Recovery After Mild Traumatic Brain Injury in Patients Presenting to US Level I Trauma Centers: A Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Study

Key Points

Question  How common are persistent, injury-related functional limitations following mild traumatic brain injury vs orthopedic trauma?

Findings  In this cohort study of 1154 patients with mild traumatic brain injury and 299 patients with orthopedic trauma serving as controls, 53% of participants with mild traumatic brain injury reported impairment 12 months postinjury vs 38% of those with orthopedic trauma. Patients with intracranial abnormalities had the poorest outcomes; however, patients without abnormalities also reported problems at 12 months.

Meaning  Many patients who present to level I trauma centers with mild traumatic brain injury experience difficulties at 12 months postinjury, suggesting that this injury is not always benign; better follow-up and treatment appear to be needed.

Importance  Most traumatic brain injuries (TBIs) are classified as mild (mTBI) based on admission Glasgow Coma Scale (GCS) scores of 13 to 15. The prevalence of persistent functional limitations for these patients is unclear.

Objectives  To characterize the natural history of recovery of daily function following mTBI vs peripheral orthopedic traumatic injury in the first 12 months postinjury using data from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study, and, using clinical computed tomographic (CT) scans, examine whether the presence (CT+) or absence (CT−) of acute intracranial findings in the mTBI group was associated with outcomes.

Design, Setting, and Participants  TRACK-TBI, a cohort study of patients with mTBI presenting to US level I trauma centers, enrolled patients from February 26, 2014, to August 8, 2018, and followed up for 12 months. A total of 1453 patients at 11 level I trauma center emergency departments or inpatient units met inclusion criteria (ie, mTBI [n = 1154] or peripheral orthopedic traumatic injury [n = 299]) and were enrolled within 24 hours of injury; mTBI participants had admission GCS scores of 13 to 15 and clinical head CT scans. Patients with peripheral orthopedic trauma injury served as the control (OTC) group.

Exposures  Participants with mTBI or OTC.

Main Outcomes and Measures  The Glasgow Outcome Scale Extended (GOSE) scale score, reflecting injury-related functional limitations across broad life domains at 2 weeks and 3, 6, and 12 months postinjury was the primary outcome. The possible score range of the GOSE score is 1 (dead) to 8 (upper good recovery), with a score less than 8 indicating some degree of functional impairment.

Results  Of the 1453 participants, 953 (65.6%) were men; mean (SD) age was 40.9 (17.1) years in the mTBI group and 40.9 (15.4) years in the OTC group. Most participants (mTBI, 87%; OTC, 93%) reported functional limitations (GOSE <8) at 2 weeks postinjury. At 12 months, the percentage of mTBI participants reporting functional limitations was 53% (95% CI, 49%-56%) vs 38% (95% CI, 30%-45%) for OTCs. A higher percentage of CT+ patients reported impairment (61%) compared with the mTBI CT− group (49%; relative risk [RR], 1.24; 95% CI, 1.08-1.43) and a higher percentage in the mTBI CT−group compared with the OTC group (RR, 1.28; 95% CI, 1.02-1.60).

Conclusions and Relevance  Most patients with mTBI presenting to US level I trauma centers report persistent, injury-related life difficulties at 1 year postinjury, suggesting the need for more systematic follow-up of patients with mTBI to provide treatments and reduce the risk of chronic problems after mTBI.

In the United States, about 2.8 million individuals are treated at hospitals annually for traumatic brain injuries (TBIs).¹ Most TBIs are classified as mild (mTBI) based on crude clinical signs, such as patients’ gross levels of consciousness up hospital admission (eg, Glasgow Coma Scale [GCS] scores of 13-15). Although it is well accepted that moderate to severe TBIs may cause permanent disability,^2-4 controversy exists surrounding the expected course of clinical recovery for patients with mTBI. In particular, although mTBI commonly causes acute symptoms,^5-7 cognitive dysfunction,^6,8-12 and problems in day-to-day functioning,¹³ findings vary as to whether patients continue to manifest sequelae of mTBI months to years postinjury.^14-16

