Centering Racial Health Equity in Systematic Reviews Paper 3: A Systematic Review of Definitions For "Racial Health Equity" and Related Terms within Health Related Articles.

OBJECTIVE: To systematically evaluate definitions of "racial health equity" and related terms within health-related academic literature. STUDY DESIGN AND SETTING: We systematically evaluated definitions of racial health equity and related terms within health-related academic articles. Articles published in English were included, and no date restrictions were imposed. RESULTS: We found 20 original articles containing relevant definitions out of 1816 retrieved articles, thirteen of which were published from 2020-2023. Themes used in the definitions varied, with racism (n= 12) and quality of healthcare (n= 10) being the most common. Additional themes, including social hierarchy or marginalization, discrimination, justice, unmet social needs, and historical events were used by some definitions. Eleven of the included manuscripts defined race as a social construct. CONCLUSION: This study depicts racial health equity as an emerging concept with limited consensus on racism, quality of health, and social determinants of health as important underlying frameworks. To center equity efforts and actions under a workable and shared vision, we recommend continued discussions regarding underlying meanings of racial health equity concepts and propose establishing a definition that promotes unity across health fields and prevents ambiguity.

Centering Racial Health Equity in Systematic Reviews Paper 6: Engaging racially and ethnically diverse stakeholders in evidence syntheses.

OBJECTIVE: To inform methods for centering racial health equity in syntheses, we explored 1) how syntheses that assess health-related interventions and explicitly address racial health inequities have engaged interest holders and 2) guidance for engaging racially and ethnically diverse interest holders. STUDY DESIGN AND SETTING: We systematically identified evidence syntheses (searches limited to January 1, 2020, through January 25, 2023) and guidance documents (no search date limits) for this overview. From syntheses we extracted data on engagement rationale and processes and extracted approaches suggested from guidance documents. We summarized findings qualitatively. RESULTS: Twenty-nine of the 157 (18%) eligible syntheses reported using engagement. Syntheses typically lacked robust detail on why and how to use and structure engagement and outcomes/effects of engagement, though syntheses involving Indigenous populations typically included more detail. When reported, engagement typically occurred in early and later synthesis phases. We did not identify guidance documents that specifically intended to provide guidance for engaging racially/ethnically diverse individuals in syntheses; some related guidance described broader equity considerations or engagement in general. CONCLUSION: This review highlights gaps in understanding of the use of engagement in racial health equity-focused syntheses and in guidance specifically addressing engaging racially and ethnically diverse populations. Syntheses and guidance materials we identified reported limited data addressing the whys, hows, and whats (i.e., rationale for, approaches to, resources needed and effects of) of engagement, and we lack information for understanding whether engagement makes a difference to the conduct and findings of syntheses and when and how engagement of specific populations may contribute to centering racial health equity. A more informed understanding of these issues, facilitated by prospective and retrospective descriptions of engagement of diverse interest holders, may help advance actionable guidance and reviews.

Centering racial health equity in systematic reviews Paper 4: A systematic review on the use of logic models and frameworks for methodological conduct of evidence synthesis.

OBJECTIVE: To identify evidence syntheses of health interventions addressing racial health equity reporting the use of equity-focused frameworks and logic models. STUDY DESIGN AND SETTING: The search strategy included three sources; a search of three bibliographic databases to identify systematic reviews assessing interventions to improve racial health equity, semi-structured interviews with diverse group and a targeted organization website searches (e.g. NIH, USPSTF) to identify relevant logic models and frameworks. The searches were conducted between January 1, 2020, and January 25, 2023. We used a qualitative approach to identify and describe key characteristics of equity-focused logic models and frameworks used in evidence syntheses. RESULTS: Of the 153 racial health equity-focused evidence syntheses identified, 2 explicitly used logic models to describe the intervention mechanism. We identified seven existing health equity frameworks from semi-structured interviews and electronic search of key websites that were categorized by stated purpose as providing guidance for 1) research, 2) health policy, 3) digital healthcare solutions, and 4) clinical preventive services. Two out of 7 frameworks included guidance on integrating frameworks or logic models in evidence synthesis while the majority provided contextual information on how to define or consider race or racism as a structural determinant of health. CONCLUSION: There is limited use of logic models and frameworks in evidence syntheses addressing racial health equity. There is a need for more applied frameworks providing guidance for framing, conducting and interpreting findings of evidence syntheses addressing racial health equity.

Definitions, terminology, and related concepts of "racial health equity": a scoping review protocol.

