Molecular epidemiology of traumatic brain injury outcome amongst individuals of Black racial identity or African ancestry: a scoping review protocol

Abstract

Introduction

Traumatic brain injury (TBI) is a leading cause of mortality and disability worldwide. In the USA, individuals who racially identify as African American or Black experience disproportionately higher rates of TBI and sustain worse prognosis compared with White patients; however, this population continues to be under-represented in contemporary translational research agendas. This protocol aims to comprehensively evaluate and synthesise what is currently known about the molecular epidemiology of TBI outcome among individuals of Black racial identity or African ancestry.

Methods and analysis

This review will use the established scoping review framework from the Joanna Briggs Institute. The search strategy will be implemented in PubMed (MEDLINE) and expanded to Embase and Cochrane CENTRAL Library (Wiley) databases in the final review. The date range will span from database inception to 20 July 2025 (date of final search). A two-stage screening process will be performed first at the title and abstract level before full-text assessment. Screening will be performed by two independent reviewers and discrepancies will be reconciled by a third reviewer. Articles that meet the following inclusion criteria will be considered: we will include human studies that investigate molecular and biochemical markers associated with TBI outcome. Studies must include individuals who are (A) of Black or African American racial identity, (B) of African ancestry and/or (C) performed in Sub-Saharan African countries. There is no eligibility criteria related to participant age, sex or gender. Eligible studies will be limited to English, Spanish or French. Data extracted from will be analysed and presented as written narrative, summary statistics of study characteristics and graphical or tabular displays.

Ethics and dissemination

Ethical approval is not required for this scoping review. The results of this review will be disseminated through peer-reviewed publications and academic conferences.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• Utilisation of a robust scoping review framework to ensure development of a quality and technically reproducible review.

• Comprehensive search strategy to capture biomarkers commonly associated with traumatic brain injury (TBI), as well as other molecular markers that may be relevant to TBI outcomes.

• Inclusion of the grey literature enables a wider scope of studies to be captured and further enables the collection of data from low- and middle-income countries, thus reducing publication bias.

• Studies that only use non-specific demographic terms such as ‘minority’ and/or ‘person of colour’ will be excluded, which may unintentionally exclude individuals from our population of interest due to a lack of specificity.

Introduction

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, with an estimated annual incidence of 1.4 million cases in the USA and 10 million cases globally.¹ In the USA, TBI occurrence disproportionately impacts individuals from racial or ethnic minority groups.^{2 3} Notably, Black individuals have a 25–35% higher incidence of TBI and suffer from worse outcomes following TBI, compared with White individuals.2,4 Previous reports have identified higher rates of mortality following TBI in individuals of Black racial identity (self-reported or hospital-assigned) as compared with White.⁵ Furthermore, Black patients are less likely to receive follow-up care compared with White patients,^{4 6} with a lower percentage of Black patients (16.1%) discharged from acute care into post-acute rehabilitation facilities compared with White patients (23.3%) following TBI.⁷ Together, these findings highlight the inequities that exist in TBI outcome across racial groups.

Despite the high incidence of, and worse outcomes following, TBI in Black populations, this group remains under-represented in contemporary research agendas. A recent study (2020) identified that 78% of studies investigating TBI between 2006 and 2017 did not report specific information on race or ethnicity and an additional 7.5% specified only the percentage of White participants included.² The lack of inclusion in TBI research—and more generally, a disregard of or inattention to the relevance of race and ancestry—is further compounded by a paucity of research produced in lower- and middle-income countries, where roughly 90% of trauma-related mortalities occur (brain-related as the leading cause).^{8 9} In a study (2022) identifying the TBI-related literature published between 2008 and 2018, the majority of articles were from North America (51.4%) and Europe (24.7%), while only 1.1% of studies were produced in continental Africa.⁹ The historical omission of African American, Black and African ancestry (AABAA) populations in TBI-related research, despite being among the most heavily impacted by TBI, endorses the need to redirect TBI-related research towards including and benefiting these groups.