Limitations in research methods have been proposed as a major factor explaining inconsistencies in the observed natural history of mTBI. Seminal World Health Organization systematic reviews and others highlighted common methodologic problems, including small, nonprospective samples; cross-sectional study designs not well suited to characterize recovery; inadequate control groups; and insufficient statistical approaches (eg, limited attention to nonrandom patterns of attrition) called for large, carefully conducted prospective studies.^14,17-19 Another important issue that may explain variable findings is heterogeneity across patients. Given current diagnostic conventions,²⁰ mTBI encompasses a wide spectrum of TBI severity, from concussive injuries with subtle signs of brain dysfunction without evidence of structural injury on computed tomographic (CT) scans^21,22 to injuries with intracranial abnormalities shown on head CT scans.^16,23,24 Thus, in describing recovery from mTBI, one should consider subgroups of patients likely to vary in prognosis.^14,25

The Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study²⁶ was designed to address calls to improve the quality of evidence in community-acquired TBI. This article describes the mTBI cohort’s course of functional limitations, reported on the Glasgow Outcome Scale–Extended (GOSE) scale compared with patients with peripheral orthopedic traumatic injuries (orthopedic trauma control [OTC] group). Patients with mTBI were also stratified based on the presence (CT+) vs absence (CT−) of acute intracranial findings on head CT. In addition, we evaluated secondary outcomes of self-reported symptoms and neurocognitive performance. We hypothesized that rates of functional limitations would be maximal soon after injury and decline over time and that the mTBI group would continue to report more symptoms than the OTC group at 12 months postinjury.¹⁶

TRACK-TBI is a prospective, multicenter study recruiting participants at 11 US level I trauma centers. Participants with mTBI who were enrolled between February 26, 2014, and May 4, 2016, and OTCs recruited by August 8, 2018, were considered for analyses. eFigure 1 in the Supplement depicts the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) diagram of the current TRACK-TBI sample (N = 1648) and the cohorts evaluated in this study (n = 1154 mTBI and n = 299 OTC). The study was approved by the institutional review board of each enrolling institution and was led by the University of California, San Francisco. Participants or their legally authorized representatives completed written informed consent and received financial compensation. Demographic, injury, and outcome variables were collected in accordance with the TBI Common Data Elements.^27,28 Demographic data were obtained through a combination of medical records and patient report. Outcome assessments occurred at 2 weeks and 3, 6, and 12 months postinjury. Three-month assessments were performed via telephone; other assessments were performed in person whenever feasible.

Inclusion criteria for TBI were for the patient to present within 24 hours of injury, have an acute head CT scan performed as part of clinical care, and show or report evidence of alterations in consciousness or amnesia. We restricted the cohort to GCS scores of 13 to 15 (ie, mTBI) on emergency department (ED) arrival. Patients in the OTC group presented with orthopedic injuries and showed no evidence of altered consciousness, amnesia, or other physical signs of head trauma. Exclusions included being in custody, pregnant, nonsurvivable physical trauma, debilitating mental health disorders, neurologic disease, or non-English speaking; however, some sites recruited Spanish-speaking participants. Although some sites recruited children, we focused on participants aged 17 years and older, given that they completed the outcome measures of interest.

The GOSE score is a measure of the association between traumatic injuries and diverse aspects of daily functioning²⁷ and is commonly used as the primary outcome measure in TBI studies.²⁹ The possible range of scores is 1 (dead) to 8 (upper good recovery), with less than 8 reflecting some degree of functional limitation after injury. The scale is completed via interview with patients or proxies. Respondents are asked to report new injury-related dependence or difficulties (including worsening of any preexisting problems) in major domains of life function: independence within (ie, activities of daily living) and outside (eg, shopping, travel) the home, work, social/leisure activities, family or friend relationships, and other injury-related symptoms or problems affecting daily life. Changes in function were counted irrespective of whether they resulted from TBI or other injury-related factors (eg, multiple trauma).

Secondary outcomes, collected at 12 months postinjury, comprised self-reported TBI-related symptoms (Rivermead Post Concussion Symptoms Questionnaire, with ratings of 1 not counted in total scores; possible range, 0-64; higher scores indicate more severe symptoms),³⁰ psychological distress (18-item Brief Symptom Inventory; mean [SD] T score normative for the general population, 50 [10]; possible range, 36-81; higher scores indicate more severe psychiatric symptoms),³¹ and general life satisfaction (Satisfaction With Life scale; possible range, 0-35; higher scores indicate more life satisfaction).³² In addition, participants performed neuropsychological measures of verbal episodic memory (Rey Auditory Verbal Learning Test; possible range for immediate memory, 0-80; higher scores indicate better memory; possible range for delayed recall, 0-16; higher scores indicate better memory),^33,34 processing speed (Wechsler Adult Intelligence Scale–Fourth Edition Processing Speed Index; mean [SD] normative score, 100 [15]; higher scores indicate better processing speed),³⁵ and executive functioning (Trail Making Test: number of seconds to complete; part A, maximum score is 90 seconds, lower score is faster/better; part B, maximum score is 300 seconds, lower score is faster/better).³⁶

