TRANSCENDENT (Transforming Research by Assessing Neuroinformatics across the Spectrum of Concussion by Embedding iNterdisciplinary Data-collection to Enable Novel Treatments): protocol for a prospective observational cohort study of concussion patients with embedded comparative effectiveness research within a network of learning health system concussion clinics in Canada ===================================================================================================================================================================================================================================================================================================================================================================================== * Roger Zemek * Lisa M Albrecht * Sharon Johnston * John Leddy * Andrée-Anne Ledoux * Nick Reed * Noah Silverberg * Keith Yeates * Monica Lamoureux * Charlotte Anderson * Nicholas Barrowman * Miriam H Beauchamp * Kitty Chen * Araba Chintoh * Achelle Cortel-LeBlanc * Miguel Cortel-LeBlanc * Daniel J Corwin * Stephanie Cowle * Kristine Dalton * Jennifer Dawson * Andrew Dodd * Khaled El Emam * Carolyn Emery * Erin Fox * Pamela Fuselli * Isabelle J Gagnon * Christopher Giza * Steven Hicks * David R Howell * Stephen Alexander Kutcher * Carlos Lalonde * Rebekah C Mannix * Christina L Master * Andrew R Mayer * Martin H Osmond * Rebecca Robillard * Kathryn J Schneider * Peter Tanuseputro * Ivan Terekhov * Richard Webster * Cheryl Lea Wellington ## Abstract **Introduction** Concussion affects over 400 000 Canadians annually, with a range of causes and impacts on health-related quality of life. Research to date has disproportionately focused on athletes, military personnel and level I trauma centre patients, and may not be applicable to the broader community. The TRANSCENDENT Concussion Research Program aims to address patient- and clinician-identified research priorities, through the integration of clinical data from patients of all ages and injury mechanisms, patient-reported outcomes and objective biomarkers across factors of intersectionality. Seeking guidance from our Community Advisory Committee will ensure meaningful patient partnership and research findings that are relevant to the wider concussion community. **Methods and analysis** This prospective observational cohort study will recruit 5500 participants over 5 years from three 360 Concussion Care clinic locations across Ontario, Canada, with a subset of participants enrolling in specific objective assessments including testing of autonomic function, exercise tolerance, vision, advanced neuroimaging and fluid biomarkers. Analysis will be predicated on pre-specified research questions, and data shared with the Ontario Brain Institute’s Brain-CODE database. This work will represent one of the largest concussion databases to date, and by sharing it, we will advance the field of concussion and prevent siloing within brain health research. **Ethics and dissemination** This study was approved by the Children’s Hospital of Eastern Ontario Research Ethics Board and preregistered on OSF (25 June 2024); [https://doi.org/10.17605/OSF.IO/HYDZC](https://doi.org/10.17605/OSF.IO/HYDZC). Dissemination of findings will be multifaceted, including conference presentations, peer-reviewed publications and sharing of adapted materials (eg, videos, infographics, plain language summaries) with community groups and key knowledge users. * Brain Injuries * REGISTRIES * EPIDEMIOLOGY * Observational Study ### Strengths and limitations of this study * To ensure findings are relevant to the concussion community, our research priorities were established in partnership with patients with lived concussion experience, caregivers and front-line clinicians as part of the James Lind Alliance Priority Setting Partnership. TRANSCENDENT will actively involve a Community Advisory Committee with lived experience to provide longitudinal input into research, outreach and knowledge translation activities. * While caring for thousands of Ontarians with concussion, we will generate a rich and robust dataset of at least 5500 participants to transform concussion care and incubate discovery on brain health and recovery across the spectrum of concussion. * Participants will be recruited from three locations of the 360 Concussion Care clinic system in three major cities in Ontario, Canada (Ottawa, Mississauga, Toronto); patients of all ages, across the spectrum of injury types, causes and acuity will be eligible. Whereas much of prior concussion research focused largely on military and athletic injuries, TRANSCENDENT findings will draw from and be applicable to the wider concussion community. * A study limitation is that treatment at 360 Concussion Care is primarily via physician referral, and recruitment and core assessments of TRANSCENDENT are conducted in the clinic; this may influence participation and retention of patients with specific demographics and/or symptom range and severity. We will assess this limitation by comparing patient characteristics of TRANSCENDENT participants to provincial health administrative datasets to determine the generalisability of our findings. ## Introduction ### Background information and scientific rationale Concussion is a complex pathophysiological process that affects the brain, induced by biomechanical forces such as a direct blow to the head (or a blow to the neck or body that is transmitted to the head).1 Concussions affect at least 400 000 Canadians annually, with almost 40% of these occurring in Ontario2 3; they have an enormous impact on health, well-being and the economy.4–8 Concussions can lead to absenteeism and/or presenteeism from school, work, sports and other meaningful activities, resulting in increased primary care9 and specialist visits10 and mental health issues, particularly in children.11–13 Certain persisting symptoms after concussion (PSaC), such as balance deficits, can also increase the probability of future concussions and other injuries.14 15 Mechanisms of concussion injury are most often falls, motor vehicle collisions and sport-related injuries.16 Workplace injury and intimate partner violence are also significant causes.7 17–19 In the paediatric population, previous research demonstrated that most patients recover within 2–4 weeks of injury, but up to one-third may experience PSaC,20 21 defined as concussion symptoms that last at least 1 month after injury22; adults show a similar prevalence of PSaC at least 1 month after injury.23–28 PSaC can significantly affect health-related quality of life across all ages.20 29–31 Though concussions are common across settings and throughout the lifespan, concussion research has predominantly focused on primarily male athletes and military personnel as these demographics experience a particularly high risk of initial and repeated concussions, coupled with greater visibility.32–36 The generalisability of these studies is further limited because participants often have high levels of preinjury athletic, visual and vestibular functioning, and are highly motivated and supported to return to their daily activities. Most civilian studies, including those from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury37 and Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury38 cohorts, recruited patients from level I trauma centres; however, many people with concussion seek care at a regional or community hospital, or do not visit any emergency department.39 40 Our understanding across the spectrum of concussion remains limited, particularly for other mechanisms of injury (eg, intimate partner violence and assaults)41 and in under-represented groups, including women,35 older adults, racialised people, Indigenous peoples, people with comorbidities and people from economically disadvantaged households. Finally, a lack of standardised definitions for concussion and mild traumatic brain injury (TBI) severity has recently been recognised by the American Congress of Rehabilitation Medicine (ACRM) as leading to diagnostic variability and uneven access to clinical care, as well as limiting comparability of research findings.42 Effective diagnosis, symptom management and treatment must be tailored to the individual based on their injury, goals, demographics, psychosocial and physiological data—as recognised in sports medicine43–45 and more recently adopted in other settings.46 47 However, precision medicine using data-driven methods is not yet attainable due to inadequately powered datasets,35 48 49 rudimentary self-reporting and limited research across the general population with concussion.50–52 State-of-the-art assessments and the application of neuroinformatics and advanced analytics are needed to better understand concussion and examine how individual factors, injury mechanisms and therapies modulate concussion recovery. To achieve our ultimate goal of precision medicine in concussion, large datasets must be generated that aggregate prospectively collected, standardised and multimodal data. TRANSCENDENT will achieve these goals by incorporating medical history, symptom evaluation, physical examination findings, assessment of mental health and resiliency, social supports, and functional outcomes (including quality-of-life), and combine these with objective biomarkers (eg, physiological, fluid and neuroimaging) across factors of intersectionality (eg, sex and gender, race and ethnicity, pre-existing comorbidities, mechanism of injury) to address patient- and clinician-identified research priorities and advance concussion care. These data will also be linked to the Ontario provincial administrative health records database ICES for additional aggregate data collection. ### Purpose and goals The purpose of the TRANSCENDENT Concussion Research Program is to integrate innovative objective assessments (eg, physiological evaluations, fluid biomarkers, advanced neuroimaging) alongside extensive, validated, concussion clinical data collection methods. These are standardised across three clinic sites and prospectively collected by interdisciplinary providers to answer pressing clinical questions about diagnosis, management and treatment across the spectrum of concussion.20 53–61 In parallel and integrated into this project, we will implement a robust knowledge translation (KT) plan that engages and works alongside patients and people with lived experience in concussion. This integrated patient and partner engagement will enhance the relevance and impact of the project, improve the quality of care, ensure that research directions and methodology are patient-centred and responsive to the needs of the community, and promote relevant and accessible dissemination of discoveries to those who can benefit most. ### Objectives The TRANSCENDENT Concussion Research Program is driven by patient, caregiver and clinician priorities established by the James Lind Alliance Priority Setting Partnership in concussion,62 which inspired the following objectives: * Determine which interventions (pharmacological or non-pharmacological) reduce post-concussion symptoms, shorten the duration of recovery, reduce PSaC incidence and improve the ability to fulfil life roles. * Evaluate how social determinants of health and their intersectionality (eg, sex/gender, age, socioeconomic status, social supports), mechanism of injury, mental health factors and comorbidities influence outcomes and long-term prognosis. * Determine the ideal timing and approach to return to cognitive activities at school or work. * Explore how physical activity and prescribed aerobic exercise treatment (timing, type and intensity) can be optimised to improve autonomic dysfunction and/or hasten recovery. * Identify which physiological (eg, autonomic dysfunction, sleep disturbances), fluid (eg, salivary and blood) and/or neuroimaging biomarkers can detect concussion, predict prolonged symptoms and measure recovery. * Evaluate whether improvements in concussion diagnosis (eg, physiological biomarkers such as fluid, neuroimaging, clinical and functional) can support equitable access to healthcare for rural and remote Canadians. * Explore the role that machine learning and advanced neuroanalytics have in supporting precision medicine approaches for concussion. * Assess the usability and impact of data linkage with population health datasets in predicting/evaluating a wide range of long-term outcomes following concussion, including an understanding of health services utilisation across health sectors (eg, outpatient care, acute care, home care and rehabilitation). ## Methods and analysis ### Study design The TRANSCENDENT Concussion Research Program is a prospective cohort study with embedded comparative effective research (CER), adhering to the Strengthening the Reporting of Observational Studies in Epidemiology checklist63 (online supplemental file 1). All patients referred to the three 360 Concussion Care clinics (Ottawa, Mississauga and Toronto) for concussion or suspected concussion who, or whose parent/guardian, can complete the informed consent process in English, French or via a translator will be eligible to participate in TRANSCENDENT research, though specific objective assessments have their own inclusion and exclusion criteria. ### Supplementary data [[bmjopen-2024-095292supp001.pdf]](pending:yes) #### 360 Concussion Care clinic model 360 Concussion Care is a physician-led, interdisciplinary network of concussion clinics grounded as a learning health system. It was founded by internationally renowned concussion clinician-researchers who developed some of the world’s most impactful advances in concussion treatment, to provide early access to concussion care and prevent long wait times. All patients are seen by physicians in neurology, paediatrics, family or emergency medicine and may be referred by emergency departments in each clinic’s respective city as well as from independent centres. The clinic treats physician-referred patients (or self-referred athletes) of all ages and injury mechanisms with an interdisciplinary team of physicians, allied health professionals (physiotherapists, occupational therapists, massage therapists and rehabilitation assistants) and mental health professionals (social workers and neuropsychologists). Physicians conduct an initial assessment using standardised questionnaires incorporating concussion-specific common data elements (some of which are patient-reported through questionnaires). The cost of the initial physician assessment is covered by provincial health coverage (Ontario Health Insurance Plan (OHIP)), and allied healthcare (such as physiotherapy, occupational therapy, mental health counselling) is through extended health insurance, via injury-specific insurance (eg, Workplace Safety and Insurance Board (WSIB) or Motor Vehicle Accident (MVA) insurance), or directly by the patient. All data are entered into the clinic’s electronic medical record (EMR) platform, Telus Collaborative Health Record (CHR). As 360 Concussion Care is a community-based clinic, it serves a diverse population. Since December 2022, motor vehicle collisions and falls have been the mechanism of injury for approximately the same number of new patients (23% and 24%, respectively). Sport-related injuries (all ages and levels) have accounted for 38% of concussions, with the remainder associated with workplace injury (12%) and assaults (3%). ### Participant recruitment and enrolment #### Study setting