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Strengthening the Evidence Base

Recommendations for Future Research Identified Through the Development of CDC's Pediatric Mild TBI Guideline

Suskauer, Stacy J. MD; Yeates, Keith Owen PhD; Sarmiento, Kelly MPH; Benzel, Edward C. MD; Breiding, Matthew J. PhD; Broomand, Catherine PhD; Haarbauer-Krupa, Juliet PhD; Turner, Michael MD; Weissman, Barbara MD; Lumba-Brown, Angela MD

Section Editor(s): Caplan, Bruce PhD, ABPP; Bogner, Jennifer PhD, ABPP; Brenner, Lisa PhD, ABPP; Malec, James PhD, ABPP

The Journal of Head Trauma Rehabilitation: July/August 2019 - Volume 34 - Issue 4 - p 215–223
doi: 10.1097/HTR.0000000000000455
Original Articles
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Objective: The recently published Centers for Disease Control and Prevention evidence-based guideline on pediatric mild traumatic brain injury (mTBI) was developed following an extensive review of the scientific literature. Through this review, experts identified limitations in existing pediatric mTBI research related to study setting and generalizability, mechanism of injury and age of cohorts studied, choice of control groups, confounding, measurement issues, reporting of results, and specific study design considerations. This report summarizes those limitations and provides a framework for optimizing the future quality of research conduct and reporting.

Results: Specific recommendations are provided related to diagnostic accuracy, population screening, prognostic accuracy, and therapeutic interventions.

Conclusion: Incorporation of the recommended approaches will increase the yield of eligible research for inclusion in future systematic reviews and guidelines for pediatric mTBI.

Kennedy Krieger Institute, and Johns Hopkins University School of Medicine, Baltimore, Maryland (Dr Suskauer); University of Calgary, Alberta, Canada (Dr Yeates); Centers for Disease Control and Prevention, Atlanta, Georgia (Ms Sarmiento and Drs Breiding and Haarbauer-Krupa); Cleveland Clinic, Ohio (Dr Benzel); Goodman Campbell Brain & Spine, Indianapolis, Indiana (Dr Turner); Emory University School of Medicine, Atlanta, Georgia (Dr Weissman); and Stanford University School of Medicine, California (Dr Lumba-Brown). Dr Broomand is retired.

Corresponding Author: Stacy J. Suskauer, MD, 707 North Broadway, Baltimore, MD 21205 (suskauer@kennedykrieger.org).

The findings and conclusions in this article are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Dr Benzel discloses 2012 Spine Prospective Clinical Research Grant #12-205, “Anatomical Differences and Protective Helmet Design in American Football,” which he received from the Orthopedic Research and Education Foundation, and his work with Prevent Biometrics, where he was awarded DOD and US Department of Transportation grants focusing on concussion dosimetry and behavioral deficits. Dr Lumba-Brown reports receiving a grant from the Department of Defense. Dr Suskauer reports receiving funding from the National Institute of Child Health and Human Development. Dr Turner discloses 2 sources of corporate financial support from Medtronic Corporation and NICO corporation. Dr Yeates discloses his role as the President of the International Neuropsychological Society, his research grant support from NIH and the Canadian Institutes of Health Research, and his research support from the Research Institute at Nationwide Children's Hospital in Columbus, Ohio. Drs Benzel, Broomand, Lumba-Brown, Suskauer, Turner, and Yeates report that they did not receive grants for this submitted work and were on the expert work group that helped form the basis for the CDC guideline. Ms Sarmiento was the designated federal official for CDC Pediatric Mild TBI Workgroup.

The authors declare no conflicts of interest.

PEDIATRIC MILD TRAUMATIC BRAIN INJURY (mTBI), including concussion, is a significant public health concern. In 2014, traumatic brain injury in children, inclusive of mTBI, accounted for more than 800 000 emergency department visits (1103.9 per 100 000 children) and 23 000 hospitalizations (31.4 per 100 000).1 Data suggest that almost 90% of children with mTBI enter the healthcare system in nonemergency department outpatient settings,2 and 65% of children with mTBI may not seek care in any organized healthcare setting.3 Most children recover from postconcussive symptoms within the first few months following injury; however, a significant subset reports long-term sequelae.4 The International Consensus Statements on Concussion in Sport, among others, highlighted the need for continued research and evidence-based strategies to improve diagnosis, prognostication, and treatment of mTBI to help improve outcomes for children with mTBI.5

The Centers for Disease Control and Prevention (CDC) responded to this need by publishing an evidence-based guideline in 2018.6 This guideline is inclusive of clinical recommendations spanning diagnosis, prognosis, and management/treatment that are applicable to healthcare professionals working in all settings. In developing the CDC guideline, the authors identified limitations in research including related to study settings and generalizability, mechanism of injury, age, control groups, confounding, measurement issues, result reporting, and specific study design considerations. This report addresses those limitations and provides a framework for optimizing the future quality of research conduct and reporting to better inform next iterations of guideline recommendations.