One approach to further understand factors that impact TBI outcome is through the investigation of its molecular epidemiology. Molecular epidemiology is a branch of epidemiology which leverages biochemical and molecular markers to further understand the mechanisms of disease.¹⁰ Investigation of molecular biomarkers associated with TBI outcomes and prognoses has already yielded promising evidence for improved clinical practice and support of patient management.¹¹ However, the roles of these biomarkers in TBI diagnostics, treatment and/or prognostication remain to be established. Establishing the molecular epidemiology of TBI in AABAA populations is imperative to address ongoing disparities in TBI outcome and to promoting health equity and inclusion in research.

In order to assess what is known about the molecular epidemiology of TBI outcomes in AABAA populations, here, we outline a planned scoping review. We recently published a narrative review (2024) highlighting the existence of literature on molecular biomarkers related to TBI outcomes in AABAA populations¹²; however, to our knowledge, no systematic or scoping reviews have been conducted to comprehensively synthesise this knowledge. A preliminary search of PubMed (MEDLINE), the Cochrane CENTRAL Library (Wiley) and the Joanna Briggs Institute (JBI) Evidence Synthesis confirmed the lack of existing reviews on this topic. The proposed scoping review will address this gap by mapping the available evidence, focusing on inclusivity and avoiding the exclusion of potentially valuable studies due to methodological limitations. By providing a clearer understanding of the molecular epidemiology of TBI outcomes in AABAA populations, this review aims to inform future research and guide efforts to reduce disparities.

Methods and analysis

The proposed scoping review will be conducted in accordance with the JBI methodology for scoping reviews¹³ and in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for Scoping Reviews guidelines.¹⁴

Research question

What is currently known about the molecular epidemiology of TBI outcome among individuals of Black racial identity or African ancestry?

Search strategy

An initial search was conducted in PubMed (MEDLINE) to identify articles with topics related to ‘epidemiology’, ‘biomarkers’ and ‘traumatic brain injury’. Using the text in the title, abstract, keywords and index terms of relevant articles, we identified additional search terms used to develop our full search strategy. Search terms were also adapted from previous literature reviews.^{12 15 16} Information on race, ethnicity and/or ancestry is often absent from the title, abstract and keywords; therefore, this eligibility criteria was not represented in our final search and instead will be screened for during study selection.

The full search strategy will first be conducted in PubMed (online supplemental appendix 1), and search terms will be adapted, when necessary, to search the Embase and Cochrane CENTRAL Library (Wiley) databases. Grey literature will additionally be searched. Reference list screening of eligible articles will also be conducted to capture other potentially relevant papers. This review will be limited to human studies with available full text in English, Spanish or French. The objective of this review is to provide the current consensus of TBI-outcome biomarkers and molecular epidemiology in AABAA individuals, so we will limit our search to primary literature.

Inclusion criteria

The inclusion criteria for this scoping review will follow the JBI framework of population, concept and context, as below.

Population

All severities of TBI (mild, moderate, severe) and the full range of GCS scores (3–15) will be considered. Eligible studies must contain at least one human subject (alive or postmortem) with a history of TBI according to clinical diagnosis or self-report. We will consider studies that investigate penetrating injury to the head resulting in the rupture of the skull and dura, closed head injury with intact skull and dura, as well as focal or diffuse intercranial injury (disease codes: NA07.Z, NA07.Y) as defined by the International Classification of Diseases, 11th revision.^{1 17} This review will also include concussion injuries (NA07.0), which are the most common form of mild TBI and represent the majority of TBI cases overall.¹ Repeat occurrences of TBI or head impact can lead to TBI-associated chronic traumatic encephalopathy (TBI-CTE, NA07.0Y),¹⁸ which will also be considered. TBI-CTE has also been historically referred to as ‘dementia pugilistica‘ and colloquially called ‘punch-drunk syndrome‘ or ‘boxer’s dementia’.19,21 This review will consider studies that include at least one AABAA individual; the definitions for this eligibility criteria are further defined below. No eligibility criteria related to participant age, sex or gender will be considered for this review.