and sample size The study setting is the 360 Concussion Care clinics located in Ottawa, Toronto and Mississauga, Ontario. The target sample size is 5500 participants over 5 years, based on approximately 2000 new patients seen annually and 75% consent rate; this consent rate is based on a previous large prospective concussion research study conducted by our team in the emergency department,20 which is known to be a challenging setting in which to obtain consent.64 Achieving ~5500 participants will allow us to develop multivariable clinical prediction rules.65 Following the recommendations in Riley *et al*65 and using the R package developed by these authors (pmsampsize), a sample size for a binary prediction model was estimated. For instance, assuming a prevalence of PSaC of 20%,20 24 66–68 Cox-Snell R2 of 0.06 (based on a Nagelkerke R2 of 0.15, as is common for binary prediction models) and assuming 35 degrees of freedom to allow for a rich set of predictors with potential non-linearity, the required sample size is 5100 (online supplemental file 2); target sample sizes for clinical prediction studies are frequently set at about 5000 patients.65 ### Supplementary data [[bmjopen-2024-095292supp002.pdf]](pending:yes) #### Informed consent As part of clinical care, all patients (or their legal guardians) being seen at 360 Concussion Care will receive pre-visit questionnaires prior to their initial assessment, via the clinic’s EMR. At that time, patients have the option to be re-directed to an e-consent link for participation in TRANSCENDENT or to speak in person with a research staff member to learn more about the study, in which case the consent process will be completed in person. The consent discussion will emphasise that receiving clinical care at the clinic is independent of study participation. Patients who request but may not have the opportunity to consent in clinic, or those who require additional time, will be followed up a maximum of three times post-visit. At the initial visit, participants will also be screened for eligibility to participate in subsequent objective assessments within TRANSCENDENT; objective assessment screening and consent will only be done in person with research staff. Consent for all research processes will be provided via a REDCap e-consent form, based at the Children’s Hospital of Eastern Ontario Research Institute (CHEO RI). Assent will be obtained from participants who lack the ability to consent, and the parent or legal guardian will provide consent in those cases. #### Enrolment and withdrawal Patients will initially consent to the secondary use of clinical data and will then be approached for consent to participate in additional objective assessments. Phased implementation and completion of assessments is strategically planned to optimise co-enrolment in objective assessments without imposing a burden on participants. Participants may withdraw from TRANSCENDENT objective assessments or secondary data use (which will automatically result in withdrawal from any additional objective assessments) at any time, resulting in the stoppage of research procedures and no further data collection. There are two withdrawal options: (1) ‘No further access’, where data collected to the withdrawal date may be retained; or (2) ‘No further use’, where all data previously collected is destroyed/excluded from further analysis (analyses resulting from data used up to the withdrawal date cannot be destroyed). #### Participant adherence and retention For research activities not completed in-person in the clinic or at subsequent research visits, participants will receive an automated email reminder and (if needed) a single reminder call per missed activity from research staff prior to recording a loss to follow-up for that activity. Alternatively, if an upcoming clinical appointment is scheduled, research assistants will attempt to collect adjunctive research data at that encounter, before recording a loss to follow-up. Additionally, participants will be reimbursed for parking expenses and receive gift cards as a token of appreciation for completing study activities. Gift card amounts are not expected to be coercive, and volunteer hours are also available if participants are high school students who prefer this for school credit. #### Secondary use of clinical data All TRANSCENDENT participants will be asked to consent to the use of de-identified 360 Concussion Care clinical data before data are used for research purposes. The data collected for this study will be captured, stored and shared via the Ontario Brain Institute’s (OBI’s) Brain-CODE neuroinformatics platform. Brain-CODE is a large-scale neuroinformatics platform designed to support the collection, storage, federation, sharing and analysis of different data types across several brain disorders, as a means to understand common underlying causes of brain dysfunction and develop novel approaches to treatment.69 70 Brain-CODE supports the principles of making data Findable, Accessible, Interoperable and Reusable (FAIR).71 Brain-CODE was designed with best-practice privacy strategies at the forefront to enable the secure capture of sensitive participant data in a manner that abides by ethical principles and government legislation while fostering data sharing and linking opportunities. Brain-CODE includes encryption and de-identification tools to protect participant data and enhanced validation certificates to guarantee the authenticity of outward-facing software applications, as well as administrative, physical and technical safeguards and security processes. As a result, OBI was named a ‘Privacy by Design’ Ambassador by the Office of the Information and Privacy Commissioner of Ontario in 2011.72 73 Working with a team of experts, OBI has developed clear and comprehensive policies and guidelines on data privacy and governance. For patients who are residents of Ontario, health card number (OHIP) will also be collected to be linked to the databases held at ICES (formerly known as the Institute for Clinical Evaluative Sciences)74 to enable research that examines patient characteristics and health services use prior to and after concussion. ICES databases can be found on their website ([www.ices.on.ca/](https://www.ices.on.ca/)) and include emergency room visit data, hospital admission data and physician claims data for all Ontarians with an OHIP number. Participants who consent to secondary data use are also eligible to participate in additional objective assessments, and may also opt to be contacted about participation in other research opportunities related to TRANSCENDENT, concussion or brain health. Once a patient completes the consent process, they will be assigned a unique research ID number (participant ID) in REDCap (Research Electronic Data Capture). REDCap is a secure, web-based application designed exclusively to support data capture for research studies.75 Enrolment will be documented in REDCap and in the clinic’s EMR. #### Participant demographic data Patient data will be collected prior to the initial clinical visit via emailed questionnaires, and follow-up via EMR will occur up to a maximum of 15 months after the initial visit. Demographic data will include date of birth, sex, gender, race/ethnicity, education level, employment, household income and partial postal code. Partial postal codes will be used to determine accessibility and neighbourhood marginalisation indices for concussion patients,76 77 and can be linked to climate data. We will calculate the Ontario Marginalization Index (ON-Marg) to assess levels of material deprivation, ethnic concentration and residential instability, as well as explore individual markers such as immigrant status and language spoken. Our research will examine how these factors vary by care location, healthcare provider type and age group, comparing outcomes such as follow-up visits and duration of care. #### Duration of participation Depending on which additional research activities participants choose to enrol in, these may be scheduled for up to 12 weeks after the initial clinic visit. Where possible, research activities will be combined with scheduled clinic visits or performed at home (eg, questionnaires, saliva sample collection, wearable devices). ### Clinical data #### Concussion questionnaires In addition to the completion of demographics, medical and social questionnaires as part of clinic intake, participants will also complete specific age-based questionnaires related to concussion symptoms and their impacts. These are outlined in figure 1 and include the Sport Concussion Assessment Tool (SCOAT678) Symptom Evaluation (≥13 years of age) or Health and Behavior Inventory79 (<13 years of age) to obtain symptom scores, the Connor-Davidson Resilience Scale80 and a suite of mental health questionnaires for patients 10 years of age and older including the Patient Health Questionnaire-981 and General Anxiety Disorder-782 scale. As validated questionnaires become available for participants below this age, these will also be added. Additionally, a quality-of-life measure (WHOQoL-BREF83 or KINDL-R,84 by age) will be administered to ‘chronic’ patients injured more than 4 weeks earlier. Of these questionnaires, symptom score, quality of life and resilience will be obtained at two additional follow-up times (4 and 12 weeks post-visit). Additional questionnaires will be administered based on the specific objective assessments in which patients participate (eg, International Physical Activity Questionnaire (IPAQ)85 will be obtained for patients undergoing exercise assessments within the first 2 weeks of their initial visit). ![Figure 1](http://bmjopen.bmj.com/https://bmjopen.bmj.com/content/bmjopen/15/4/e095292/F1.medium.gif) [Figure 1](http://bmjopen.bmj.com/content/15/4/e095292/F1) Figure 1 Participant clinical and research activity timeline. BCBT, Buffalo Concussion Bike Test; BP, blood pressure; HR, heart rate; HRV, HR variability; SCOAT6, Sport Concussion Assessment Tool. #### Physical examination At initial clinic visits, physicians will conduct a physical examination using the Buffalo Concussion Physical Examination61 and the Visio-Vestibular Examination (VVE) within the SCOAT686 87 (figure 1). This includes orthostatic vitals, neurological examination, complex tandem gait test88 89 and balance assessment (using components of the Balance Error Scoring System, BESS,90 such as tandem stance as in our group’s previous research20). Additional outcomes include assessment of the vestibulo-ocular reflex (VOR) using a clinical test of dynamic visual acuity.91 ACRM criteria42 is used by physicians to augment clinical judgement and diagnose concussion as ‘definite’ or ‘probable’. As part of the initial visit, all physicians employ standardised algorithmic questions on each of the ACRM criteria. For example, for criterion 1, they document the type of force that produced the injury to determine whether it could plausibly cause concussion. #### Clinical interventions Consent to de-identified use of secondary data will allow documentation of specific treatments and interventions received by participants. This includes time-stamped clinic-based procedures (eg, rehabilitation activities, referrals to mental health specialists, pharmacological and non-pharmacological treatments) as well as patient-reported external treatments and accommodations (eg, back-to-school or back-to-work plans, lifestyle interventions, additional non-clinic treatment). ### Research biomarkers TRANSCENDENT includes numerous objective assessments, and participants may enrol in as many as they are eligible for. A priori planned objective assessments include: (1) autonomic dysfunction (head-up tilt test), (2) aerobic exercise tolerance (Buffalo Concussion Bike Test (BCBT)/Buffalo Concussion Treadmill Test (BCTT)),92 (3) pupillometry using PLR-4000 (NeurOptics, Irvine, California, USA), (4) eye-tracking using EyeBOX (Oculogica, New Richmond, Wisconsin, USA), (5) salivary biomarkers, (6) blood biomarkers and (7) advanced neuroimaging (MRI). Each has specific eligibility criteria and research activities (see table 1) and enrolment targets. View this table: [Table 1](http://bmjopen.bmj.com/content/15/4/e095292/T1) Table 1 Objective assessment criteria and summary of research activities* Additional objective assessments (eg, wearable devices) may be added or incorporated into the a priori assessments with specific research activities and enrolment targets dependent on resource availability and enrolment rates. ### Physiological biomarkers Objective assessments and clinical examinations will involve measurement of specific physiological biomarkers, known or suspected to be impacted by concussion. #### Autonomic dysregulation and dysfunction Autonomic dysregulation/dysfunction (AD) describes a condition in which the autonomic nervous system cannot maintain homeostasis of physiological functions (eg, blood pressure and heart rate), resulting in physiological anomalies and/or symptom exacerbation. Although AD has been described after moderate and severe forms of TBI93 94 investigation of AD characterised by orthostatic intolerance following concussion is relatively recent.95–98 Autonomic dysfunction may contribute to the persistence of post-concussion symptoms, whereas normal autonomic function may correlate with symptom reduction.94 98 99 Although there is no gold standard test,100 the head-up tilt test is considered a reference test,101 and simultaneous heart rate variability will be measured using validated software as detailed in table 1. Tilt table testing as a means of assessing orthostatic hypotension or autonomic dysregulation has been studied across all ages, with age-specific guidelines for identifying autonomic dysfunction.102–106 #### Symptom provocation during exercise In addition to symptoms that are reported at rest, some concussion patients report increased symptom frequency and severity during exercise as heart rate increases, preventing them from exercising to the level of their preinjury physical fitness.59 107 However, physical activity may be beneficial even while symptomatic, as prior concussion studies confirm that early physical activity as tolerated (eg, walking), as well as individualised targeted heart rate aerobic exercise treatment based on the results of formal exercise testing facilitate symptom recovery in athletes and in youth.54 108–110 Thus, early low-risk aerobic exercise treatment is recommended for facilitating recovery in athletes and in youth according to the latest international concussion guidelines,86 but the role of this approach for treating concussion in older adults and non-athletes remains unclear. The BCBT was adapted from and validated against the BCTT in adolescents with acute concussion.111 The BCTT has also produced comparable results to the Calgary Concussion Cycle Test in a cross-over study of healthy adults,112 which supports the integration of TRANSCENDENT findings with existing literature. #### Visual and visio-vestibular dysfunction Concussion is known to affect the visual system, with clinicians routinely assessing pupils and eye-tracking capability of patients with known or suspected TBI as part of their neurological examination.113–116 Vision disorders and visio-vestibular dysfunction have been linked to PSaC in children and adolescents,117 118 and can be identified via pupillometry, eye tracking and assessment of the visio-vestibular system using