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DEVELOPMENT OF THE CDC PEDIATRIC mTBI GUIDELINE

The CDC Pediatric mTBI Guideline was developed through a rigorous stepwise process guided by the American Academy of Neurology methodology and 2010 National Academy of Sciences methodology for the development of evidence-based guidelines.6,7 This evidence-based guideline was directed by an extensive review of the scientific literature7 focused on 6 clinical questions (see Table 1). The literature search spanned 25 years (January 1, 1990, to July 31, 2015). Using a modified Grading of Recommendations Assessment Development and Evaluation (GRADE) methodology, guideline investigators reviewed studies of mTBI that provided analyzable data on youth 18 years and younger. The inclusion of youth through 18 years of age allowed for applicability of results to older high school populations still commonly cared for in pediatric practices. A broad definition of mTBI was utilized encompassing Glasgow Coma Scale scores of 13 to 15, regardless of the presence of intracranial imaging findings and related care needs, to better understand outcomes and provide inclusive recommendations for the management of children representing the full spectrum of children diagnosed with concussion/mTBI, including children at the more severe end of that spectrum who are at risk for “falling through the cracks” of services.8

TABLE 1

TABLE 1

Of the more than 37 000 abstracts identified through the literature search, the guideline authors selected over 2900 articles in a dual-reviewer process that met the inclusion criteria for full-text review. Approximately 345 articles were deemed sufficiently relevant for data extraction, and ultimately datasets from 66 studies were included in the text of the systematic review, which formed the basis of the guideline. Included studies were classified according to risk bias with varying strengths of evidence. Confidence in the evidence was evaluated across studies per clinical question and was downgraded or upgraded based on consistency, precision, plausibility, directness, reporting bias, magnitude of effect, dose response, and the direction of bias.9

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CURRENT LIMITATIONS AND OPPORTUNTIES FOR FUTURE RESEACH IDENTIFIED THROUGH GUIDELINE DEVELOPMENT

Limitations identified generally focused on study design, data presentation (such as not separating findings by age and TBI severity level), use of small sample sizes and exclusion of control groups, and generalizability and applicability of research findings (such as due to unclear inclusion/exclusion criteria and unrepresentative samples). Table 1 summarizes limitations in the evidence consistently identified by the guideline authors for each of the 6 clinical questions.

Opportunities to optimize the conduct and reporting of future research, applicable to all study designs, are discussed below and summarized in Table 2.

TABLE 2

TABLE 2

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Study settings and generalizability

Capturing a broad spectrum of youth with mTBI is critical for study outcome generalizability to clinical populations. This will require recruitment of children with mTBI from a range of healthcare settings (eg, pediatric offices, subspecialty clinics, varying types of emergency departments, or urgent care settings) and also outside of healthcare settings, such as in schools. The importance of capturing youth from varying settings is underscored by data demonstrating that site of care varies based on children's age, race/ethnicity, and socioeconomic status.2 The severity and duration of symptoms are also likely to influence whether and where care is sought. In all cases, clear inclusion and exclusion criteria must be used and reported for the purposes of evaluating generalizability, as well as facilitating replication and comparison across studies.

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Mechanism of injury

Most studies focus on sports-related injuries; however, 30% to 50% of children treated for mTBI in healthcare settings sustain injuries through other mechanisms (eg, falls and motor vehicle crashes).10,11 While the distribution of sports- versus non-sports-related mechanisms of injury will vary by age and setting, it is important to study children with mTBI of all etiologies and to understand mechanism-related differences and similarities.

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Age range

To date, mTBI research has been particularly limited in young children, despite their high rate of TBI12 and high risk for behavioral and learning problems following mTBI.13–16 One challenge that needs to be addressed is how to reliably diagnose mTBI in infants and toddlers incapable of articulating their symptoms, especially in the setting of nonspecific symptoms such as vomiting, fussiness, or irritability. Currently available postconcussive symptom inventories have not been validated for children younger than 5 to 6 years.17,18 Research is needed to define symptoms and signs of mTBI in very young children and to validate age-appropriate symptom inventories inclusive of younger age groups. In addition, the identification of objective diagnostic tools, such as serum biomarkers, is likely to play a critical role in young children.