Concept

Biomarkers associated with TBI outcome through a molecular epidemiological lens. Molecular epidemiology is a branch of epidemiology that focuses on biochemical and molecular markers (biomarkers) associated with disease outcomes and factors.¹⁰ Therefore, studies that investigate the presence, variation or alteration of molecular biomarkers associated with TBI outcome will be eligible. Biomarkers will be defined as any molecular or biochemical measurement used to differentiate normal and pathological processes; studies must include a biomarker as a primary outcome measure to be considered. This review protocol proposes investigating both ‘omics’ and ‘non-omics’ biomarkers: omics markers include genetic, genomic, transcriptomic, proteomic, metabolomic, lipidomic and epigenetic data; while non-omics markers may include, but are not limited to, magnetic resonance spectroscopy. Furthermore, biomarkers previously associated with TBI outcome will be included in the search term, including (but not limited to): cytokines such as interleukin-6, genetic markers including apolipoprotein E and serum-related biomarkers: neuron-specific enolase, ubiquitin c-terminal hydrolase-l1, s100b, glial fibrillar acidic protein, neurofilament-light, myelin basic protein and tau protein.¹¹

Context

This review aims to abridge studies that investigate biomarkers associated with TBI outcomes among individuals of African American or Black racial identity or African ancestry. Therefore, it is crucial to consider the implications of using race as an inclusion criterion in the context of biomedical research. In the USA, race has been included in the census since its start in 1790.²² However, the classification and questions regarding race on the census have evolved over time, with current social scholars describing race as a fluid variable with political and social influence.²³ There has been recent emphasis on the addition of race and ethnicity information in research studies and grants to promote inclusion of under-represented groups in research, exemplified by national programmes including the enactment of the National Institutes of Health Revitalization Act (Public Law 103–43) in 1993. This has manifested as the inclusion of race as a defining variable in many contemporary studies.²⁴ Due to the inconsistent definitions of races throughout US history and the current weight placed on including race in biomedical research,^{24 25} it is crucial to emphasise that the use of race does not place any biological significance on this social construction.

While it is well established that there is not a biological basis for race, Best and Chenault (2014) caution against the perpetuation of this false equivalency through the implementation of race operating as a biological proxy.²⁴ This distinction is further entangled by the established statistical correlation between self-identified race and genetic ancestry in the USA.²⁶ Recent studies have cautioned that this association can be harmful and misleading in population genetics and lead to racial bias in research.^{27 28} Instead, a multifaceted approach is proposed which investigates (a) racial disparities through measures of structural racism and (b) relevant disease pathways through genetic factors, including genetic ancestry.^{27 28} Disease risk can be assessed independently through each facet as well as together through their interaction. In this review, we aim to address both aspects; we will include both race and ancestry as methods to define our population of interest to avoid unintended exclusion.

This review aims to appropriately distinguish the intersectionality between Black or African American racial identity and African ancestry to focus on the entire African diaspora. The African diaspora has been defined as the forced removal of Africans from their homes as a result of the trans-Atlantic (and other) slave trade networks to the Americas.²⁹ Previous work has identified that African ancestry in the USA has been enriched for West-Central African and Western-African genetic ancestry clusters.³⁰ Therefore, to more broadly capture studies that pertain to the AABAA population, we will additionally consider studies conducted in Sub-Saharan African countries from which formerly enslaved African people were forcibly removed from. Countries were selected according to the Transatlantic Slave Trade Database (www.slavevoyages.org), an online data repository containing over 36 000 documented slavery voyages (online supplemental appendix 2). Furthermore, studies investigating individuals who identify with any ethnic group historically impacted by the trans-Atlantic slave trade will also be considered (online supplemental appendix 3).²⁴ This review will consider research produced globally if other eligibility criteria are met.

One limitation of this review is the exclusion of studies that solely describe the population studied as ‘minority’ and/or ‘person of colour’. Although these terms may include individuals from our population of interest, they lack the necessary specificity to address our review question.

Date range

We aim to comprehensively assess what is known about the molecular epidemiology of TBI outcomes among AABAA individuals; therefore, no date limitations are established for this review; studies will be included from database inception to 20 July 2025 (date of final search).