the VVE within the SCOAT6.86 87 Of these tools, the complex tandem gait task included within the VVE has shown high interrater reliability among non-specialists,119 the VVE has been used across populations120 and settings,121 and the BESS can detect balance deficits associated with concussion with moderate to good reliability,89 122 particularly in the paediatric population.123 The behavioural function of the VOR will be assessed using a clinical test of dynamic visual acuity.91 Additional components of the SCOAT6 will be performed as applicable—including cervical spine assessment, cranial nerves and neurological evaluation, and gradient exercise testing. Early identification and appropriate management of visual and vestibular symptoms may mitigate concussion symptoms,117 124 facilitate return to school118 and potentially identify those at risk of PSaC or prolonged recovery.125 #### Fluid biomarkers Several plasma proteins have been assessed as potential diagnostic biomarkers for concussion with some demonstrating resilience to previous concussion history126 127 and improved discrimination of concussed athletes when compared with symptom severity alone.128 129 Although inflammatory markers are known to be influenced by external factors (eg, diet and lifestyle), these have the potential for prognostic value when analysed holistically in light of these external factors.128 130 Technologies to quantify blood-based biomarkers for neurological indications including concussion are rapidly expanding, with highly multi-plexed options available to optimise the number of biomarkers that can be assessed in small volumes of plasma.131 Small non-coding(nc)RNAs play an essential role in the control of gene expression throughout the body,132–135 and the best-studied in concussion are micro(mi)RNAs.136 These extremely stable137 ncRNAs are altered in pathway-specific patterns138 139 to block translation of specific proteins in response to environmental changes, such as a concussion.140 They are found at high concentrations in saliva,141 and comparison of salivary miRNA with blood-based biomarkers has the potential to improve non-invasive diagnostics for PSaC and other functional concussion outcomes.142 143 Further, as the largest studies of miRNAs focus on diagnosis and sport-related concussion,144 145 TRANSCENDENT is positioned to continue developing this area of research in the broader concussion population and for prognosis and tracking of recovery. #### Advanced neuroimaging Concussion pathophysiology has been associated with axonal injuries, neurochemical imbalances, alterations in brain perfusion, changes in glucose metabolism and other cerebral pathophysiology.146–148 It has been suggested that insults to the cerebrovascular control system, including neurovascular coupling (increased flow in response to increased neuronal activity and metabolic demand), cerebral vasoreactivity and cerebral autoregulation mechanisms could contribute to the symptoms reported in concussion—such as cognitive difficulties, headaches and dizziness.149 CT scans are not sensitive to the most probable pathological features of concussions,150 nor is routine structural MRI.150 However, advanced MRI is a promising field for the detection of neurophysiological disturbances implicated in concussion recovery.151–153 #### Wearable data collection Outside of a priori planned objective assessments, additional research activities will be integrated with appropriate funding and time, primarily using wearable technology. These assessments will include but are not limited to: * Movement—for a subset of participants in the exercise tolerance assessment, wearable Polar H10 (Kempele, FI) heart rate monitors and ActiGraph (Pensacola, USA) wGT3X-BT activity trackers (accelerometers) will be used to obtain activity data during the 2-week interim between exercise tolerance assessments. * Neurological activity during sleep—participant sleep EEG recordings will be obtained using the low-cost portable Muse EEG system (Toronto, Canada). This device measures multiple waveforms across the left and right temporal lobes and has been used extensively in research applications, including diagnosis of stroke154 155 and other neurological disorders. * Neurological activity and event-related potentials (ERPs)—by rapidly obtaining EEGs in-clinic using state-of-the-art wearable devices, device algorithms will be used to identify ERP data as a measure of cognitive function deviation from baseline. ### Data handling #### Data collection, management and transfer Data collection will primarily be done through 360 Concussion Clinic’s EMR (Telus CHR) and through the CHEO RI validated instance of REDCap. The application and data are stored on CHEO servers, and local support is provided by CHEO RI’s Clinical Research Unit (CRU). All EMR data being used for research purposes will be de-identified and sent to the CHEO RI via SharePoint for data management and analyses at the CRU (linkable by participant study ID); REDCap information may be directly accessed by the CRU. Research data will then be securely transferred from the CHEO RI to OBI via OBI’s Brain-CODE neuroinformatics platform (linkable by an OBI participant ID).69 Study data at CHEO RI will be stored for 7 years after the completion of the study and then destroyed. #### Data use and analysis We will analyse the de-identified research data considering the programme’s research objectives, with separate statistical analysis plans for each. These analyses will examine factors that may mediate recovery, prognosis and effectiveness of management, while adjusting for potential confounders for recovery including known risk factors. Additionally, exploration of diverse populations and the impact of factors of intersectionality will be critical to better understand the true impact of concussion and to innovate targeted approaches for a diverse population. Data analyses will be focused on the epidemiology of outcomes of concussion and comparative effectiveness research, as detailed in the Analysis section. #### Confidentiality and privacy protection Study measures protecting participant confidentiality and privacy will include: (1) the replacement of direct participant identifiers with participant ID numbers, with storage of identifiers and codes in a separate database; (2) restricting access to this linking information to authorised members of the research programme; and (3) using secure data sharing mechanisms. Personal information will be kept strictly confidential except as required or permitted by law. In terms of platforms in use, Brain-CODE uses encryption and de-identification tools, enhanced validation certificates, and administrative, physical and technical security considerations. Information will be transferred from CHEO RI to the ICES secure environment via the ICES Axway Secure Transport web portal, where identifying information linked to OHIP numbers will be de-identified and instead assigned an ICES Key Number to link it to administrative datasets for project analyses. Research outputs will only contain non-identifiable, aggregate data (ie, no line-level data, no data that could be subsequently re-identified). #### Open science and data interoperability TRANSCENDENT will integrate and openly share diverse data sources on concussion patients and will adhere to FAIR Data Principles. To be interoperable, metadata will use a formal, accessible, shared and broadly applicable language for knowledge representation, using standard controlled vocabularies. Critically, instead of piecewise manual or bidirectional connections, information exchange will be automated and built for this complex data ecosystem. This will reduce the chance of human error when exchanging information and allow for data architects to efficiently maintain these database connections. While our original investigators will have a responsibility to adhere to FAIR principles, external researchers re-using TRANSCENDENT data will have shared responsibility; we will partner with OBI and Brain-CODE to review data access requests. Furthermore, a thorough understanding of the original protocols and processes is necessary to properly reanalyse open-access data. TRANSCENDENT established a reproducibility policy: a GitHub repository will be used to share version control for the data analysis code and analysis files. Data interoperability will enable data linkage with provincial and federal databases (eg, ON-Marg, Canadian Health Measures Survey Biobank, as well as existing research databases (eg, our team’s 5P dataset),20 also housed in Brain-CODE). ### Analysis All design and analyses will be carried out by a diverse team of expert methodologists (eg, epidemiologists, biostatisticians and machine learning experts). As the TRANSCENDENT Concussion Research Program will result in numerous objective assessments, each analysis will be predicated on the research question; the variables included in the data analysis plans for each substudy may vary and therefore may include adjunctive factors such as clinic setting, provider type, individual provider and seasonal variation. The following provides exemplars to summarise the statistical considerations for several planned assessments. #### Analysis of race data A standardised approach will be used for race data preprocessing and analysis choices; race dummy variables will be converted into a race composite variable to facilitate analysis, and any participants who select the not applicable level will be excluded. For research questions where race is being adjusted for (ie, not the primary exposure of interest) the minimum sample size to include race groups will be set at n≥30. Further, to avoid the ‘Table Two Fallacy’ neither the race omnibus nor level-specific p values will be reported. For research questions where race is the primary exposure of interest, higher confidence is required for reporting race group differences, so the minimum sample size to include race groups will be increased to n≥50. Further, sensitivity analysis will be performed to vary the definition of the multiracial group (figure 2). The default definition of the multiracial group may vary according to the research/clinical context. While the separate Indigeneity instrument variable is a distinct construct from race, to improve comparability across various intersectionality groups, race and indigeneity may be presented together. ![Figure 2](http://bmjopen.bmj.com/https://bmjopen.bmj.com/content/bmjopen/15/4/e095292/F2.medium.gif) [Figure 2](http://bmjopen.bmj.com/content/15/4/e095292/F2) Figure 2 Illustration of two ways to discretise and define the multiracial group (ie, those participants who self-identify with two or more racial groups). #### Comparative effectiveness research questions Causal diagrams (ie, directed acyclic graphs) will be refined by expert working groups and provided to the methodological team to inform each comparative effectiveness research (CER) study. This will inform the decision as to whether a variable is included/excluded as either a model covariate or used for propensity-score methods. This will also allow the expert team to identify potential sources of unmeasured confounding and consider mitigation strategies. One CER exemplar is the determination of optimal timing (early vs late) for resumption of physical activity to reduce symptom duration (outcome). Patients with different characteristics may be more or less likely to return to physical activity sooner. Therefore, to draw valid conclusions about this intervention’s effect, it is necessary to take this into account using appropriate analytic methods (eg, adjusting for characteristics, matching propensity scores or inverse probability of treatment weighting). Missing data will be summarised and handled as appropriate (eg, list-wise deletion, multiple imputation). Multivariable regression models will be fitted, and if non-linearity is present, extra flexibility will be achieved using restricted cubic splines. #### Epidemiological risk factor questions Following concussion, some patients experience AD, but its distribution in this population remains unknown. Incidence/prevalence measures will be estimated, as well as risk factors for AD, using Poisson and logistic regression models. Measures of association such as ORs and relative risks will be reported along with 95% CIs. #### Clinical prediction questions Whereas epidemiological models often focus on a priori identified risk-factor variables, prediction modelling uses all available data to derive rules that perform well. Continuing the exemplar above, to predict which patients are most likely to develop autonomic dysfunction, prediction models will be developed through a three-stage process of derivation, model assessment and validation. Model derivation will be performed using data subsets with techniques that limit overfitting (eg, Least Absolute Shrinkage and Selection Operator (LASSO)), as well as with machine learning methods, employing internal validation using bootstrapping and cross-validation. Model performance (discrimination and calibration) will be assessed. Finally, internal validation will be performed on the ‘holdout’ dataset. We will follow the Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis reporting guidelines for predictive algorithms.156 157 #### Precision medicine One approach to advance personalised medicine will be to leverage neuroinformatics—the combination of clinical data, advanced brain imaging, physiological data and fluid biomarker data, and apply advanced computational models including machine learning (eg, deep learning via convolutional neural networks) to detect patterns and uncover new insights in diagnosis, prognosis and recovery following concussion. This could allow for the identification of phenotypes that may be associated with symptom duration and severity, as well as those who may benefit from specific tailored interventions—which can be integrated with demographics and injury information to inform clinical care. As an example, research on our group’s 5P concussion data set58 has identified phenotypic symptom clusters of patients experiencing persistent high emotional, cognitive and fatigue domains but with minimal physical symptoms; these individuals would benefit from a targeted biopsychosocial approach to treatment based on mental health symptoms. ## Ethics and dissemination This study will be conducted in accordance with the Declaration of Helsinki and according to Canadian and international standards of Good Clinical Practice. The study protocol was approved by the Children’s Hospital of Eastern Ontario Research Ethics Board (REB Protocol No 24/17X) on 25 March 2024 and preregistered on OSF on 25 June 2024 ([https://doi.org/10.17605/OSF.IO/HYDZC](https://doi.org/10.17605/OSF.IO/HYDZC)). Enrolment began on 08 April 2024. Research data will be shared via OBI’s Brain-CODE neuroinformatics platform. KT, which aims to close the gap between research and practice,158 is central to TRANSCENDENT. TRANSCENDENT aims to disseminate research findings and support the implementation of best practices (eg, clinical practice guidelines) within the community. Dissemination, which involves identifying key knowledge users, framing research findings to their context and needs and using appropriate dissemination products and channels to share research findings with the selected knowledge users,159 will be multifaceted. Key dissemination products for TRANSCENDENT