Sample characteristics were compared between groups using Fisher exact tests (categorical variables) and Mann-Whitney tests (continuous variables). Primary analyses were adjusted for patterns of missing outcomes with propensity weights.³⁷ Propensity weights were derived separately by measure type (GOSE, self-report, neuropsychological) and time (2 weeks and 3, 6, 12 months) from boosted logistic regression models predicting completion vs noncompletion of outcomes from enrollment site and demographic, history, and injury variables. Weights were proportional to the inverse of the probability of measure completion and normed so the sum equaled the number of cases with the measure completed. Prevalence of functional difficulty by GOSE domain and report of injury-related symptoms on the Rivermead Post Concussion Symptoms Questionnaire (ie, ratings of 2-4) were evaluated through percentages and compared using Fisher exact tests for pairwise comparisons between groups (first, all mTBI vs OTC; second, pairwise comparisons among mTBI CT+, mTBI CT−, and OTC groups). Prevalence rates (percentages) and effect sizes of group differences (risk ratios [RRs]) are reported alongside 95% CIs.³⁸ Differences that remained significant after multiple comparison correction (within outcome domain and time point using a 5% false discovery rate)³⁹ are discussed.

Group comparisons on 12-month secondary outcome measures used 2-tailed, independent-samples, unpaired t tests for continuous self-report measures, with effect sizes reported as Cohen d (with 95% CIs). General linear models were used to compare groups on neuropsychological measures adjusting for age, sex, and educational level. Results were considered significant at P < .05.

Propensity probabilities were generated using the twang software package developed for R, version 3.2.2 (R Foundation for Statistical Computing), which was accessed via script files generated by an SAS, version 9.3 macro package (SAS Institute Inc). Other statistical analyses were conducted in SPSS Statistics for Windows, version 19 (IBM Corp).

Of the 1349 participants with TBI, 1154 patients (85.5%) met the criteria for mTBI. The mTBI group included 754 men (65.1%); mean (SD) age was 40.9 (17.1) years (Table 1). The OTC group (n = 299) included 199 men (66.6%); mean age was 40.9 (15.4) years. The mTBI sample size with available outcome data ranged from 975 to 768 at 2 weeks through 12 months postinjury, respectively (eFigure 1 in the Supplement). The number of OTCs with available outcome data ranged from 240 to 146 across the same time. The mTBI and OTC groups were well matched on demographic and history variables. Sample characteristics stratified by CT scan status are presented in eTable 1 in the Supplement. Because of differences in cause of injury between groups, sensitivity analyses were performed to confirm that covarying for this variable did not affect the results (eTables 6-10 in the Supplement).

The Figure illustrates the percentage and 95% CIs of participants in each group who reported injury-related functional problems in 1 or more areas of function on the GOSE score (ie, GOSE <8) at each assessment. Functional limitation rates were highest at 2 weeks postinjury (mTBI: 87%; 95% CI, 84%-89%; OTC: 93%; 95% CI, 89%-96%) and lowest at 12 months (mTBI: 53%; 95% CI, 49%-56%; OTC: 38%; 95% CI, 30%-45%). The mTBI and OTC groups were not significantly different from 2 weeks to 6 months postinjury: 2-week RR, 0.93 (95% CI, 0.89-0.98); 2-month RR, 0.92 (95% CI, 0.84-1.02); 6-month, RR, 1.14 (95% CI, 0.99-1.31). At 12 months, more participants in the mTBI group (53%; 95% CI, 49%-56%) continued to report functional limitations compared with the OTC group (38%; 95% CI, 30%-45%) (RR, 1.38; 95% CI, 1.12-1.71). In other words, 47.2% of patients with mTBI and 62.3% of the OTCs reported full return to preinjury levels of day-to-day functioning at 12 months postinjury (P = .001). Stratifying the CT+ and CT− subsamples of the mTBI group at 12 months (eFigure 2 in the Supplement) revealed a significantly higher percentage of patients with limitations in the mTBI CT+ group (61%) than the mTBI CT− group (49%) (RR, 1.24; 95% CI, 1.08-1.43), and a higher percentage in the mTBI CT− group (49%) vs the OTC group (38%) (RR, 1.28; 95% CI, 1.02-1.60).