BACKGROUND: In the USA, access to quality healthcare varies greatly across racial and ethnic groups, resulting in significant health disparities. A new term, "racial health equity" (RHE), is increasingly reported in the medical literature, but there is currently no consensus definition of the term. Additionally, related terms such as "health disparities," "health inequities," and "equality" have been inconsistently used when defining RHE. METHODS: The primary purpose of this scoping review is to investigate the current use and underlying concepts used to define racial health equity. The study will address two key questions: (1) "What terminology and definitions have been used to characterize RHE?" and (2) "What knowledge gaps and challenges are present in the current state of RHE research and theory?" The review will collect and analyze data from three sources: (1) websites from key national and international health organizations, (2) theoretical and narrative published articles, and (3) evidence synthesis studies addressing interventions targeting racial health equity and minority stakeholder engagement. DISCUSSION: Defining "racial health equity" and related terminology is the first step to advancing racial health equity within the USA. This review aims to offer an improved understanding of RHE constructs and definitions, bringing greater unity to national racial health equity research efforts across disciplines. SYSTEMATIC REVIEW REGISTRATION: This protocol is registered with the Open Science Framework at https://osf.io/7pvzq .

Rare Coding Variants in Patients with Non-Syndromic Vestibular Dysfunction.

Vertigo due to vestibular dysfunction is rare in children. The elucidation of its etiology will improve clinical management and the quality of life of patients. Genes for vestibular dysfunction were previously identified in patients with both hearing loss and vertigo. This study aimed to identify rare, coding variants in children with peripheral vertigo but no hearing loss, and in patients with potentially overlapping phenotypes, namely, Meniere's disease or idiopathic scoliosis. Rare variants were selected from the exome sequence data of 5 American children with vertigo, 226 Spanish patients with Meniere's disease, and 38 European-American probands with scoliosis. In children with vertigo, 17 variants were found in 15 genes involved in migraine, musculoskeletal phenotypes, and vestibular development. Three genes, OTOP1, HMX3, and LAMA2, have knockout mouse models for vestibular dysfunction. Moreover, HMX3 and LAMA2 were expressed in human vestibular tissues. Rare variants within ECM1, OTOP1, and OTOP2 were each identified in three adult patients with Meniere's disease. Additionally, an OTOP1 variant was identified in 11 adolescents with lateral semicircular canal asymmetry, 10 of whom have scoliosis. We hypothesize that peripheral vestibular dysfunction in children may be due to multiple rare variants within genes that are involved in the inner ear structure, migraine, and musculoskeletal disease.

Genetic variants associated with the occurrence and progression of adolescent idiopathic scoliosis: a systematic review protocol.

BACKGROUND: Adolescent idiopathic scoliosis (AIS) is a structural lateral spinal curvature of ≥ 10° with rotation. Approximately 2-3% of children in most populations are affected with AIS, and this condition is responsible for approximately $1.1 billion in surgical costs to the US healthcare system. Although a genetic factor for AIS has been demonstrated for decades, with multiple potentially contributory loci identified across populations, treatment options have remained limited to bracing and surgery. METHODS: The databases MEDLINE (via PubMed), Embase, Google Scholar, and Ovid MEDLINE will be searched and limited to articles in English. We will conduct title and abstract, full-text, and data extraction screening through Covidence, followed by data transfer to a custom REDCap database. Quality assessment will be confirmed by multiple reviewers. Studies containing variant-level data (i.e., GWAS, exome sequencing) for AIS subjects and controls will be considered. Outcomes of interest will include presence/absence of AIS, scoliosis curve severity, scoliosis curve progression, and presence/absence of nucleotide-level variants. Analyses will include odds ratios and relative risk assessments, and subgroup analysis (i.e., males vs. females, age groups) may be applied. Quality assessment tools will include GRADE and Q-Genie for genetic studies. DISCUSSION: In this systematic review, we seek to evaluate the quality of genetic evidence for AIS to better inform research efforts, to ultimately improve the quality of patient care and diagnosis. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration #CRD42021243253.

Genetic animal modeling for idiopathic scoliosis research: history and considerations.

PURPOSE: Idiopathic scoliosis (IS) is defined as a structural lateral spinal curvature ≥ 10° in otherwise healthy children and is the most common pediatric spinal deformity. IS is known to have a strong genetic component; however, the underlying etiology is still largely unknown. Animal models have been used historically to both understand and develop treatments for human disease, including within the context of IS. This intended audience for this review is clinicians in the fields of musculoskeletal surgery and research. METHODS: In this review article, we synthesize current literature of genetic animal models of IS and introduce considerations for researchers. RESULTS: Due to complex genetic and unique biomechanical factors (i.e., bipedalism) hypothesized to contribute to IS in humans, scoliosis is a difficult condition to replicate in model organisms. CONCLUSION: We advocate careful selection of animal models based on the scientific question and introduce gaps and limitations in the current literature. We advocate future research efforts to include animal models with multiple characterized genetic or environmental perturbations to reflect current understanding of the human condition.

Severity of Idiopathic Scoliosis Is Associated with Differential Methylation: An Epigenome-Wide Association Study of Monozygotic Twins with Idiopathic Scoliosis.