will include videos, infographics, manuscripts and plain language summaries. Products will be shared through channels such as peer-reviewed journals (open access when possible), presentations at relevant conferences, community education days, social media posts and through the programme’s website ([www.transcendentconcussion.ca](http://www.transcendentconcussion.ca)). When developing dissemination plans, the KT team will rely on the five questions to support the transfer of knowledge identified by Lavis and colleagues160 and will engage with the community through a community and patient advisory committee to identify and adapt knowledge transfer strategies. Additionally, initiatives to support implementation will be adopted (such as education and training) to promote the use of best practices developed through the research programme and will be guided by the Knowledge to Action Framework.161 All KT activities will be monitored, evaluated and refined throughout the course of the programme to maximise the impact of TRANSCENDENT’s KT efforts. All future projects led by TRANSCENDENT investigators seeking access to data and/or samples will require appropriate approvals; external requests will be reviewed by the principal investigator and other investigators as needed, and subject to appropriate approvals from governing institutions. Findings from this study will be integrated into clinical practice guidelines, which our team is also involved in developing. These guidelines are available in English and French and are shared internationally to ensure rapid translation of evidence to improve practices, policies and patient outcomes.162 163 Whereas TRANSCENDENT collaborators are represented on the adult guidelines development expert panel and on both the paediatric expert panel and project team, guideline methodology (eg, consensus and voting with quorum) prevents bias of guidelines toward including TRANSCENDENT findings. ### Patient and public involvement An important part of this research is engaging with and working alongside patients, people with lived experience and community members. We aim to ensure that the voices of people directly affected by concussion are heard and integrated into our research. This approach will help improve the reach of our project, include relevant real-world insights, promote transparency and build trust between researchers and the community.164–166 Patients and members of the public will be involved at all stages from planning to final project dissemination and implementation. TRANSCENDENT’s research objectives and research questions are driven by patient, caregiver and clinician priorities. Prior to developing this protocol, these priorities were established by members of our team using two national cross-sectional surveys and a consensus workshop as part of a formal James Lind Alliance Priority Setting Partnership Project.167 This project focused on identifying the top 10 concussion research questions from the perspectives of patients, caregivers and clinicians. Through this unique collaboration, patients, caregivers and clinicians worked together through a Priority Setting Partnership to determine the most important patient-oriented research questions in concussion.62 A Community Advisory Committee will be assembled that includes people with lived experience from diverse backgrounds. Committee members will include (but are not limited to) caregivers, coaches, teachers, youth and individuals who have experienced concussions through various mechanisms and at different stages of life. This committee will be formed using Abelson’s patient engagement strategy168 and based on feedback from CHEO’s Patient and Family Partnership Committee, the Canadian Institutes of Health Research Strategy for Patient-Oriented Research,169 the OBI’s knowledge translation and patient engagement professionals, and the Brain Heart Interconnectome Patient Engagement Team at the University of Ottawa. This committee will be involved in all aspects of TRANSCENDENT including study design, recruitment, review of patient/public-facing materials, approaches to data collection, knowledge translation and dissemination/implementation of research findings. The Community Advisory Committee will meet quarterly throughout the life cycle of the project with smaller sub-team meetings occurring as needed to support the research team. Feedback will be obtained using various approaches including personal interviews, group workshops, accessible online surveys and telephone calls. All committee feedback will be recorded and implemented as appropriate to advance the research programme. Community Advisory Committee activities will be evaluated to ensure the meaningful engagement of committee members and to support the development of best practices for community engagement. ### Feasibility Concussions impact health, quality of life and health care, with the potential for lasting effects. The TRANSCENDENT Concussion Research Program aims to improve diagnosis, treatment and recovery across the spectrum of concussion. We will achieve this by integrating research and clinic activities within a learning health system, incorporating novel objective physiological, fluid and neuroimaging biomarkers, and cross-linking national and provincial datasets to generate a broad and deep dataset to answer priority questions identified by patients, caregivers and providers. The generated dataset will be openly shared on Brain-CODE adhering to FAIR principles, greatly expanding the opportunities for additional discoveries and impact. We will mitigate anticipated challenges of participant enrolment and retention with patient incentives (eg, gift cards) and longitudinal feedback throughout the study from our patient and community advisory committee. ### Impact We will holistically investigate concussion physiology in the context of individual patient demographics and clinical variables in order to quantify the added benefit of adjunctive biomarkers to improve the diagnosis, prognosis, real-world progress monitoring and determination of recovery after concussion. This will be conducted across all ages and mechanisms of concussion injury. Identifying novel test batteries and markers for diagnosing concussion and monitoring recovery will be particularly impactful for resource-limited environments or underserved communities where medical teams may not have access to specialised personnel or equipment. Further, optimal timing for resumption of physical and cognitive activity for reduction of symptom duration will be helpful for athletes and non-athletes alike. Mobilising knowledge and implementing our findings is an essential step in this work. By sharing our work on the OBI’s Brain-CODE database and building international collaborations and industry partnerships, we will prevent siloing and promote integration with interdisciplinary clinician-scientists and neuroscientists. This is significant not just to the field of concussion research, but also mental health, memory, addiction and moderate-to-severe TBIs. Our national collaborative work with stakeholders, guideline developers and policy makers will ensure rapid translation of research into updated clinical practice, programmes and policy, and ultimately improved patient outcomes. ICES linkage will also enable research into the impact of concussion on health services use across other health sectors. Finally, paramount to our project is the role of the Community Advisory Committee, which includes members of the James Lind Alliance Concussion Priority Setting Partnership. Integration of community members and those with lived experience into this research will lead to meaningful health outcomes and more effective dissemination and implementation of our research findings to the broader public. ### Equity, diversity, inclusivity Under-representation in concussion research and lack of generalisability of results was highlighted as a national priority by our priority setting partnership,62 and determination of how the intersectionality of factors (eg, sex/gender, age, socioeconomic status, mechanism of injury, social supports, comorbidities) influence concussion outcomes and long-term prognosis was prioritised. Concussion incidence, symptom burden and recovery patterns are influenced by sex and gender,20 21 54 170–173 and although concussion incidence is higher in males, females are at a higher risk of prolonged recovery.20 Intersectionality research for concussion has been largely limited to sex and gender; however, the TRANCENDENT Concussion Research Program will ensure fair and equitable access to concussion research and the applicability of research results, by capturing and analysing data from under-represented populations (see the Analysis of race data section). As consent is obtained prior to/at initial clinic visit and physician intake appointments are billed through OHIP, under-represented populations are expected to have equitable participation opportunities in this research. ### Limitations Whereas this work will significantly expand concussion care research beyond its traditional focus on elite athletes and military veterans to the general population, it is nevertheless limited to those assessed at one of three clinics located in Ontario urban settings. Participation and retention may be disproportionate compared to the general patient population. We addressed this challenge from a feasibility standpoint by integrating research activities with scheduled appointments or allowing participation from home whenever possible, and we will monitor our demographic ratios compared to provincial health administrative datasets. Moreover, we believe that our referral streams will mitigate this limitation; given that clinic referrals stem from strong relationships with primary care clinics (eg, family health organisations), emergency departments, urgent care clinics, workplace occupational health personnel and sports therapists, we believe that the clinic population will well represent the breadth of those who experience concussion. In terms of data quality, we will record patients who are lost to follow-up for subsequent clinical and demographic comparison. No gold standard exists to confirm the diagnosis of concussion. The non-specific nature of concussion symptoms may overlap with migraine, anxiety, depression, post-traumatic stress disorder, headache disorders or other comorbidities. To mitigate this limitation, the ACRM established new criteria for the diagnosis of concussion to improve research and clinical care.42 The ACRM algorithmic criteria are embedded into the TRANSCENDENT standardised clinical assessment, and our analyses will stratify on definite versus suspected concussion cases as well as on provider confidence in the likelihood of concussion diagnosis, as recommended by ACRM guidance for researchers for improving generalisability without sacrificing rigour.42 Further, participants who are later diagnosed as not having a concussion will be withdrawn from the study. As the ACRM criteria are widely used in the diagnosis of concussion and the authors of the updated criteria expect its diagnostic sensitivity and specificity to have improved, this will ensure the applicability of findings. To date, no biomarkers (physiological, neuroimaging, fluid) have been validated for diagnosis across all populations and time points. Recognising this limitation, the TRANSCENDENT cohort provides an opportunity to advance this and/or validate work across factors of intersectionality (eg, age, sex, gender, mechanism). To obtain the symptom score, we are using the SCAT6 symptom score; while this was designed for use in sports injuries, it can be used outside of the sport setting and was recommended by the National Institute of Neurological Disorders and Strokes of the NIH and other major international consensus groups as common data elements for concussion.174 175 Furthermore, these can be directly compared to other validated symptom inventories such as the Rivermead Post-concussion Symptoms Questionnaire.176 Finally, our community advisory committee is comprised of volunteers, which affects our ability to specifically recruit a diverse group of committee members if any specific populations are not represented on the committee. To address this limitation, we (1) have compiled a large, diverse research team, (2) sought input from the CHEO RI institutional patient and family partnership committee and (3) are ensuring that the TRANSCENDENT community advisory committee’s involvement supports the predetermined study priorities. ### Future directions By demonstrating the feasibility of integrating clinical care and research via a learning health system, the TRANSCENDENT Concussion Research Program aims to conform all stages of clinical care to evidence-based best practices, with the collaboration of international experts and an active patient community. The creation of this large dataset will also identify further areas of research that can be investigated through the programme and allow for future data linkages of other brain injury studies. ## Ethics statements ### Patient consent for publication Not applicable. ## Acknowledgments Thank you to our programme administrative team, as well as our data and knowledge translation team. Thank you also to the clinical, administrative and research staff at 360 Concussion Care where the TRANSCENDENT Concussion Research Program is integrated into the learning health system. The authors would like to acknowledge Dr Barry Willer for his valuable guidance in planning this research. A special thank you to the patients who participate in the study and whose contributions make this research possible. ## Footnotes * X @silverberg_lab, @kelemam * Contributors All authors meet the four ICMJE criteria for authorship and all authors have read and approved the final manuscript. RZ is the guarantor and principal investigator (PI) of the study; he and co-PIs SJ, JL, A-AL, NR, NS, KY are responsible for study design, execution, analysis planning/interpretation and manuscript drafting/editing. The following coauthors were involved in specific objective assessment design and analysis planning/interpretation, as well as manuscript editing: MHB, AC, AC-L, MC-L, DJC, KD, AD, KEE, CE, IJG, CG, SH, DRH, RCM, CLM, ARM, MHO, RR, KJS, PT, CLW. The following coauthors were involved in data/statistical analysis planning and manuscript editing: KC, AD, SAK, IT, RW. Coauthors CA, NB, SC, JD, EF, PF and CL were involved in study design planning from a clinical and/or community engagement standpoint, and manuscript editing. Coauthors LMA and ML were involved in study design planning and execution, and manuscript drafting/editing. * Funding This research was conducted with the support of the Ontario Brain Institute, an independent non-profit corporation, funded partially by the Ontario government. The opinions, results and conclusions are those of the authors and no endorsement by the Ontario Brain Institute is intended or should be inferred. Additional funding was provided by Canada First Research Excellence Fund for the Brain-Heart Interconnectome (CFREF-2022-00007). * Competing interests MHB received grant funding from federal and provincial grants as well as through the Canada Research Chair in Pediatric TBI; she is an unpaid member of the board of directors of the International Brain Injury Association and International Pediatric Brain Injury Society, and received