Table 2 provides the percentage of participants in the mTBI and OTC groups who reported injury-related problems in each GOSE score domain. Table 3 provides effect sizes (RRs) for associated between-group comparisons. Overall, rates of dysfunction were highest for complex tasks, such as work (eg, mTBI: 61%; 95% CI, 57%-64%; OTC: 69%; 95% CI, 63%-74% at 2 weeks), and social/leisure functioning (eg, mTBI: 59%; 95% CI, 55%-62%; OTC: 70%; 95% CI, 63%-75% at 2 weeks) and lower in more basic activities, such as home independence (eg, mTBI: 12%; 95% CI, 9%-14%; OTC: 9%; 95% CI, 5%-13% at 2 weeks). Rates of dysfunction in each domain declined over time; for example, at 12 months, only 0% (95% CI 0%-3%) of the OTC group and 1% (95% CI, 1%-2%) of the mTBI group reported limitations in home independence; 17% of both groups (mTBI: 95% CI, 15%-20%; OTC: 95% CI, 12%-23%) reported problems with work and 17% (95% CI, 15%-20%) of the mTBI and 18% (95% CI, 13%-25%) of the OTC groups had limitations in social functioning. Compared with the OTC group, the mTBI group reported injury-related symptoms that affect daily life (from 73% vs 46% at 2 weeks: RR, 1.59; 95% CI, 1.37-1.84; to 48% vs 20% at 12 months: RR, 2.33;95% CI, 1.68-3.21) more frequently, with more family disruption reported at most time points. The OTC group reported more work and social dysfunction than the mTBI group through 6 months, but these group differences were no longer significant at 12 months.

eTables 3 and 4 in the Supplement present analyses of GOSE score domains by mTBI subgroup (CT+/CT−). At 2 weeks, the mTBI CT+ subgroup more commonly needed assistance at home (RR, 1.82; 95% CI, 1.17-2.81) and could not work (RR, 1.34; 95% CI, 1.09-1.65) compared with the CT− group. At 3, 6, and 12 months, the mTBI CT+ group reported higher rates of symptoms that affect daily life (RR, 1.21; 95% CI, 1.06-1.39; to RR, 1.29; 95% CI, 1.13-1.47). At select times, the mTBI CT+ group reported higher rates of psychological problems that affect relationships (at 6 months: RR, 1.43; 95% CI, 1.11-1.84) and more limitations with home independence (at 12 months: RR, 5.08; 95% CI, 1.33-19.47) and travel (at 12 months: RR, 6.54; 95% CI, 1.79-23.91) than the mTBI CT− group.

Because the mTBI group continued to report substantial rates of injury-related problems at 12 months on the GOSE scale, we evaluated group differences in secondary outcome measures at 12 months to inform possible causes or consequences of chronic impairments. Table 4 and eTable 11 in the Supplement present mTBI vs OTC comparisons. Participants with mTBI reported more severe symptoms on the Rivermead Post Concussion Symptoms Questionnaire (d = 0.46) and, to a lesser degree, psychological distress (18-item Brief Symptom Inventory, d = 0.20) than the OTCs. The mTBI group demonstrated significantly poorer performance vs the OTC group in verbal learning and memory retrieval (d = 0.24-0.25) and on 1 measure of psychomotor processing speed (Trail Making Test, Part A; d = 0.30). Comparisons between the mTBI CT+ and CT− groups (eTable 5 in the Supplement) were not statistically significant on any secondary outcome measure.

In this longitudinal observational study of patients who presented to US level I trauma centers with mTBI, only 47.2% of patients with mTBI (defined as ED admission GCS score, 13-15) reported full return to preinjury levels of day-to-day functioning at 12 months postinjury vs 62.3% of OTCs (P = .001). In addition to more frequently reporting functional limitations at 12 months, patients with mTBI reported more persistent injury-related symptoms (eg, headaches, fatigue, depression, forgetfulness) and performed more poorly on cognitive tests than those in the OTC group.