Epigenetic mechanisms may contribute to idiopathic scoliosis (IS). We identified 8 monozygotic twin pairs with IS, 6 discordant (Cobb angle difference > 10°) and 2 concordant (Cobb angle difference ≤ 2°). Genome-wide methylation in blood was measured with the Infinium HumanMethylation EPIC Beadchip. We tested for differences in methylation and methylation variability between discordant twins and tested the association between methylation and curve severity in all twins. Differentially methylated region (DMR) analyses identified gene promoter regions. Methylation at cg12959265 (chr. 7 DPY19L1) was less variable in cases (false discovery rate (FDR) = 0.0791). We identified four probes (false discovery rate, FDR < 0.10); cg02477677 (chr. 17, RARA gene), cg12922161 (chr. 2 LOC150622 gene), cg08826461 (chr. 2), and cg16382077 (chr. 7) associated with curve severity. We identified 57 DMRs where hyper- or hypo-methylation was consistent across the region and 28 DMRs with a consistent association with curve severity. Among DMRs, 21 were correlated with bone methylation. Prioritization of regions based on methylation concordance in bone identified promoter regions for WNT10A (WNT signaling), NPY (regulator of bone and energy homeostasis), and others predicted to be relevant for bone formation/remodeling. These regions may aid in understanding the complex interplay between genetics, environment, and IS.

Whole Exome Sequencing of 23 Multigeneration Idiopathic Scoliosis Families Reveals Enrichments in Cytoskeletal Variants, Suggests Highly Polygenic Disease.

Adolescent idiopathic scoliosis (AIS) is a lateral spinal curvature >10° with rotation that affects 2-3% of healthy children across populations. AIS is known to have a significant genetic component, and despite a handful of risk loci identified in unrelated individuals by GWAS and next-generation sequencing methods, the underlying etiology of the condition remains largely unknown. In this study, we performed exome sequencing of affected individuals within 23 multigenerational families, with the hypothesis that the occurrence of rare, low frequency, disease-causing variants will co-occur in distantly related, affected individuals. Bioinformatic filtering of uncommon, potentially damaging variants shared by all sequenced family members revealed 1448 variants in 1160 genes across the 23 families, with 132 genes shared by two or more families. Ten genes were shared by >4 families, and no genes were shared by all. Gene enrichment analysis showed an enrichment of variants in cytoskeletal and extracellular matrix related processes. These data support a model that AIS is a highly polygenic disease, with few variant-containing genes shared between affected individuals across different family lineages. This work presents a novel resource for further exploration in familial AIS genetic research.

Mutations in KIF7 implicated in idiopathic scoliosis in humans and axial curvatures in zebrafish.

Idiopathic scoliosis (IS) is a spinal disorder affecting up to 3% of otherwise healthy children. IS has a strong familial genetic component and is believed to be genetically complex due to significant variability in phenotype and heritability. Previous studies identified putative loci and variants possibly contributing to IS susceptibility, including within extracellular matrix, cilia, and actin networks, but the genetic architecture and underlying mechanisms remain unresolved. Here, we used whole-exome sequencing from three affected individuals in a multigenerational family with IS and identified 19 uncommon variants (minor allele frequency < 0.05). Genotyping of additional family members identified a candidate heterozygous variant (H1115Q, G>C, rs142032413) within the ciliary gene KIF7, a regulator within the hedgehog (Hh) signaling pathway. Resequencing of the second cohort of unrelated IS individuals and controls identified several severe mutations in KIF7 in affected individuals only. Subsequently, we generated a mutant zebrafish model of kif7 using CRISPR-Cas9. kif7co63/co63 zebrafish displayed severe scoliosis, presenting in juveniles and progressing through adulthood. We observed no deformities in the brain, Reissner fiber, or central canal cilia in kif7co63/co63 embryos, although alterations were seen in Hh pathway gene expression. This study suggests defects in KIF7-dependent Hh signaling, which may drive pathogenesis in a subset of individuals with IS.

Idiopathic Scoliosis Families Highlight Actin-Based and Microtubule-Based Cellular Projections and Extracellular Matrix in Disease Etiology.

Idiopathic scoliosis (IS) is a structural lateral spinal curvature of ≥10° that affects up to 3% of otherwise healthy children and can lead to life-long problems in severe cases. It is well-established that IS is a genetic disorder. Previous studies have identified genes that may contribute to the IS phenotype, but the overall genetic etiology of IS is not well understood. We used exome sequencing to study five multigenerational families with IS. Bioinformatic analyses identified unique and low frequency variants (minor allele frequency ≤5%) that were present in all sequenced members of the family. Across the five families, we identified a total of 270 variants with predicted functional consequences in 246 genes, and found that eight genes were shared by two families. We performed GO term enrichment analyses, with the hypothesis that certain functional annotations or pathways would be enriched in the 246 genes identified in our IS families. Using three complementary programs to complete these analyses, we identified enriched categories that include stereocilia and other actin-based cellular projections, cilia and other microtubule-based cellular projections, and the extracellular matrix (ECM). Our results suggest that there are multiple paths to IS and provide a foundation for future studies of IS pathogenesis.