book royalties from Guilford Press. MC-L has received honoraria for educational activities from AbbVie, Lundbeck, Pfizer, the Canadian Association of Emergency Physicians and the GBS Foundation. He has received remuneration for medico-legal consulting. IJG’s programme of research has received financial support through competitively funded research grants from Canadian Institutes of Health Research (CIHR), Fonds de la recherche du Québec – Santé (FRQS), McGill University Health Center Research Institute (MUHC-RI), McGill University and Montreal Children’s Hospital Foundation. All grant funding goes directly to the institution. IJG is employed by McGill University and by the McGill University Health Center. SH formerly served as a paid medical officer and advisory board member for Quadrant Biosciences and Spectrum Solutions. He receives funding from the National Institutes of Health (R01NS115942) and is named as a co-inventor on intellectual property held by the Pennsylvania State University for using salivary microRNA in neurologic assessments. A-AL’s programme of research has received financial support through competitive funding research grants from: Physician Services Incorporated (PSI) Foundation, CHEO Foundation, University of Ottawa Brain and Mind Research Institute, Ontario Brain Institute (OBI) and Mobio Interactive. NR is a holder of a Canada Research Chair (Tier 2) in Pediatric Concussion and has received research funding from the Canadian Institutes of Health Research (CIHR), the Social Sciences and Humanities Research Council (SSHRC) Ontario Neurotrauma Foundation (ONF), Public Health Agency of Canada (PHAC), Parachute Canada, Special Olympics Canada, Greater Toronto Hockey League, Dr. Tom Pashby Sport Safety Fund, Holland Bloorview Kids Rehabilitation Hospital and Scotiabank. NR is the Chair of the Board of Directors for the International Pediatric Brain Injury Society (IPBIS), which is a volunteer (unpaid) role. KY receives an editorial stipend from the American Psychological Association; is principal investigator on grants from the Canadian Institutes of Health Research and Canada Foundation for Innovation; is a coinvestigator on grants from the Canadian Institutes of Health Research, Brain Canada Foundation and the National Football League Scientific Advisory Board; is a paid research consultant with University of California San Francisco, Pennsylvania State University and Research Institute at Nationwide Children’s Hospital; receives book royalties from Guilford Press and Cambridge University Press; receives travel support and honorariums for presentations to multiple organisations; serves on the Data Safety and Monitoring Board for the Concussion Health Improvement Program (CHIP) Trial, University of Washington, and on the National Research Advisory Council for the National Pediatric Rehabilitation Resource Center, Virginia Tech University. RZ’s programme of research has received financial support through competitively funded research grants from Canadian Institutes of Health Research (CIHR), Ontario Neurotrauma Foundation (ONF), Physician Services Incorporated (PSI) Foundation, CHEO Foundation, University of Ottawa Brain and Mind Research Institute, Ontario Brain Institute (OBI), National Football League (NFL), Ontario Ministry of Health (MOH), Public Health Agency of Canada (PHAC), Health Canada, Parachute Canada and Ontario SPOR Support Unit (OSSU). RZ is supported by a Tier 1 Clinical Research Chair in Pediatric Concussion from University of Ottawa. All grant funding goes directly to the institution. RZ sits on the board of directors for North American Brain Injury Society (NABIS), which is a volunteer (unpaid) role. Finally, RZ is Scientific Director and a minority shareholder of 360 Concussion Care (a learning health system and network of interdisciplinary concussion clinics in Ontario); no proceeds have been transferred to RZ. * Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Ethics and dissemination section for further details. * Provenance and peer review Not commissioned; externally peer reviewed. * Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. [http://creativecommons.org/licenses/by-nc/4.0/](http://creativecommons.org/licenses/by-nc/4.0/) This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: [http://creativecommons.org/licenses/by-nc/4.0/](http://creativecommons.org/licenses/by-nc/4.0/). ## References 1. McCrory P, Meeuwisse W, Aubry M, et al. Consensus statement on concussion in sport: the 4th International Conference on Concussion in Sport held in Zurich, November 2012. Br J Sports Med 2013;23:89–117. [doi:10.1097/JSM.0b013e31828b67cf](http://dx.doi.org/10.1097/JSM.0b013e31828b67cf) 2. Langer L, Levy C, Bayley M. Increasing Incidence of Concussion: True Epidemic or Better Recognition? J Head Trauma Rehabil 2020;35:E60–6. [doi:10.1097/HTR.0000000000000503](http://dx.doi.org/10.1097/HTR.0000000000000503) 3. Ontario Brain Institute. Concussion [online]. 2024. 4. Agnihotri S, Penner M, Mallory KD, et al. Healthcare utilization and costs associated with persistent post-concussive symptoms. Brain Inj 2021;35:1382–9. [doi:10.1080/02699052.2021.1972151](http://dx.doi.org/10.1080/02699052.2021.1972151) 5. Doroszkiewicz C, Gold D, Green R, et al. Anxiety, Depression, and Quality of Life: A Long-Term Follow-Up Study of Patients with Persisting Concussion Symptoms. J Neurotrauma 2021;38:493–505. [doi:10.1089/neu.2020.7313](http://dx.doi.org/10.1089/neu.2020.7313) 6. Choudhury R, Kolstad A, Prajapati V, et al. Loss and recovery after concussion: Adolescent patients give voice to their concussion experience. Health Expect 2020;23:1533–42. [doi:10.1111/hex.13138](http://dx.doi.org/10.1111/hex.13138) 7. Kristman VL, Côté P, Hogg-Johnson S, et al. The burden of work disability associated with mild traumatic brain injury in Ontario compensated workers: a prospective cohort study. Open Occup Health Saf J 2010;2. 8. Sheldrake E, Al-Hakeem H, Lam B, et al. Mental Health Outcomes Across the Lifespan in Individuals With Persistent Post-Concussion Symptoms: A Scoping Review. Front Neurol 2022;13:850590. [doi:10.3389/fneur.2022.850590](http://dx.doi.org/10.3389/fneur.2022.850590) 9. Galili SF, Bech BH, Vestergaard C, et al. Use of general practice before and after mild traumatic brain injury: a nationwide population-based cohort study in Denmark. BMJ Open 2017;7:e017735. [doi:10.1136/bmjopen-2017-017735](http://dx.doi.org/10.1136/bmjopen-2017-017735) 10. Langer LK, Bayley MT, Levy C, et al. Medical Care Among Individuals with a Concussion in Ontario: A Population-based Study. Can J Neurol Sci 2024;51:87–97. [doi:10.1017/cjn.2022.346](http://dx.doi.org/10.1017/cjn.2022.346) 11. Ledoux A-A, Webster RJ, Clarke AE, et al. Risk of Mental Health Problems in Children and Youths Following Concussion. JAMA Netw Open 2022;5:e221235. [doi:10.1001/jamanetworkopen.2022.1235](http://dx.doi.org/10.1001/jamanetworkopen.2022.1235) 12. Gornall A, Takagi M, Morawakage T, et al. Mental health after paediatric concussion: a systematic review and meta-analysis. Br J Sports Med 2021;55:1048–58. [doi:10.1136/bjsports-2020-103548](http://dx.doi.org/10.1136/bjsports-2020-103548) [Abstract/FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6ODoiYmpzcG9ydHMiO3M6NToicmVzaWQiO3M6MTA6IjU1LzE4LzEwNDgiO3M6NDoiYXRvbSI7czoyNjoiL2Jtam9wZW4vMTUvNC9lMDk1MjkyLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 13. Izzy S, Tahir Z, Grashow R, et al. Concussion and Risk of Chronic Medical and Behavioral Health Comorbidities. J Neurotrauma 2021;38:1834–41. [doi:10.1089/neu.2020.7484](http://dx.doi.org/10.1089/neu.2020.7484) 14. Sweeny M, Inness EL, Singer J, et al. The Toronto Concussion Study: a longitudinal analysis of balance deficits following concussion in community-dwelling adults. Brain Inj 2020;34:1384–94. [doi:10.1080/02699052.2020.1802665](http://dx.doi.org/10.1080/02699052.2020.1802665) 15. Cusimano MD, Saarela O, Hart K, et al. A population-based study of fall-related traumatic brain injury identified in older adults in hospital emergency departments. Neurosurg Focus 2020;49:E20. [doi:10.3171/2020.7.FOCUS20520](http://dx.doi.org/10.3171/2020.7.FOCUS20520) 16. Peterson AB, Xu L, Daugherty J, et al. Surveillance report of traumatic brain injury-related emergency department visits, hospitalizations, and deaths. United States, 2014. 17. Mollayeva T, Colantonio A. Concussion in Ontario health care workers: implications for prevention. 2021. 18. Zieman G, Bridwell A, Cárdenas JF. Traumatic Brain Injury in Domestic Violence Victims: A Retrospective Study at the Barrow Neurological Institute. J Neurotrauma 2017;34:876–80. [doi:10.1089/neu.2016.4579](http://dx.doi.org/10.1089/neu.2016.4579) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1089/neu.2016.4579&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 19. Colantonio A, Valera EM. Brain Injury and Intimate Partner Violence. J Head Trauma Rehabil 2022;37:2–4. [doi:10.1097/HTR.0000000000000763](http://dx.doi.org/10.1097/HTR.0000000000000763) 20. Zemek R, Barrowman N, Freedman SB, et al. Clinical Risk Score for Persistent Postconcussion Symptoms Among Children With Acute Concussion in the ED. JAMA 2016;315:1014–25. [doi:10.1001/jama.2016.1203](http://dx.doi.org/10.1001/jama.2016.1203) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1001/jama.2016.1203&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=26954410&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 21. Ledoux A-A, Tang K, Yeates KO, et al. Natural Progression of Symptom Change and Recovery From Concussion in a Pediatric Population. JAMA Pediatr 2019;173:e183820. [doi:10.1001/jamapediatrics.2018.3820](http://dx.doi.org/10.1001/jamapediatrics.2018.3820) 22. Broshek DK, Pardini JE, Herring SA. Persisting symptoms after concussion: Time for a paradigm shift. PM R 2022;14:1509–13. [doi:10.1002/pmrj.12884](http://dx.doi.org/10.1002/pmrj.12884) 23. Cancelliere C, Verville L, Stubbs JL, et al. Post-Concussion Symptoms and Disability in Adults With Mild Traumatic Brain Injury: A Systematic Review and Meta-Analysis. J Neurotrauma 2023;40:1045–59. [doi:10.1089/neu.2022.0185](http://dx.doi.org/10.1089/neu.2022.0185) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1089/neu.2022.0185&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=36472218&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 24. Varner C, Thompson C, de Wit K, et al. Predictors of persistent concussion symptoms in adults with acute mild traumatic brain injury presenting to the emergency department. CJEM 2021;23:365–73. [doi:10.1007/s43678-020-00076-6](http://dx.doi.org/10.1007/s43678-020-00076-6) 25. Savola O, Hillbom M. Early predictors of post-concussion symptoms in patients with mild head injury. Eur J Neurol 2003;10:175–81. [doi:10.1046/j.1468-1331.2003.00552.x](http://dx.doi.org/10.1046/j.1468-1331.2003.00552.x) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1046/j.1468-1331.2003.00552.x&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=12603294&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000181229800009&link_type=ISI) 26. Ponsford J, Nguyen S, Downing M, et al. Factors associated with persistent post-concussion symptoms following mild traumatic brain injury in adults. J Rehabil Med 2019;51:32–9. [doi:10.2340/16501977-2492](http://dx.doi.org/10.2340/16501977-2492) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.2340/16501977&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=30426138&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 27. Røe C, Sveen U, Alvsåker K, et al. Post-concussion symptoms after mild traumatic brain injury: influence of demographic factors and injury severity in a 1-year cohort study. Disabil Rehabil 2009;31:1235–43. [doi:10.1080/09638280802532720](http://dx.doi.org/10.1080/09638280802532720) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1080/09638280802532720&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=19116810&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 28. Langer LK, Alavinia SM, Lawrence DW, et al. Prediction of risk of prolonged post-concussion symptoms: Derivation and validation of the TRICORDRR (Toronto Rehabilitation Institute Concussion Outcome Determination and Rehab Recommendations) score. PLoS Med 2021;18:e1003652. [doi:10.1371/journal.pmed.1003652](http://dx.doi.org/10.1371/journal.pmed.1003652) 29. Moran LM, Taylor HG, Rusin J, et al. Quality of life in pediatric mild traumatic brain injury and its relationship to postconcussive symptoms. J Pediatr Psychol 2012;37:736–44. [doi:10.1093/jpepsy/jsr087](http://dx.doi.org/10.1093/jpepsy/jsr087) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1093/jpepsy/jsr087&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=21994421&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000306965500004&link_type=ISI) 30. Novak Z, Aglipay M, Barrowman N, et al. Association of Persistent Postconcussion Symptoms With Pediatric Quality of Life. JAMA Pediatr 2016;170:e162900. [doi:10.1001/jamapediatrics.2016.2900](http://dx.doi.org/10.1001/jamapediatrics.2016.2900) 31. Nelson LD, Temkin NR, Barber J, et al. Functional Recovery, Symptoms, and Quality of Life 1 to 5 Years After Traumatic Brain Injury. JAMA Netw Open 2023;6:e233660. [doi:10.1001/jamanetworkopen.2023.3660](http://dx.doi.org/10.1001/jamanetworkopen.2023.3660) 32. 1. Laskowitz D, 2. Grant G Leo P, McCrea M. Frontiers in neuroscience epidemiology. In: Laskowitz D, Grant G, eds. Translational research in traumatic brain injury. Boca Raton (FL): CRC Press/Taylor and Francis Group ©, 2016. 