Our findings highlight an apparent need for improved treatment of mTBI. Although there are currently no validated pharmacologic treatments for mTBI, nonpharmacologic interventions to provide psychoeducation and symptom management can help patients. For example, a number of studies support the efficacy of providing a clinical encounter soon (eg, 1 week) after injury to offer accurate and reassuring information about the expected symptoms and recovery course from mTBI.^40-43 In contrast, about half of patients with mTBI who present to the ED do not receive any TBI diagnosis,⁴⁴ a significant minority do not receive adequate discharge instructions,⁴⁵ and most do not receive follow-up care after their ED visit.⁴⁶ Thus, outcomes may be improved by increasing the rate of early identification of mTBI and providing patient education about the condition. In addition, given that many of the symptoms reported after mTBI (eg, headache, psychiatric symptoms) have validated treatments in other clinical populations,^47,48 such established treatments may be efficacious in the mTBI population but require more systematic validation in patients with mTBI.^49-51

These data also suggest that patients who demonstrate acute intracranial CT scan findings of mTBI vs those without such findings more commonly report injury-related difficulties in several aspects of daily life even 1 year postinjury. This result is consistent with other findings that complicated (CT+) mTBI represents a more severe brain injury than uncomplicated (CT−) mTBI. However, across other outcome domains at 1 year (eg, self-report of symptoms, cognitive functioning), the CT+ and CT− subgroups were similar. In combination with the high degree of heterogeneity in outcomes, these results appear to support the need to further refine mTBI classification systems beyond current approaches focused on the crude variables of admission GCS score and normal vs abnormal head CT scan. Although we focused on these variables because of their broad clinical use, other pathophysiologic indicators of brain injury may soon inform diagnostic, treatment, and prognostic decisions. Beyond the presence of CT abnormalities, for example, the magnitude and nature of CT abnormalities may be relevant to mTBI classification.⁵² Furthermore, a significant percentage of patients who present without evidence of brain injury on head CT scans show signs of intracranial injury on brain magnetic resonance imaging scans, and the findings from these scans predict outcomes.^53,54 In addition, peripheral blood biomarkers of brain injury may inform clinical decision making in the future.⁵⁵ These examples highlight the potential for neurobiological discoveries to improve the classification of patients with mTBI and perhaps develop precision medicine treatment approaches. Ongoing studies, such as TRACK-TBI, are collecting the translational data needed to advance this goal in the coming years.

Data presented on the OTC group shed light on the relevance of peripheral injuries outcomes after traumatic injuries. In particular, 38% of the OTCs reported injury-related life difficulties at the 1-year study end point. Most patients with mTBI in this sample had some degree of peripheral injuries. The finding that some life problems were equally prevalent across the mTBI and OTC groups (eg, in work and social functioning at 12 months) may suggest that factors other than brain injury contributed to these types of problems. However, chronic symptoms and cognitive impairments were more prevalent in the patients with mTBI than OTC group, implying some contribution of mTBI toward these outcomes. Within the subsample of admitted patients for whom we could quantify peripheral injury severity, the mTBI CT+ group manifested less-severe peripheral injuries than the mTBI CT− and OTC groups (eTable 1 in the Supplement). This finding might imply that poorer functional outcomes in the mTBI CT+ subgroup may partly reflect the consequences of brain injury as opposed to peripheral trauma. These observations highlight the need for methods that parse the sequelae of brain vs peripheral injuries and underscore the recommendation that clinicians should consider the entirety of individual patients’ injuries, histories, and life experiences when treating them after traumatic injuries. For example, in addition to physical injuries, patients with trauma may experience emotional distress and other life stressors after injury that affect their recoveries.^56-60 In addition, premorbid risk and resilience factors appear to contribute to injury response and recovery.^61-64 Although additional work is needed to understand the dynamic process by which diverse factors lead to resilient vs poor outcomes,^61,65 clinicians are encouraged to take a patient-centered treatment approach that addresses patients’ symptoms and presenting concerns, regardless of their apparent source.³⁹

This study had several limitations. Because we only enrolled patients seen at level I trauma centers who received head CT scans, the findings may not generalize to the broader mTBI population, such as patients who meet criteria for mTBI but are triaged to a lower level of care and those who do not present to EDs.⁶⁶ However, the findings can be generalized to a large group of patients seen in acute care settings where CT imaging was clinically indicated to rule out more severe TBI. Although the OTC sample was relatively small at 12 months, groups were well matched at enrollment (except for select injury-related variables, such as the presence of orthopedic injuries, cause of injury, and highest level of care), and appropriate statistical analyses were used to ensure that any group differences at enrollment or possible nonrandom patterns of attrition did not bias results. Despite these efforts, there was significant heterogeneity within both the mTBI and OTC groups in the nature and severity of injuries, alongside limited available methods to quantify brain and peripheral injury severity. Thus, although these data shed some light on the potential contribution of brain and nonbrain injuries to outcomes, more work is needed to better understand how these and other factors (eg, preinjury risk factors, emotional trauma due to injury) affect recovery from traumatic injuries. Our primary outcome may be prone to response bias; however, we observed mTBI-related responses on objective cognitive performance measures, which strengthens our findings. Future work should clarify how variables other than head CT scan status (eg, other biomarkers, preinjury factors, multiple trauma, postinjury social and rehabilitative support) should inform clinical decisions for individual patients.