Types of evidence to be included

This scoping review will consider published and unpublished studies involving human subjects including randomised control trials, cross-sectional studies, cohort studies, case reports and case series. Basic science studies that investigate TBI-outcome associated biomarkers in postmortem samples may also be considered. Reviews, editorials, study protocols, opinion articles and commentaries will be excluded to avoid duplication. Grey literature, including unpublished research, that meets the identified eligibility criteria will be additionally screened. Literature that does not directly involve human subjects, including in vivo and in vitro preclinical studies, will be excluded.

Following the search and extraction of records, the identified records will be uploaded to Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia; www.covidence.org), collated and duplicates will be removed. Title and abstract level screening will be performed by two independent reviewers against the eligibility criteria. Studies of uncertain significance will not be excluded at this phase and will be assessed during the full text portion of study selection. Discrepancy in study eligibility will be resolved through a third reviewer. Reviewer agreement will be assessed after every 100 papers using inter-rater reliability through the Cohen’s κ-coefficient. If low agreement between reviewers is observed (κ<0.4), reviewers will re-assess eligibility criteria and modify, if necessary, before proceeding with the screening process.

Potentially relevant papers will be retrieved in full, and their citation details will be recorded in Covidence systematic review software. Two independent reviewers will assess each study in full according to the eligibility criteria, and reasons for exclusion will be recorded. Any disagreement in eligibility during full text screening will be discussed with a third independent reviewer who will make the final decision. In the occurrence that additional search terms are identified during the study selection process, the additional term will be discussed with the group and added to the search strategy criteria when appropriate. The full results of the search, including disqualified studies and reasons for exclusion, will be presented in the final scoping review as a PRISMA flow diagram.³¹

Data extraction

The data extraction tool will record study information including the title, year, author names, country, study design, the biomarker(s) investigated in the study and disease classification (online supplemental appendix 4). Study characteristics including the total number of participants and number of AABAA participants will be recorded for each eligible study. Studies will additionally be categorised by the following criteria: (a) solely including individuals from our population of interest without specifically focusing on the group; (b) using race, ethnicity or ancestry demographics as a covariate in data analysis or (c) focusing specifically on our population of interest by comparing across populations or only including AABAA participants. For studies that primarily focus on our population of interest (category c), a summary of the findings will be recorded.

Data analysis and presentation of results

Studies will be assessed on the level of inclusion of race, ethnicity or ancestry as a variable in study methodology, that is, whether demographic information was solely included or if the study primarily focused their research question on our population of interest. Studies will be categorised (see the Data Extraction section) and arranged on a sliding scale that summarises the inclusion of race, ethnicity or ancestry in the study methods (figure 1). Summary statistics on the representation of AABAA individuals in studies investigating biomarkers associated with TBI outcome will be reported in graphical and tabular format. For studies that include race, ethnicity or ancestry as a primary aspect of their research question or include only participants from the population of interest, a summary of study findings, biomarkers used and association with TBI outcome will be reported through a descriptive narrative, tables and infographics.

Figure 1. Draft of the sliding scale schematic proposed to classify eligible studies by the incorporation of race, ethnicity and/or ancestry in study methodology. AABAA, African American, Black and African ancestry.

Knowledge translation

The anticipated audience for this review will include clinicians, researchers and advocacy organisations in order to highlight disparities in TBI outcomes among individuals of Black racial identity or African ancestry as well as to foster more inclusive approaches to research related to TBI outcomes. We plan to disseminate the findings of this review through peer-reviewed publications and presentations at academic conferences. By identifying gaps in existing literature surrounding biomarkers associated with TBI outcomes in underrepresented populations, the dissemination of results will inform future investigation and support the development of inclusive methodologies for TBI research.

Patient and public involvement

The development and execution of this review will not involve direct contributions from patients or the public in its design, conduct, reporting or dissemination plans. However, the results of this review are aimed to support efforts for improving outcomes among individuals and groups most affected by TBI.

Ethics and dissemination

This review does not require ethical approval, as it relies on the existing literature and does not involve new data collection. This scoping review will adhere to established scoping review guidelines to ensure accuracy and transparency. The findings will be shared through peer-reviewed articles and academic conferences. Dissemination efforts will be tailored towards academic journals and conferences that promote health equity and global health efforts in order to make its results both widely accessible and actionable.