33. Fralick M, Sy E, Hassan A, et al. Association of Concussion With the Risk of Suicide: A Systematic Review and Meta-analysis. JAMA Neurol 2019;76:144–51. [doi:10.1001/jamaneurol.2018.3487](http://dx.doi.org/10.1001/jamaneurol.2018.3487) 34. Voss JD, Connolly J, Schwab KA, et al. Update on the Epidemiology of Concussion/Mild Traumatic Brain Injury. Curr Pain Headache Rep 2015;19:32. [doi:10.1007/s11916-015-0506-z](http://dx.doi.org/10.1007/s11916-015-0506-z) 35. D’Lauro C, Jones ER, Swope LM, et al. Under-representation of female athletes in research informing influential concussion consensus and position statements: an evidence review and synthesis. Br J Sports Med 2022;56:981–7. [doi:10.1136/bjsports-2021-105045](http://dx.doi.org/10.1136/bjsports-2021-105045) [Abstract/FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6ODoiYmpzcG9ydHMiO3M6NToicmVzaWQiO3M6OToiNTYvMTcvOTgxIjtzOjQ6ImF0b20iO3M6MjY6Ii9ibWpvcGVuLzE1LzQvZTA5NTI5Mi5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 36. Merritt VC, Padgett CR, Jak AJ. A systematic review of sex differences in concussion outcome: What do we know? Clin Neuropsychol 2019;33:1016–43. [doi:10.1080/13854046.2018.1508616](http://dx.doi.org/10.1080/13854046.2018.1508616) 37. Schneider ALC, Huie JR, Boscardin WJ, et al. Cognitive Outcome 1 Year After Mild Traumatic Brain Injury: Results From the TRACK-TBI Study. Neurology (ECronicon) 2022;98:e1248–61. [doi:10.1212/WNL.0000000000200041](http://dx.doi.org/10.1212/WNL.0000000000200041) 38. Steyerberg EW, Wiegers E, Sewalt C, et al. Case-mix, care pathways, and outcomes in patients with traumatic brain injury in CENTER-TBI: a European prospective, multicentre, longitudinal, cohort study. Lancet Neurol 2019;18:923–34. [doi:10.1016/S1474-4422(19)30232-7](http://dx.doi.org/10.1016/S1474-4422(19)30232-7) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/S1474-4422(19)30232-7&link_type=DOI) 39. Arbogast KB, Curry AE, Pfeiffer MR, et al. Point of Health Care Entry for Youth With Concussion Within a Large Pediatric Care Network. JAMA Pediatr 2016;170:e160294. [doi:10.1001/jamapediatrics.2016.0294](http://dx.doi.org/10.1001/jamapediatrics.2016.0294) 40. Womack LS, Breiding MJ, Daugherty J. Concussion Evaluation Patterns Among US Adults. J Head Trauma Rehabil 2022;37:303–10. [doi:10.1097/HTR.0000000000000756](http://dx.doi.org/10.1097/HTR.0000000000000756) 41. Means MJ, Myers RK, Master CL, et al. Assault-Related Concussion in a Pediatric Population. Pediatr Emerg Care 2022;38:e1503–7. [doi:10.1097/PEC.0000000000002664](http://dx.doi.org/10.1097/PEC.0000000000002664) 42. Silverberg ND, Iverson GL, Cogan A, et al. The American Congress of Rehabilitation Medicine Diagnostic Criteria for Mild Traumatic Brain Injury. Arch Phys Med Rehabil 2023;104:1343–55. [doi:10.1016/j.apmr.2023.03.036](http://dx.doi.org/10.1016/j.apmr.2023.03.036) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/j.apmr.2023.03.036&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=37211140&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 43. Schneider KJ, Emery CA, Black A, et al. Adapting the Dynamic, Recursive Model of Sport Injury to Concussion: An Individualized Approach to Concussion Prevention, Detection, Assessment, and Treatment. J Orthop Sports Phys Ther 2019;49:799–810. [doi:10.2519/jospt.2019.8926](http://dx.doi.org/10.2519/jospt.2019.8926) 44. Collins MW, Kontos AP, Reynolds E, et al. A comprehensive, targeted approach to the clinical care of athletes following sport-related concussion. Knee Surg Sports Traumatol Arthrosc 2014;22:235–46. [doi:10.1007/s00167-013-2791-6](http://dx.doi.org/10.1007/s00167-013-2791-6) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1007/s00167-013-2791-6&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=24337463&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 45. Hunt TN, Roberts K, Taylor EM, et al. The Effect of Social Determinants of Health on Clinical Recovery Following Concussion: A Systematic Review. J Sport Rehabil 2025;34:28–36. [doi:10.1123/jsr.2023-0068](http://dx.doi.org/10.1123/jsr.2023-0068) 46. Kapadia M, Scheid A, Fine E, et al. Review of the Management of Pediatric Post-Concussion Syndrome-a Multi-Disciplinary, Individualized Approach. Curr Rev Musculoskelet Med 2019;12:57–66. [doi:10.1007/s12178-019-09533-x](http://dx.doi.org/10.1007/s12178-019-09533-x) 47. Thastum MM, Rask CU, Næss-Schmidt ET, et al. Novel interdisciplinary intervention, GAIN, vs. enhanced usual care to reduce high levels of post-concussion symptoms in adolescents and young adults 2-6 months post-injury: A randomised trial. EClinicalMedicine 2019;17:100214. [doi:10.1016/j.eclinm.2019.11.007](http://dx.doi.org/10.1016/j.eclinm.2019.11.007) 48. Foundation ON. Concussion advisory subcommittee of the Ontario Neurotrauma Foundation. Standards for post-concussion care: from diagnosis to the interdisciplinary. Concussion Clinic, 2017. 49. Cook NE, Gaudet CE, Kissinger-Knox A, et al. Race, ethnicity, and clinical outcome following sport-related concussion: a systematic review. Front Neurol 2023;14:1110539. [doi:10.3389/fneur.2023.1110539](http://dx.doi.org/10.3389/fneur.2023.1110539) 50. Daugherty J, DePadilla L, Sarmiento K, et al. Self-Reported Lifetime Concussion Among Adults: Comparison of 3 Different Survey Questions. J Head Trauma Rehabil 2020;35:E136–43. [doi:10.1097/HTR.0000000000000534](http://dx.doi.org/10.1097/HTR.0000000000000534) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1097/htr.0000000000000534&link_type=DOI) 51. Voormolen DC, Cnossen MC, Polinder S, et al. Prevalence of post-concussion-like symptoms in the general population in Italy, The Netherlands and the United Kingdom. Brain Inj 2019;33:1078–86. [doi:10.1080/02699052.2019.1607557](http://dx.doi.org/10.1080/02699052.2019.1607557) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=31032649&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 52. Comper P, Foster E, Chandra T, et al. The Toronto Concussion Study: a prospective investigation of characteristics in a cohort of adults from the general population seeking care following acute concussion, 2016-2020. Front Neurol 2023;14:1152504. [doi:10.3389/fneur.2023.1152504](http://dx.doi.org/10.3389/fneur.2023.1152504) 53. Dawson J, Ledoux AAA, Provvidenza C, et al. Living guideline for pediatric concussion care. PedsConcussion, 2021. 54. Ledoux A-A, Barrowman N, Bijelić V, et al. Is early activity resumption after paediatric concussion safe and does it reduce symptom burden at 2 weeks post injury? The Pediatric Concussion Assessment of Rest and Exertion (PedCARE) multicentre randomised clinical trial. Br J Sports Med 2022;56:271–8. [doi:10.1136/bjsports-2021-105030](http://dx.doi.org/10.1136/bjsports-2021-105030) [Abstract/FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6ODoiYmpzcG9ydHMiO3M6NToicmVzaWQiO3M6ODoiNTYvNS8yNzEiO3M6NDoiYXRvbSI7czoyNjoiL2Jtam9wZW4vMTUvNC9lMDk1MjkyLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 55. Gravel J, Ledoux A-A, Tang K, et al. Early versus delayed emergency department presentation following mild Traumatic Brain Injury and the presence of symptom at 1, 4 and 12 weeks in children. Emerg Med J 2020;37:338–43. [doi:10.1136/emermed-2019-209054](http://dx.doi.org/10.1136/emermed-2019-209054) [Abstract/FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NzoiZW1lcm1lZCI7czo1OiJyZXNpZCI7czo4OiIzNy82LzMzOCI7czo0OiJhdG9tIjtzOjI2OiIvYm1qb3Blbi8xNS80L2UwOTUyOTIuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 56. Yeates KO, Tang K, Barrowman N, et al. Derivation and Initial Validation of Clinical Phenotypes of Children Presenting with Concussion Acutely in the Emergency Department: Latent Class Analysis of a Multi-Center, Prospective Cohort, Observational Study. J Neurotrauma 2019;36:1758–67. [doi:10.1089/neu.2018.6009](http://dx.doi.org/10.1089/neu.2018.6009) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1089/neu.2018.6009&link_type=DOI) 57. Cairncross M, Yeates KO, Tang K, et al. Early Postinjury Screen Time and Concussion Recovery. Pediatrics 2022;150:e2022056835. [doi:10.1542/peds.2022-056835](http://dx.doi.org/10.1542/peds.2022-056835) 58. Lyons TW, Mannix R, Tang K, et al. Paediatric post-concussive symptoms: symptom clusters and clinical phenotypes. Br J Sports Med 2022;56:785–91. [doi:10.1136/bjsports-2021-105193](http://dx.doi.org/10.1136/bjsports-2021-105193) [Abstract/FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6ODoiYmpzcG9ydHMiO3M6NToicmVzaWQiO3M6OToiNTYvMTQvNzg1IjtzOjQ6ImF0b20iO3M6MjY6Ii9ibWpvcGVuLzE1LzQvZTA5NTI5Mi5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 59. Leddy JJ, Hinds AL, Miecznikowski J, et al. Safety and Prognostic Utility of Provocative Exercise Testing in Acutely Concussed Adolescents: A Randomized Trial. Clin J Sport Med 2018;28:13–20. [doi:10.1097/JSM.0000000000000431](http://dx.doi.org/10.1097/JSM.0000000000000431) 60. Haider MN, Cunningham A, Darling S, et al. Derivation of the Buffalo Concussion Physical Examination risk of delayed recovery (RDR) score to identify children at risk for persistent postconcussive symptoms. Br J Sports Med 2021;55:1427–33. [doi:10.1136/bjsports-2020-103690](http://dx.doi.org/10.1136/bjsports-2020-103690) [Abstract/FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6ODoiYmpzcG9ydHMiO3M6NToicmVzaWQiO3M6MTA6IjU1LzI0LzE0MjciO3M6NDoiYXRvbSI7czoyNjoiL2Jtam9wZW4vMTUvNC9lMDk1MjkyLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 61. Haider MN, Leddy JJ, Du W, et al. Practical Management: Brief Physical Examination for Sport-Related Concussion in the Outpatient Setting. Clin J Sport Med 2020;30:513–7. [doi:10.1097/JSM.0000000000000687](http://dx.doi.org/10.1097/JSM.0000000000000687) 62. Osmond MH, Legace E, Gill PJ, et al. Partnering With Patients, Caregivers, and Clinicians to Determine Research Priorities for Concussion. JAMA Netw Open 2023;6:e2316383. [doi:10.1001/jamanetworkopen.2023.16383](http://dx.doi.org/10.1001/jamanetworkopen.2023.16383) 63. von Elm E, Altman DG, Egger M, et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. BMJ 2007;335:806–8. [doi:10.1136/bmj.39335.541782.AD](http://dx.doi.org/10.1136/bmj.39335.541782.AD) [FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiRlVMTCI7czoxMToiam91cm5hbENvZGUiO3M6MzoiYm1qIjtzOjU6InJlc2lkIjtzOjEyOiIzMzUvNzYyNC84MDYiO3M6NDoiYXRvbSI7czoyNjoiL2Jtam9wZW4vMTUvNC9lMDk1MjkyLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 64. Miller RL, Comstock RD, Pierpoint L, et al. Facilitators and barriers for parental consent to pediatric emergency research. Pediatr Res 2022;91:1156–62. [doi:10.1038/s41390-021-01600-9](http://dx.doi.org/10.1038/s41390-021-01600-9) 65. Riley RD, Ensor J, Snell KIE, et al. Calculating the sample size required for developing a clinical prediction model. BMJ 2020;368:m441. [doi:10.1136/bmj.m441](http://dx.doi.org/10.1136/bmj.m441) 66. Lumba-Brown A, Tang K, Yeates KO, et al. Post-concussion symptom burden in children following motor vehicle collisions. J Am Coll Emerg Physicians Open 2020;1:938–46. [doi:10.1002/emp2.12056](http://dx.doi.org/10.1002/emp2.12056) 67. Lubbers VF, van den Hoven DJ, van der Naalt J, et al. Emergency Department Risk Factors for Post-Concussion Syndrome After Mild Traumatic Brain Injury: A Systematic Review. J Neurotrauma 2024;41:1253–70. [doi:10.1089/neu.2023.0302](http://dx.doi.org/10.1089/neu.2023.0302) 68. Ledoux A-A, Sicard V, Bijelic V, et al. Symptom Recovery in Children Aged 5 to 12 Years With Sport-Related and Non-Sport-Related Concussion. JAMA Netw Open 2024;7:e2448797. [doi:10.1001/jamanetworkopen.2024.48797](http://dx.doi.org/10.1001/jamanetworkopen.2024.48797) 69. Vaccarino AL, Dharsee M, Strother S, et al. Brain-CODE: A Secure Neuroinformatics Platform for Management, Federation, Sharing and Analysis of Multi-Dimensional Neuroscience Data. Front Neuroinform 2018;12:28. [doi:10.3389/fninf.2018.00028](http://dx.doi.org/10.3389/fninf.2018.00028) 70. Stuss DT. The Ontario Brain Institute: completing the circle. Can J Neurol Sci 2014;41:683–93. [doi:10.1017/cjn.2014.36](http://dx.doi.org/10.1017/cjn.2014.36) 71. Behan B, Jeanson F, Cheema H, et al. FAIR in action: Brain-CODE - A neuroscience data sharing platform to accelerate brain research. Front Neuroinform 2023;17:1158378. [doi:10.3389/fninf.2023.1158378](http://dx.doi.org/10.3389/fninf.2023.1158378) 72. OBI. Ontario Brain Institute (OBI) is the first research institution to be designated as Privacy by Design (PbD) by Ambassador: Cision. n.d. Available: [https://www.newswire.ca/news-releases/ontario-brain-institute-obi-is-the-first-research-institution-to-be-designated-as-privacy-by-design-pbd-ambassador-511057511.html](https://www.newswire.ca/news-releases/ontario-brain-institute-obi-is-the-first-research-institution-to-be-designated-as-privacy-by-design-pbd-ambassador-511057511.html) 73. Brain-CODE. Brain-CODE security & privacy. n.d. Available: [https://www.braincode.ca/content/security-privacy](https://www.braincode.ca/content/security-privacy) 74. Schull MJ, Azimaee M, Marra M, et al. ICES: Data, Discovery, Better Health. Int J Popul Data Sci 2020;4:1135. [doi:10.23889/ijpds.v4i2.1135](http://dx.doi.org/10.23889/ijpds.v4i2.1135) 75. Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42:377–81. [doi:10.1016/j.jbi.2008.08.010](http://dx.doi.org/10.1016/j.jbi.2008.08.010) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/j.jbi.2008.08.010&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=18929686&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000264958800018&link_type=ISI) 76. van Ingen T, Matheson FI. The 2011 and 2016 iterations of the Ontario Marginalization Index: updates, consistency and a cross-sectional study of health outcome associations. Can J Public Health 2022;113:260–71. [doi:10.17269/s41997-021-00552-1](http://dx.doi.org/10.17269/s41997-021-00552-1) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=34432255&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 77. Axelrod D, Ziegler T, Pincus D, et al. Basketball vs. Hockey-The Changing Face of Sport-Related Injuries in Canada. Clin J Sport Med 2022;32:e281–7. [doi:10.1097/JSM.0000000000000908](http://dx.doi.org/10.1097/JSM.0000000000000908) 78. Echemendia RJ, Brett BL, Broglio S, et al. Introducing the Sport Concussion Assessment Tool 6 (SCAT6). Br J Sports Med 2023;57:619–21. [doi:10.1136/bjsports-2023-106849](http://dx.doi.org/10.1136/bjsports-2023-106849) [FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiRlVMTCI7czoxMToiam91cm5hbENvZGUiO3M6ODoiYmpzcG9ydHMiO3M6NToicmVzaWQiO3M6OToiNTcvMTEvNjE5IjtzOjQ6ImF0b20iO3M6MjY6Ii9ibWpvcGVuLzE1LzQvZTA5NTI5Mi5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 79. Ayr LK, Yeates KO, Taylor HG, et al. Dimensions of postconcussive symptoms in children with mild traumatic brain injuries. J Int Neuropsychol Soc 2009;15:19–30. [doi:10.1017/S1355617708090188](http://dx.doi.org/10.1017/S1355617708090188) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1017/S1355617708090188&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=19128525&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 80. Connor KM, Davidson JR. Connor–Davidson resilience scale. Confirmatory factor analysis of the Connor-Davidson resilience scale. 2003. 81. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 2001;16:606–13. [doi:10.1046/j.1525-1497.2001.016009606.x](http://dx.doi.org/10.1046/j.1525-1497.2001.016009606.x) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1046/j.1525-1497.2001.016009606.x&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=11556941&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000171184700005&link_type=ISI) 82. Löwe B, Decker O, Müller S, et al. Validation and standardization of the Generalized Anxiety Disorder Screener (GAD-7) in the general population. Med Care 2008;46:266–74. [doi:10.1097/MLR.0b013e318160d093](http://dx.doi.org/10.1097/MLR.0b013e318160d093) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1097/MLR.0b013e318160d093&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=18388841&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000253665200006&link_type=ISI) 83. The Whoqol Group. Development of the World Health Organization WHOQOL-BREF Quality of Life Assessment. Psychol Med 1998;28:551–8. [doi:10.1017/S0033291798006667](http://dx.doi.org/10.1017/S0033291798006667) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1017/S0033291798006667&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=9626712&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000073793600006&link_type=ISI) 84. 1. Ravens-Sieberer U, 2. Bullinger M , eds. Der kindl-r fragebogen zur erfassung der gesundheitsbezogenen lebensqualität bei kindern und jugendlichen-revidierte form. Diagnostische Verfahren Zu Lebensqualität Und Wohlbefinden 2003. 