In this prospective, observational TRACK-TBI study cohort, patients with mTBI presenting to level I trauma centers commonly report difficulties in aspects of day-to-day functioning to at least 12 months postinjury, especially with TBI-related symptoms and interpersonal functioning, suggesting that this injury is not always benign. These findings contrast with the rapid recovery observed in prospective studies of sport-related concussion,^6,22 and appear to demonstrate that the natural history of mTBI recovery differs across patient populations. Furthermore, patients with mTBI with CT scan evidence of structural brain injury commonly have a higher prevalence of persisting functional limitations in some life areas but a similar degree of persistent symptoms compared with those with normal CT scan findings. The term mild TBI misrepresents the immediate and long-term burden of TBI and other cooccurring factors experienced by this patient population.

Accepted for Publication: April 5, 2019.

Published Online: June 3, 2019. doi:10.1001/jamaneurol.2019.1313

Correction: This article was corrected on October 21, 2019, to fix an error in the byline.

Corresponding Author: Lindsay D. Nelson, PhD, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI 53226 (linelson@mcw.edu).

The TRACK-TBI Investigators: Opeolu Adeoye, MD; Neeraj Badjatia, MD; Kim Boase, BA; Yelena Bodien, PhD; M. Ross Bullock, MD, PhD; Randall Chesnut, MD; John D. Corrigan, PhD, ABPP; Karen Crawford, MIS; Ann-Christine Duhaime, MD; Richard Ellenbogen, MD; V. Ramana Feeser, MD; Adam Ferguson, PhD; Brandon Foreman, MD; Raquel Gardner, MD; Etienne Gaudette, PhD; Luis Gonzalez, BA; Shankar Gopinath, MD; Rao Gullapalli, PhD; J Claude Hemphill, MD; Gillian Hotz, PhD; Sonia Jain, PhD; Frederick Korley, MD, PhD; Joel Kramer, PsyD; Natalie Kreitzer, MD; Chris Lindsell, PhD; Joan Machamer, MA; Christopher Madden, MD; Alastair Martin, PhD; Thomas McAllister, MD; Randall Merchant, PhD; Florence Noel, PhD; Eva Palacios, PhD; Daniel Perl, MD; Ava Puccio, PhD; Miri Rabinowitz, PhD; Jonathan Rosand, MD, MSc; Angelle Sander, PhD; Gabriela Satris, MSc; David Schnyer, PhD; Seth Seabury, PhD; Mark Sherer, PhD; Sabrina Taylor, PhD; Arthur Toga, PhD; Alex Valadka, MD; Mary J. Vassar, RN, MS; Paul Vespa, MD; Kevin Wang, PhD; John K. Yue, MD; Ross Zafonte, DO.

Affiliations of The TRACK-TBI Investigators: Massachusetts General Hospital, Boston (Bodien, Rosand); University of California, San Diego, La Jolla (Jain); Department of Physical Medicine and Rehabilitation, Baylor College of Medicine, Houston, Texas (Sander); University of Cincinnati, Cincinnati, Ohio (Adeoye, Foreman, Kreitzer); University of Maryland, College Park (Badjatia, Gullapalli); Department of Rehabilitation Medicine, University of Washington, Seattle (Boase, Machamer); University of Miami, Coral Gables, Florida (Bullock, Hotz); Department of Neurological Surgery, University of Washington, Seattle (Chesnut, Ellenbogen); Ohio State University, Columbus (Corrigan); University of Southern California, Los Angeles (Crawford, Gaudette, Seabury, Toga); MassGeneral Hospital for Children, Boston, Massachusetts (Duhaime); Department of Emergency Medicine, Virginia Commonwealth University, Richmond (Feeser); Department of Neurological Surgery, University of California, San Francisco (Ferguson, Taylor, Vassar); Department of Neurology, University of California, San Francisco (Gardner, Hemphill, Kramer); TIRR Memorial Hermann, Houston, Texas (Gonzalez, Sherer); Department of Neurosurgery, Baylor College of Medicine, Houston, Texas (Gopinath); Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor (Korley); Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee (Lindsell); Department of Neurological Surgery, UT Southwestern Medical Center, Dallas, Texas (Madden); Department of Radiology & Biomedical Imaging, University of California, San Francisco (Martin, Palacios); Department of Psychiatry, Indiana University School of Medicine, Indianapolis (McAllister); Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond (Merchant); Dan L. Duncan Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas (Noel); Department of Pathology, Uniformed Services University, Bethesda, Maryland (Perl); Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (Puccio); Department of Neurology, University of Pennsylvania, Philadelphia (Rabinowitz); Brain and Spinal Cord Injury Center, Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, California (Satris); Department of Psychology, University of Texas at Austin, Austin (Schnyer); Department of Neurosurgery, Virginia Commonwealth University, Richmond (Valadka); Brain and Spinal Cord Injury Center, Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, California (Vassar, Yue); Department of Neurology, University of California Los Angeles School of Medicine, Los Angeles (Vespa); Department of Psychiatry, University of Florida, Gainesville (Wang); Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, Massachusetts (Zafonte).