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Control groups

Selection of control groups in mTBI research is important. Even in study designs for which non-mTBI controls may not be necessary for addressing the primary question (eg, questions 2, 4, and 5 included in the systematic review), the inclusion of controls allows contextualization of outcomes in the mTBI cohort. Utilization of an injured comparison group that experienced nonhead trauma controls for factors related to a child's likelihood of sustaining an injury as well as for nonspecific physiologic and emotional responses to trauma. However, as brain injury can occur secondary to translational forces in the absence of direct blows to the head, as in body-checking during hockey or tackling in football, deliberate care should be taken to identify and exclude control group children with subtle signs of mTBI. Noninjury control groups will not provide an understanding of the effects of mTBI relative to trauma more generally but may provide a clearer understanding of how children with mTBI compare to a broader sample of their peers. When possible, use of a child's own preinjury data for comparison purposes best controls for interindividual variability, although nonhead injury controls are still useful in this context for establishing normative expectations for reliable change over time.19

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Accounting for confounding

Across participants with mTBI and controls, identification of and accounting for confounding factors is critical to quality research. Factors to consider include a child's preinjury functioning (eg, preinjury symptom level, academic performance, medical, and/or mental health diagnoses), family functioning (eg, socioeconomic status and parenting styles), and other exposures (eg, prior mTBI and nonconcussive head trauma). A priori sample size calculations need to account for inclusion of multiple confounders in analyses.

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Measurement issues

Careful attention is needed in the selection of measures used to describe mTBI populations with respect to preinjury and postinjury status. Consistent use of the same, validated measures (eg, NIH Common Data Elements20–22) to assess common constructs (eg, postconcussive symptoms, cognitive functioning, and behavioral adjustment) will facilitate comparison of results across studies, including through meta-analysis techniques. Given the evolving nature of evaluation and management of mTBI, however, the call for common data elements must be balanced against the continued need to evaluate and report on novel measures that may show improved sensitivity to subtle findings, such as changes in school performance that may not be reflected in traditional standardized measures of academic achievement and novel imaging acquisitions/analyses that may more fully capture disruption of structure and function as compared with standard clinical imaging. For findings to be optimally translatable into clinical practice, diagnostic and prognostic measures should be publicly available and feasible for widespread use.

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Reporting of results

When publishing research, key reporting features will optimize inclusion of results in systematic reviews and meta-analyses and thereby promote future guideline development. If the research cohort includes participants spanning adolescence through early adulthood or with more severe forms of TBI, data should be presented for the subset of participants who are 18 years and younger or have mTBI. In addition, sufficient raw data must be provided in the text or as supplemental files to allow calculation of effect sizes and inclusion in meta-analyses; 95% confidence intervals are a preferred measure of precision9 and should be provided.

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Specific study design considerations

To address study design-specific strategies for optimizing research quality, recommended approaches were compiled for each of the 6 questions included in the systematic review (see Tables 3–6). Each table addresses 1 or 2 of the questions included in the systematic review. For each question, a recommended approach is provided for critical elements of study design and reporting. These recommended approaches represent a translation of general study design and reporting principles to pediatric mTBI-specific language and concepts and are intended to aid researchers by providing models for designing high-quality studies and optimizing dissemination of findings. The systematic review questions were used for convenience purposes and are not intended to reflect a recommendation for a specific research agenda.

TABLE 3

TABLE 3

TABLE 4

TABLE 4

TABLE 5

TABLE 5

TABLE 6

TABLE 6

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Other research directions/gaps

While this article describes limitations in research related to the specific, focused questions utilized in the CDC Pediatric Mild TBI Guideline, other questions related to identification of risk for mTBI, prevention of mTBI, and reduction in possible long-term adverse outcomes remain important areas in need of quality research. In addition, children live in home and school environments that may contribute to their long-term outcomes. Factors such as family education, parental income, and parenting styles, as well as receipt of appropriate support at school, contribute to the risk and outcomes of mTBI. Data collection about a child's environment is important to consider in future research. Prospective study of a broad, nationally representative cohort over time to determine which children with mTBI have good versus poor outcomes is needed. In addition, high-quality research is needed to understand the effects of blows to the head in the absence of diagnosed mTBI.

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CONCLUSION

Pediatric mTBI is a significant public health concern representing a research priority that warrants increased attention. Fortunately, the literature related to pediatric mTBI continues to expand rapidly, and continued updates of evidence-based systematic reviews and guidelines will be needed, as the amount and quality of research grows. Incorporation of the concrete approaches outlined here would increase the yield of eligible research for inclusion in future systematic reviews and recommendations for pediatric mTBI, thereby directing optimized standard care in this vulnerable population.

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REFERENCES

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    Keywords:

    child; concussion; guideline; mild traumatic brain injury; pediatrics; study design

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