-23.8%, cardiac (structural/valvular/ischemic)-20.4%, gastrointestinal-15.8%, pulmonary-15.0%, and headache/migraine-11.5%. At 3- and 6-months separately, 30.8% had GOSE ≤ 6. At 3-months, psychiatric (GOSE ≤ 6: OR = 2.75, 95% CI 1.44-5.27; ACE-physical: B = 1.06 0.38-1.73; ACE-cognitive: B = 0.72 0.26-1.17; ACE-sleep: B = 0.46 0.17-0.75; ACE-emotional: B = 0.64 0.25-1.03), headache/migraine (GOSE ≤ 6: OR = 4.10 1.67-10.07; ACE-sleep: B = 0.57 0.15-1.00; ACE-emotional: B = 0.92 0.35-1.49), and gastrointestinal history (ACE-physical: B = 1.25 0.41-2.10) were multivariable predictors of worse outcomes. At 6-months, psychiatric (GOSE ≤ 6: OR = 2.57 1.38-4.77; ACE-physical: B = 1.38 0.68-2.09; ACE-cognitive: B = 0.74 0.28-1.20; ACE-sleep: B = 0.51 0.20-0.83; ACE-emotional: B = 0.93 0.53-1.33), and headache/migraine history (ACE-physical: B = 1.81 0.79-2.84) predicted worse outcomes.
Pre-injury psychiatric and pre-injury headache/migraine symptoms are risk factors for worse functional and post-concussive outcomes at 3- and 6-months post-mTBI. mTBI patients presenting to acute care should be evaluated for psychiatric and headache/migraine history, with lower thresholds for providing TBI education/resources, surveillance, and follow-up/referrals.
www.ClinicalTrials.gov, identifier NCT01565551.
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