Author Contributions: Dr Temkin and Mr Barber had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Nelson, Dikmen, Giacino, McCrea, Okonkwo, Diaz-Arrastia, Manley, Adeoye, Bodien, Corrigan, Goldman, Sherer, Valadka, Vespa, Wang, Yue.

Acquisition, analysis, or interpretation of data: Nelson, Temkin, Dikmen, Barber, Giacino, Yuh, Levin, McCrea, Stein, Mukherjee, Okonkwo, Diaz-Arrastia, Manley, Adeoye, Badjatia, Boase, Bodien, Bullock, Chesnut, Corrigan, Crawford, Duhaime, Ellenbogen, Feeser, Ferguson, Foreman, Gardner, Gaudette, Gonzalez, Gopinath, Gullapalli, Hemphill, Hotz, Jain, Korley, Kramer, Kreitzer, Lindsell, Machamer, Madden, Martin, McAllister, Merchant, Noel, Palacios, Perl, Puccio, Rabinowitz, Robertson, Rosand, Sander, Satris, Schnyer, Sherer, Taylor, Toga, Vassar, Yue, Zafonte.

Drafting of the manuscript: Nelson, McCrea, Okonkwo, Noel, Rabinowitz, Sherer, Taylor, Vassar, Yue.

Critical revision of the manuscript for important intellectual content: Temkin, Dikmen, Barber, Giacino, Yuh, Levin, McCrea, Stein, Mukherjee, Okonkwo, Diaz-Arrastia, Manley, Adeoye, Badjatia, Boase, Bodien, Bullock, Chesnut, Corrigan, Crawford, Duhaime, Ellenbogen, Feeser, Ferguson, Foreman, Gardner, Gaudette, Goldman, Gonzalez, Gopinath, Gullapalli, Hemphill, Hotz, Jain, Korley, Kramer, Kreitzer, Lindsell, Machamer, Madden, Martin, McAllister, Merchant, Palacios, Perl, Puccio, Robertson, Rosand, Sander, Satris, Schnyer, Toga, Valadka, Vespa, Wang, Yue, Zafonte.

Statistical analysis: Temkin, Barber, McCrea, Okonkwo, Ferguson, Jain, Yue.

Obtained funding: Mukherjee, Diaz-Arrastia, Manley, Adeoye, Corrigan, Duhaime, Goldman, Valadka, Wang.

Administrative, technical, or material support: Dikmen, McCrea, Mukherjee, Okonkwo, Manley, Adeoye, Bodien, Crawford, Duhaime, Ellenbogen, Ferguson, Foreman, Gonzalez, Gopinath, Gullapalli, Lindsell, Martin, McAllister, Noel, Palacios, Perl, Puccio, Rabinowitz, Robertson, Rosand, Satris, Schnyer, Taylor, Valadka, Vassar.

Supervision: Giacino, McCrea, Okonkwo, Diaz-Arrastia, Chesnut, Corrigan, Ellenbogen, Gopinath, Robertson, Sander.