85. Hagströmer M, Oja P, Sjöström M. The International Physical Activity Questionnaire (IPAQ): a study of concurrent and construct validity. Public Health Nutr 2006;9:755–62. [doi:10.1079/phn2005898](http://dx.doi.org/10.1079/phn2005898) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1079/PHN2005898&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=16925881&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000239972500013&link_type=ISI) 86. Patricios JS, Schneider KJ, Dvorak J, et al. Consensus statement on concussion in sport: the 6th International Conference on Concussion in Sport-Amsterdam, October 2022. Br J Sports Med 2023;57:695–711. [doi:10.1136/bjsports-2023-106898](http://dx.doi.org/10.1136/bjsports-2023-106898) [Abstract/FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6ODoiYmpzcG9ydHMiO3M6NToicmVzaWQiO3M6OToiNTcvMTEvNjk1IjtzOjQ6ImF0b20iO3M6MjY6Ii9ibWpvcGVuLzE1LzQvZTA5NTI5Mi5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 87. Davis GA, Patricios JS, Purcell LK, et al. Introducing the Child Sport Concussion Office Assessment Tool 6 (Child SCOAT6). Br J Sports Med 2023;57:668–71. [doi:10.1136/bjsports-2023-106858](http://dx.doi.org/10.1136/bjsports-2023-106858) [FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiRlVMTCI7czoxMToiam91cm5hbENvZGUiO3M6ODoiYmpzcG9ydHMiO3M6NToicmVzaWQiO3M6OToiNTcvMTEvNjY4IjtzOjQ6ImF0b20iO3M6MjY6Ii9ibWpvcGVuLzE1LzQvZTA5NTI5Mi5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 88. Davis GA, Purcell L, Schneider KJ, et al. The Child Sport Concussion Assessment Tool 5th Edition (Child SCAT5): Background and rationale. Br J Sports Med 2017;51:859–61. [doi:10.1136/bjsports-2017-097492](http://dx.doi.org/10.1136/bjsports-2017-097492) [Abstract/FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6ODoiYmpzcG9ydHMiO3M6NToicmVzaWQiO3M6OToiNTEvMTEvODU5IjtzOjQ6ImF0b20iO3M6MjY6Ii9ibWpvcGVuLzE1LzQvZTA5NTI5Mi5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 89. Corwin DJ, McDonald CC, Arbogast KB, et al. Clinical and Device-based Metrics of Gait and Balance in Diagnosing Youth Concussion. Med Sci Sports Exerc 2020;52:542–8. [doi:10.1249/MSS.0000000000002163](http://dx.doi.org/10.1249/MSS.0000000000002163) 90. Riemann BL, Guskiewicz KM, Shields EW. Relationship between clinical and forceplate measures of postural stability. J Sport Rehabil 1999;8:71–82. [doi:10.1123/jsr.8.2.71](http://dx.doi.org/10.1123/jsr.8.2.71) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1123/JSR.8.2.71&link_type=DOI) [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000080173200001&link_type=ISI) 91. Schneider KJ, Meeuwisse WH, Palacios-Derflingher L, et al. Changes in Measures of Cervical Spine Function, Vestibulo-ocular Reflex, Dynamic Balance, and Divided Attention Following Sport-Related Concussion in Elite Youth Ice Hockey Players. J Orthop Sports Phys Ther 2018;48:974–81. [doi:10.2519/jospt.2018.8258](http://dx.doi.org/10.2519/jospt.2018.8258) 92. Leddy JJ, Willer B. Use of graded exercise testing in concussion and return-to-activity management. Curr Sports Med Rep 2013;12:370–6. [doi:10.1249/JSR.0000000000000008](http://dx.doi.org/10.1249/JSR.0000000000000008) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1249/JSR.0000000000000008&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=24225521&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 93. Purkayastha S, Stokes M, Bell KR. Autonomic nervous system dysfunction in mild traumatic brain injury: a review of related pathophysiology and symptoms. Brain Inj 2019;33:1129–36. [doi:10.1080/02699052.2019.1631488](http://dx.doi.org/10.1080/02699052.2019.1631488) 94. Pertab JL, Merkley TL, Cramond AJ, et al. Concussion and the autonomic nervous system: An introduction to the field and the results of a systematic review. NeuroRehabilitation 2018;42:397–427. [doi:10.3233/NRE-172298](http://dx.doi.org/10.3233/NRE-172298) 95. Worley ML, O’Leary MC, Sackett JR, et al. Preliminary Evidence of Orthostatic Intolerance and Altered Cerebral Vascular Control Following Sport-Related Concussion. Front Neurol 2021;12:620757. [doi:10.3389/fneur.2021.620757](http://dx.doi.org/10.3389/fneur.2021.620757) 96. Haider MN, Patel KS, Willer BS, et al. Symptoms upon postural change and orthostatic hypotension in adolescents with concussion. Brain Inj 2021;35:226–32. [doi:10.1080/02699052.2021.1871951](http://dx.doi.org/10.1080/02699052.2021.1871951) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1080/02699052.2021.1871951&link_type=DOI) 97. Miranda NA, Boris JR, Kouvel KM, et al. Activity and Exercise Intolerance After Concussion: Identification and Management of Postural Orthostatic Tachycardia Syndrome. J Neurol Phys Ther 2018;42:163–71. [doi:10.1097/NPT.0000000000000231](http://dx.doi.org/10.1097/NPT.0000000000000231) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1097/NPT.0000000000000231&link_type=DOI) 98. Heyer GL, Fischer A, Wilson J, et al. Orthostatic Intolerance and Autonomic Dysfunction in Youth With Persistent Postconcussion Symptoms: A Head-Upright Tilt Table Study. Clin J Sport Med 2016;26:40–5. [doi:10.1097/JSM.0000000000000183](http://dx.doi.org/10.1097/JSM.0000000000000183) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1097/JSM.0000000000000183&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=25706664&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 99. Leddy JJ, Kozlowski K, Fung M, et al. Regulatory and autoregulatory physiological dysfunction as a primary characteristic of post concussion syndrome: implications for treatment. NeuroRehabilitation 2007;22:199–205. [doi:10.3233/NRE-2007-22306](http://dx.doi.org/10.3233/NRE-2007-22306) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=17917170&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000249884800006&link_type=ISI) 100.Naschitz JE, Rosner I. Orthostatic hypotension: framework of the syndrome. Postgrad Med J 2007;83:568–74. [doi:10.1136/pgmj.2007.058198](http://dx.doi.org/10.1136/pgmj.2007.058198) [Abstract/FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTI6InBvc3RncmFkbWVkaiI7czo1OiJyZXNpZCI7czoxMDoiODMvOTgzLzU2OCI7czo0OiJhdG9tIjtzOjI2OiIvYm1qb3Blbi8xNS80L2UwOTUyOTIuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 101.Matuszak JM, McVige J, McPherson J, et al. A Practical Concussion Physical Examination Toolbox. Sports Health 2016;8:260–9. [doi:10.1177/1941738116641394](http://dx.doi.org/10.1177/1941738116641394) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1177/1941738116641394&link_type=DOI) 102.Marigold JRG, Arias M, Vassallo M, et al. Autonomic dysfunction in older people. Rev Clin Gerontol 2011;21:28–44. [doi:10.1017/S0959259810000286](http://dx.doi.org/10.1017/S0959259810000286) 103.Freeman R, Wieling W, Axelrod FB, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res 2011;21:69–72. [doi:10.1007/s10286-011-0119-5](http://dx.doi.org/10.1007/s10286-011-0119-5) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1007/s10286-011-0119-5&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=21431947&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 104.Cheshire WP, Goldstein DS. Autonomic uprising: the tilt table test in autonomic medicine. Clin Auton Res 2019;29:215–30. [doi:10.1007/s10286-019-00598-9](http://dx.doi.org/10.1007/s10286-019-00598-9) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1007/s10286-019-00598-9&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=30838497&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 105.Laitinen T, Niskanen L, Geelen G, et al. Age dependency of cardiovascular autonomic responses to head-up tilt in healthy subjects. J Appl Physiol (1985) 2004;96:2333–40. [doi:10.1152/japplphysiol.00444.2003](http://dx.doi.org/10.1152/japplphysiol.00444.2003) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1152/japplphysiol.00444.2003&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=14766788&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000221296600044&link_type=ISI) 106.Balestrini CS, Moir ME, Abbott KC, et al. Autonomic Dysregulation in Adolescent Concussion Is Sex- and Posture-Dependent. Clin J Sport Med 2021;31:257–65. [doi:10.1097/JSM.0000000000000734](http://dx.doi.org/10.1097/JSM.0000000000000734) 107.Kozlowski KF, Graham J, Leddy JJ, et al. Exercise intolerance in individuals with postconcussion syndrome. J Athl Train 2013;48:627–35. [doi:10.4085/1062-6050-48.5.02](http://dx.doi.org/10.4085/1062-6050-48.5.02) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.4085/1062-6050-48.5.02&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=23952041&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 108.Grool AM, Aglipay M, Momoli F, et al. Association Between Early Participation in Physical Activity Following Acute Concussion and Persistent Postconcussive Symptoms in Children and Adolescents. JAMA 2016;316:2504–14. [doi:10.1001/jama.2016.17396](http://dx.doi.org/10.1001/jama.2016.17396) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=27997652&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 109.Leddy JJ, Haider MN, Ellis M, et al. Exercise is Medicine for Concussion. Curr Sports Med Rep 2018;17:262–70. [doi:10.1249/JSR.0000000000000505](http://dx.doi.org/10.1249/JSR.0000000000000505) 110.Leddy JJ, Haider MN, Ellis MJ, et al. Early Subthreshold Aerobic Exercise for Sport-Related Concussion: A Randomized Clinical Trial. JAMA Pediatr 2019;173:319–25. [doi:10.1001/jamapediatrics.2018.4397](http://dx.doi.org/10.1001/jamapediatrics.2018.4397) 111.Haider MN, Johnson SL, Mannix R, et al. The Buffalo Concussion Bike Test for Concussion Assessment in Adolescents. Sports Health 2019;11:492–7. [doi:10.1177/1941738119870189](http://dx.doi.org/10.1177/1941738119870189) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 112.Miutz LN, Burma JS, Brassard P, et al. Comparison of the Buffalo Concussion Treadmill Test With a Physiologically Informed Cycle Test: Calgary Concussion Cycle Test. Sports Health 2024;16:837–50. [doi:10.1177/19417381231217744](http://dx.doi.org/10.1177/19417381231217744) 113.Samadani U, Ritlop R, Reyes M, et al. Eye tracking detects disconjugate eye movements associated with structural traumatic brain injury and concussion. J Neurotrauma 2015;32:548–56. [doi:10.1089/neu.2014.3687](http://dx.doi.org/10.1089/neu.2014.3687) 114.Master CL, Podolak OE, Ciuffreda KJ, et al. Utility of Pupillary Light Reflex Metrics as a Physiologic Biomarker for Adolescent Sport-Related Concussion. JAMA Ophthalmol 2020;138:1135–41. [doi:10.1001/jamaophthalmol.2020.3466](http://dx.doi.org/10.1001/jamaophthalmol.2020.3466) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1001/jamaophthalmol.2020.3466&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=32970102&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 115.Podolak OE, Joshi N, Ciuffreda K, et al. The utility of pupillary light reflex as an objective biomarker of acute concussion in the adolescent athlete. Orthop J Sports Med 2019;7:2325967119S00155. [doi:10.1177/2325967119S00155](http://dx.doi.org/10.1177/2325967119S00155) 116.Snegireva N, Derman W, Patricios J, et al. Eye tracking technology in sports-related concussion: a systematic review and meta-analysis. Physiol Meas 2018;39:12TR01. [doi:10.1088/1361-6579/aaef44](http://dx.doi.org/10.1088/1361-6579/aaef44) 117.Master CL, Bacal D, Grady MF, et al. Vision and Concussion: Symptoms, Signs, Evaluation, and Treatment. Pediatrics 2022;150:e2021056047. [doi:10.1542/peds.2021-056047](http://dx.doi.org/10.1542/peds.2021-056047) 118.Master CL, Scheiman M, Gallaway M, et al. Vision Diagnoses Are Common After Concussion in Adolescents. Clin Pediatr (Phila) 2016;55:260–7. [doi:10.1177/0009922815594367](http://dx.doi.org/10.1177/0009922815594367) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1177/0009922815594367&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=26156977&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 119.Corwin DJ, Arbogast KB, Swann C, et al. Reliability of the visio-vestibular examination for concussion among providers in a pediatric emergency department. Am J Emerg Med 2020;38:1847–53. [doi:10.1016/j.ajem.2020.06.020](http://dx.doi.org/10.1016/j.ajem.2020.06.020) 120.Corwin DJ, McDonald CC, Arbogast KB, et al. Visio-Vestibular Deficits in Healthy Child and Adolescent Athletes. Clin J Sport Med 2022;32:376–84. [doi:10.1097/JSM.0000000000000955](http://dx.doi.org/10.1097/JSM.0000000000000955) 121.Corwin DJ, Propert KJ, Zorc JJ, et al. Use of the vestibular and oculomotor examination for concussion in a pediatric emergency department. Am J Emerg Med 2019;37:1219–23. [doi:10.1016/j.ajem.2018.09.008](http://dx.doi.org/10.1016/j.ajem.2018.09.008) 122.Bell DR, Guskiewicz KM, Clark MA, et al. Systematic review of the balance error scoring system. Sports Health 2011;3:287–95. [doi:10.1177/1941738111403122](http://dx.doi.org/10.1177/1941738111403122) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1177/1941738111403122&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=23016020&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 123.Hansen C, Cushman D, Chen W, et al. Reliability Testing of the Balance Error Scoring System in Children Between the Ages of 5 and 14. Clin J Sport Med 2017;27:64–8. [doi:10.1097/JSM.0000000000000293](http://dx.doi.org/10.1097/JSM.0000000000000293) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=26829611&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 124.Corwin DJ, Arbogast KB, Haber RA, et al. Characteristics and Outcomes for Delayed Diagnosis of Concussion in Pediatric Patients Presenting to the Emergency Department. J Emerg Med 2020;59:795–804. [doi:10.1016/j.jemermed.2020.09.017](http://dx.doi.org/10.1016/j.jemermed.2020.09.017) 125.Master CL, Master SR, Wiebe DJ, et al. Vision and Vestibular System Dysfunction Predicts Prolonged Concussion Recovery in Children. Clin J Sport Med 2018;28:139–45. [doi:10.1097/JSM.0000000000000507](http://dx.doi.org/10.1097/JSM.0000000000000507) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1097/JSM.0000000000000507&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=29064869&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 126.Tabor JB, Penner LC, Cooper JG, et al. Characterizing Factors Influencing Baseline Plasma Biomarkers for Sport-Related Concussion in Adolescents. J Neurotrauma 2023;40:1638–50. [doi:10.1089/neu.2022.0501](http://dx.doi.org/10.1089/neu.2022.0501) 127.Tabor JB, Galarneau J-M, Penner LC, et al. Use of Biostatistical Models to Manage Replicate Error in Concussion Biomarker Research. JAMA Netw Open 2023;6:e2339733. [doi:10.1001/jamanetworkopen.2023.39733](http://dx.doi.org/10.1001/jamanetworkopen.2023.39733) 128.Meier TB, Huber DL, Bohorquez-Montoya L, et al. A Prospective Study of Acute Blood-Based Biomarkers for Sport-Related Concussion. Ann Neurol 2020;87:907–20. [doi:10.1002/ana.25725](http://dx.doi.org/10.1002/ana.25725) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1002/ana.25725&link_type=DOI) 129.McCrea M, Broglio SP, McAllister TW, et al. Association of Blood Biomarkers With Acute Sport-Related Concussion in Collegiate Athletes: Findings From the NCAA and Department of Defense CARE Consortium. JAMA Netw Open 2020;3:e1919771. [doi:10.1001/jamanetworkopen.2019.19771](http://dx.doi.org/10.1001/jamanetworkopen.2019.19771) 130.Tabor JB, McCrea MA, Meier TB, et al. Hiding in Plain Sight: Factors Influencing the Neuroinflammatory Response to Sport-Related Concussion. Neurotrauma Rep 2022;3:200–6. [doi:10.1089/neur.2021.0081](http://dx.doi.org/10.1089/neur.2021.0081) 131.Li LM, Kodosaki E, Heselgrave A, et al. High-dimensional proteomic analysis for pathophysiological classification of traumatic brain injury. Neuroscience [Preprint] 2024. [doi:10.1101/2024.04.23.590636](http://dx.doi.org/10.1101/2024.04.23.590636) 132.Shi X, Sun M, Liu H, et al. Long non-coding RNAs: a new frontier in the study of human diseases. Cancer Lett 2013;339:159–66. [doi:10.1016/j.canlet.2013.06.013](http://dx.doi.org/10.1016/j.canlet.2013.06.013) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/j.canlet.2013.06.013&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=23791884&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 133.Taft RJ, Pang KC, Mercer TR, et