Conflict of Interest Disclosures: Dr Nelson reported grants from Department of Defense (DoD) during the conduct of the study; grants from National Institutes of Health (NIH), grants from Medical College of Wisconsin Center for Patient Care and Outcomes Research, grants from Advancing a Healthier Wisconsin, and grants from the DoD outside the submitted work. Dr Temkin reported grants from NIH-National Institute of Neurological Disorders and Stroke (NINDS) during the conduct of the study. Dr Giacino reported grants from the NIH-NINDS during the conduct of the study. Dr Yuh reported grants from the University of California, San Francisco during the conduct of the study; in addition, Dr Yuh had a patent for USPTO No. 62/269,778 pending. Dr McCrea reported grants from the NIH and DoD during the conduct of the study. Dr Stein reported personal fees from Aptinyx, Bionomics, Janssen, and Neurocrine; as well as personal fees and stock options from Oxeia Biopharmaceuticals outside the submitted work. Dr Mukherjee reported grants from GE Healthcare and nonfinancial support from GE-NFL Head Health Initiative outside the submitted work; in addition, Dr Mukherjee had a patent for USPTO No. 62/269,778 pending. Dr Diaz-Arrastia reported personal fees and research funding from Neural Analytics Inc and travel reimbursement from Brain Box Solutions Inc outside the submitted work. Dr Manley reported grants from the NINDS during the conduct of the study; research funding from the US Department of Energy, grants from the DoD, research funding from Abbott Laboratories, grants from the National Football League Scientific Advisory Board, and research funding from One Mind outside the submitted work; in addition, Dr Manley had a patent for Interpretation and Quantification of Emergency Features on Head Computed Tomography issued. He served for 2 seasons as an unaffiliated neurologic consultant for home games of the Oakland Raiders; he was compensated $1500 per game for 6 games during the 2017 season but received no compensation for this work during the 2018 season. Dr Adeoye reported grants from the NIH/NINDS during the conduct of the study. Dr Boase reported grants from TRACK-TBI Grant during the conduct of the study. Dr Bodien reported grants from Spaulding Rehabilitation Hospital during the conduct of the study. Dr Corrigan reported grants from University of California, San Francisco during the conduct of the study. Dr Duhaime reported grants from the NIH during the conduct of the study. Dr Feeser reported grants from Virginia Commonwealth University during the conduct of the study. Drs Merchant and Dr Valadka are Track-TBI investigators at Virginia Commonwealth University. Dr Ferguson reported grants from the NIH/NINDS, the DoD, Veterans Affairs, Craig H. Neilsen Foundation, Wings for Life Foundation, and the Department of Energy during the conduct of the study. Dr Goldman reported grants from the NINDS and USC Schaeffer Center during the conduct of the study; personal fees from Amgen, Avanir Pharmaceuticals, Acadia Pharmaceuticals, Aspen Health Strategy Group, and Celgene outside the submitted work. Dr Gopinath reported grants from the NIH and DoD during the conduct of the study. Dr Kreitzer reported personal fees from Portola outside the submitted work. Dr Lindsell reported grants from the NIH during the conduct of the study. Dr Machamer reported grants from the NIH during the conduct of the study. Dr Madden reported grants from the NIH Track TBI Study and One Mind for Research during the conduct of the study. Dr McAllister reported grants from UCSF from the NIH and the National Collegiate Athletic Association and the DoD during the conduct of the study. Dr Robertson reported grants from the NIH and DoD during the conduct of the study. Dr Rosand reported grants from the NIH during the conduct of the study; personal fees from Boehringer Ingelheim and New Beta Innovations outside the submitted work. Dr Sander reported grants from the NIH during the conduct of the study. Dr Sherer reported receiving partial funding through a grant for this study. Dr Vespa reported grants from the NIH during the conduct of the study. Dr Zafonte received royalties from Oakstone for an educational CD (Physical Medicine and Rehabilitation: a Comprehensive Review) and Demos publishing for serving as coeditor of Brain Injury Medicine. Dr Zafonte serves or served on the scientific advisory boards of Myomo, Oxeia Biopharma, Biodirection, and Elminda. He also evaluates patients in the MGH Brain and Body-TRUST Program, which is funded by the National Football League Players Association. Dr Zafonte had served on the Mackey White Committee. No other disclosures were reported.

Funding/Support: The study was funded by US NIH-NINDS grant U01 NS1365885, OneMind, NeuroTrauma Sciences LLC, and US DoD TBI Endpoints Development Initiative grant W81XWH-14-2-0176.

Role of the Funder/Sponsor: The primary funder of the study (NIH) contributed to the design and conduct of the study. They played no role in collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication

Disclaimer: The article contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH and are not necessarily endorsed by the US Department of Defense or other study sponsors.

Additional Contributions: Amy J. Markowitz, JD (Program Manager, TRACK-TBI/TED Traumatic Brain Injury Research Network, University of California, San Francisco), provided editorial services for the manuscript. Compensation was received for these editorial services.