al. Non-coding RNAs: regulators of disease. J Pathol 2010;220:126–39. [doi:10.1002/path.2638](http://dx.doi.org/10.1002/path.2638) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1002/path.2638&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=19882673&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000273710100003&link_type=ISI) 134.Esteller M. Non-coding RNAs in human disease. Nat Rev Genet 2011;12:861–74. [doi:10.1038/nrg3074](http://dx.doi.org/10.1038/nrg3074) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1038/nrg3074&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=22094949&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 135.Pasinetti GM, Ho L, Dooley C, et al. Select non-coding RNA in blood components provide novel clinically accessible biological surrogates for improved identification of traumatic brain injury in OEF/OIF Veterans. Am J Neurodegener Dis 2012;1:88–98. [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=22737634&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 136.Atif H, Hicks SD. A Review of MicroRNA Biomarkers in Traumatic Brain Injury. J Exp Neurosci 2019;13:1179069519832286. [doi:10.1177/1179069519832286](http://dx.doi.org/10.1177/1179069519832286) 137.Bahn JH, Zhang Q, Li F, et al. The landscape of microRNA, Piwi-interacting RNA, and circular RNA in human saliva. Clin Chem 2015;61:221–30. [doi:10.1373/clinchem.2014.230433](http://dx.doi.org/10.1373/clinchem.2014.230433) [Abstract/FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6ODoiY2xpbmNoZW0iO3M6NToicmVzaWQiO3M6ODoiNjEvMS8yMjEiO3M6NDoiYXRvbSI7czoyNjoiL2Jtam9wZW4vMTUvNC9lMDk1MjkyLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 138.Majem B, Rigau M, Reventós J, et al. Non-coding RNAs in saliva: emerging biomarkers for molecular diagnostics. Int J Mol Sci 2015;16:8676–98. [doi:10.3390/ijms16048676](http://dx.doi.org/10.3390/ijms16048676) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=25898412&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 139.Gilad S, Meiri E, Yogev Y, et al. Serum microRNAs are promising novel biomarkers. PLoS One 2008;3:e3148. [doi:10.1371/journal.pone.0003148](http://dx.doi.org/10.1371/journal.pone.0003148) 140.Rogelj B, Giese KP. Expression and function of brain specific small RNAs. Rev Neurosci 2004;15:185–98. [doi:10.1515/revneuro.2004.15.3.185](http://dx.doi.org/10.1515/revneuro.2004.15.3.185) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=15357141&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000223411400003&link_type=ISI) 141.Weber JA, Baxter DH, Zhang S, et al. The microRNA spectrum in 12 body fluids. Clin Chem 2010;56:1733–41. [doi:10.1373/clinchem.2010.147405](http://dx.doi.org/10.1373/clinchem.2010.147405) [Abstract/FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6ODoiY2xpbmNoZW0iO3M6NToicmVzaWQiO3M6MTA6IjU2LzExLzE3MzMiO3M6NDoiYXRvbSI7czoyNjoiL2Jtam9wZW4vMTUvNC9lMDk1MjkyLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 142.LaRocca D, Barns S, Hicks SD, et al. Comparison of serum and saliva miRNAs for identification and characterization of mTBI in adult mixed martial arts fighters. PLoS One 2019;14:e0207785. [doi:10.1371/journal.pone.0207785](http://dx.doi.org/10.1371/journal.pone.0207785) 143.Tabor JB, Penner LC, Galarneau J-M, et al. Plasma Biomarkers of Traumatic Brain Injury in Adolescents With Sport-Related Concussion. JAMA Netw Open 2024;7:e2431959. [doi:10.1001/jamanetworkopen.2024.31959](http://dx.doi.org/10.1001/jamanetworkopen.2024.31959) 144.Di Pietro V, O’Halloran P, Watson CN, et al. Unique diagnostic signatures of concussion in the saliva of male athletes: the Study of Concussion in Rugby Union through MicroRNAs (SCRUM). Br J Sports Med 2021;55:1395–404. [doi:10.1136/bjsports-2020-103274](http://dx.doi.org/10.1136/bjsports-2020-103274) [Abstract/FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6ODoiYmpzcG9ydHMiO3M6NToicmVzaWQiO3M6MTA6IjU1LzI0LzEzOTUiO3M6NDoiYXRvbSI7czoyNjoiL2Jtam9wZW4vMTUvNC9lMDk1MjkyLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 145.Hicks SD, Onks C, Kim RY, et al. Diagnosing mild traumatic brain injury using saliva RNA compared to cognitive and balance testing. Clin Transl Med 2020;10:e197. [doi:10.1002/ctm2.197](http://dx.doi.org/10.1002/ctm2.197) 146.Giza CC, Hovda DA. The new neurometabolic cascade of concussion. Neurosurgery 2014;75 Suppl 4:S24–33. [doi:10.1227/NEU.0000000000000505](http://dx.doi.org/10.1227/NEU.0000000000000505) 147.Barkhoudarian G, Hovda DA, Giza CC. The Molecular Pathophysiology of Concussive Brain Injury - an Update. Phys Med Rehabil Clin N Am 2016;27:373–93. [doi:10.1016/j.pmr.2016.01.003](http://dx.doi.org/10.1016/j.pmr.2016.01.003) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/j.pmr.2016.01.003&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=27154851&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 148.Giza CC, Hovda DA. The Neurometabolic Cascade of Concussion. J Athl Train 2001;36:228–35. [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1227/NEU.0000000000000505&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=12937489&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000175913800003&link_type=ISI) 149.Tan CO, Meehan WP, Iverson GL, et al. Cerebrovascular regulation, exercise, and mild traumatic brain injury. Neurology (ECronicon) 2014;83:1665–72. [doi:10.1212/WNL.0000000000000944](http://dx.doi.org/10.1212/WNL.0000000000000944) 150.Hughes DG, Jackson A, Mason DL, et al. Abnormalities on magnetic resonance imaging seen acutely following mild traumatic brain injury: correlation with neuropsychological tests and delayed recovery. Neuroradiology 2004;46:550–8. [doi:10.1007/s00234-004-1227-x](http://dx.doi.org/10.1007/s00234-004-1227-x) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1007/s00234-004-1227-x&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=15185054&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000222691500004&link_type=ISI) 151.Maas AIR, Menon DK, Manley GT, et al. Traumatic brain injury: progress and challenges in prevention, clinical care, and research. Lancet Neurol 2022;21:1004–60. [doi:10.1016/S1474-4422(22)00309-X](http://dx.doi.org/10.1016/S1474-4422(22)00309-X) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/s1474-4422(22)00309-x&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=36183712&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 152.Sicard V, Fang Z, Kardish R, et al. Longitudinal Brain Perfusion and Symptom Presentation Following Pediatric Concussion: A Pediatric Concussion Assessment of Rest and Exertion+MRI (PedCARE+MRI) Substudy. J Neurotrauma 2024;41:552–70. [doi:10.1089/neu.2023.0071](http://dx.doi.org/10.1089/neu.2023.0071) 153.Nencka AS, Meier TB, Wang Y, et al. Stability of MRI metrics in the advanced research core of the NCAA-DoD concussion assessment, research and education (CARE) consortium. Brain Imaging Behav 2018;12:1121–40. [doi:10.1007/s11682-017-9775-y](http://dx.doi.org/10.1007/s11682-017-9775-y) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1007/s11682-017-9775-y&link_type=DOI) 154.Wilkinson CM, Burrell JI, Kuziek JWP, et al. Predicting stroke severity with a 3-min recording from the Muse portable EEG system for rapid diagnosis of stroke. Sci Rep 2020;10:18465. [doi:10.1038/s41598-020-75379-w](http://dx.doi.org/10.1038/s41598-020-75379-w) 155.Gottlibe M, Rosen O, Weller B, et al. Stroke identification using a portable EEG device - A pilot study. Neurophysiol Clin 2020;50:21–5. [doi:10.1016/j.neucli.2019.12.004](http://dx.doi.org/10.1016/j.neucli.2019.12.004) 156.TRIPOD. n.d. Available: [https://www.tripod-statement.org](https://www.tripod-statement.org) 157.Collins GS, Reitsma JB, Altman DG, et al. Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD): the TRIPOD statement. The TRIPOD Group. Circulation 2015;131:211–9. [doi:10.1161/CIRCULATIONAHA.114.014508](http://dx.doi.org/10.1161/CIRCULATIONAHA.114.014508) [Abstract/FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTQ6ImNpcmN1bGF0aW9uYWhhIjtzOjU6InJlc2lkIjtzOjk6IjEzMS8yLzIxMSI7czo0OiJhdG9tIjtzOjI2OiIvYm1qb3Blbi8xNS80L2UwOTUyOTIuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 158.Straus SE, Tetroe J, Graham I. Defining knowledge translation. CMAJ 2009;181:165–8. [doi:10.1503/cmaj.081229](http://dx.doi.org/10.1503/cmaj.081229) [FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiRlVMTCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiY21haiI7czo1OiJyZXNpZCI7czoxMToiMTgxLzMtNC8xNjUiO3M6NDoiYXRvbSI7czoyNjoiL2Jtam9wZW4vMTUvNC9lMDk1MjkyLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 159.Brownson RC, Eyler AA, Harris JK, et al. Getting the Word Out: New Approaches for Disseminating Public Health Science. J Public Health Manag Pract 2018;24:102–11. [doi:10.1097/PHH.0000000000000673](http://dx.doi.org/10.1097/PHH.0000000000000673) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1097/PHH.0000000000000673&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 160.Lavis JN, Robertson D, Woodside JM, et al. How can research organizations more effectively transfer research knowledge to decision makers? Milbank Q 2003;81:221–48, . [doi:10.1111/1468-0009.t01-1-00052](http://dx.doi.org/10.1111/1468-0009.t01-1-00052) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1111/1468-0009.t01-1-00052&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=12841049&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000183519400002&link_type=ISI) 161.Graham ID, Logan J, Harrison MB, et al. Lost in knowledge translation: time for a map? J Contin Educ Health Prof 2006;26:13–24. [doi:10.1002/chp.47](http://dx.doi.org/10.1002/chp.47) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1002/chp.47&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=16557505&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000236855300003&link_type=ISI) 162.Reed N, Dawson J, Ledoux AA. Living guideline for diagnosing and managing pediatric concussion. 2021. Available: [www.pedsconcussion.com](http://www.pedsconcussion.com) 163.Marshall S, Curran D, Fischer L, et al. Living concussion guidelines: guideline for concussion & prolonged symptoms for adults 18 years of age or older. 2023. Available: [https://concussionsontario.org](https://concussionsontario.org) 164.Goodman MS, Sanders Thompson VL. The science of stakeholder engagement in research: classification, implementation, and evaluation. Transl Behav Med 2017;7:486–91. [doi:10.1007/s13142-017-0495-z](http://dx.doi.org/10.1007/s13142-017-0495-z) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 165.Duffett L. Patient engagement: What partnering with patient in research is all about. Thromb Res 2017;150:113–20. [doi:10.1016/j.thromres.2016.10.029](http://dx.doi.org/10.1016/j.thromres.2016.10.029) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/j.thromres.2016.10.029&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=27817863&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 166.Roehr B. More stakeholder engagement is needed to improve quality of research, say US experts. BMJ 2010;341:c4193. [doi:10.1136/bmj.c4193](http://dx.doi.org/10.1136/bmj.c4193) 167.National Institute for Health Research. James Lind Alliance priority setting partnerships internet. n.d. Available: [https://www.jla.nihr.ac.uk](https://www.jla.nihr.ac.uk) 168.Abelson J, Li K, Wilson G, et al. Supporting quality public and patient engagement in health system organizations: development and usability testing of the Public and Patient Engagement Evaluation Tool. Health Expect 2016;19:817–27. [doi:10.1111/hex.12378](http://dx.doi.org/10.1111/hex.12378) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1111/hex.12378&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 169.Canadian Institute of Health Research. Foundations of strategy for patient-oriented research (SPOR). 2019. Available: [https://cihr-irsc.gc.ca/e/51039.html](https://cihr-irsc.gc.ca/e/51039.html) 170.Veronik S, Olivier B, Lauren B, et al. Acceptability, usability, and credibility of an early mindfulness-based intervention delivered via a mobile app for pediatric concussion. Philadelphia: Lippincott Williams & Wilkins, 2022. 171.Sicard V, Moore RD, Ellemberg D. Long-term cognitive outcomes in male and female athletes following sport-related concussions. Int J Psychophysiol 2018;132:3–8. [doi:10.1016/j.ijpsycho.2018.03.011](http://dx.doi.org/10.1016/j.ijpsycho.2018.03.011) 172.Kerr ZY, Chandran A, Nedimyer AK, et al. Concussion Incidence and Trends in 20 High School Sports. Pediatrics 2019;144:e20192180. [doi:10.1542/peds.2019-2180](http://dx.doi.org/10.1542/peds.2019-2180) 173.Mollayeva T, El-Khechen-Richandi G, Colantonio A. Sex & gender considerations in concussion research. Concussion 2018;3:CNC51. [doi:10.2217/cnc-2017-0015](http://dx.doi.org/10.2217/cnc-2017-0015) 174.Gagnon I, Friedman D, Beauchamp MH, et al. The Canadian Pediatric Mild Traumatic Brain Injury Common Data Elements Project: Harmonizing Outcomes to Increase Understanding of Pediatric Concussion. J Neurotrauma 2018;35:1849–57. [doi:10.1089/neu.2018.5887](http://dx.doi.org/10.1089/neu.2018.5887) 175.Broglio SP, Kontos AP, Levin H, et al. National Institute of Neurological Disorders and Stroke and Department of Defense Sport-Related Concussion Common Data Elements Version 1.0 Recommendations. J Neurotrauma 2018;35:2776–83. [doi:10.1089/neu.2018.5643](http://dx.doi.org/10.1089/neu.2018.5643) 176.Langer LK, Comper P, Ruttan L, et al. Can Sport Concussion Assessment Tool (SCAT) Symptom Scores Be Converted to Rivermead Post-concussion Symptoms Questionnaire (RPQ) Scores and Vice Versa? Findings From the Toronto Concussion Study. Front Sports Act Living 2021;3:737402. [doi:10.3389/fspor.2021.737402](http://dx.doi.org/10.3389/fspor.2021.737402) 177.Tarvainen MP, Ranta-Aho PO, Karjalainen PA. An advanced detrending method with application to HRV analysis. IEEE Trans Biomed Eng 2002;49:172–5. [doi:10.1109/10.979357](http://dx.doi.org/10.1109/10.979357) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1109/10.979357&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=12066885&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000173482500010&link_type=ISI) 178.Tarvainen MP, Niskanen J-P, Lipponen JA, et al. Kubios HRV--heart rate variability analysis software. Comput Methods Programs Biomed 2014;113:210–20. [doi:10.1016/j.cmpb.2013.07.024](http://dx.doi.org/10.1016/j.cmpb.2013.07.024) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/j.cmpb.2013.07.024&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=24054542&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 179.Lipponen JA, Tarvainen MP. A robust algorithm for heart rate variability time series artefact correction using novel beat classification. J Med Eng Technol 2019;43:173–81. [doi:10.1080/03091902.2019.1640306](http://dx.doi.org/10.1080/03091902.2019.1640306) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1080/03091902.2019.1640306&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=31314618&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) 180.Niskanen J-P, Tarvainen MP, Ranta-Aho PO, et al. Software for advanced HRV analysis. Comput Methods Programs Biomed 2004;76:73–81. [doi:10.1016/j.cmpb.2004.03.004](http://dx.doi.org/10.1016/j.cmpb.2004.03.004) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/j.cmpb.2004.03.004&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=15313543&link_type=MED&atom=%2Fbmjopen%2F15%2F4%2Fe095292.atom) [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000223715700007&link_type=ISI)