A novel approach for equitable characterization of gender and its use in exposing subgroup discrepancies in polygenic score associations

一种公平描述性别的新方法及其在揭示多基因评分关联中亚组差异中的应用

• 批准号: 10710044
• 负责人: Jacob James Michaelson
• 金额: $ 54.87万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-26 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10710044
• 关键词: Address; Adult; Biomedical Research; Calibration; Categories; Communities; Complex; Data; Descriptor; Dimensions; Disease; Disparity; Dissociation; Equity; Ethics; Exclusion; Female; Gender; Gender Identity; Genetic; Genetic Research; Genetic Risk; Genomics; Genotype; Health; Heterogeneity; Hip region structure; Individual; Ions; Measures; Medical; Mental Health; Methods; Minority Groups; Modeling; Nature; Outcome; Patient Self-Report; Pattern; Persons; Psyche structure; Questionnaires; Research; Risk; Risk Assessment; Sampling; Scientist; Subgroup; Writing; autism spectrum disorder; cisgender; clinical risk; community partnership; experience; gender diversity; gender minority; gender minority group; insight; male; nonbinary; novel; novel strategies; personalized medicine; potassium cyanate; recruit; resilience; sex; suicidal risk; trait

ABSTRACT Polygenic scores — summaries of the genomic contribution to risk and resilience for biomedical traits — are an emerging and promising approach for clinical risk assessment and personalized medicine. Minoritized groups, such as gender minorities, do not currently benefit from insights gained via studies of polygenic scores because these groups have not been sufficiently included or characterized in this research. This disparity must be addressed both by inclusion during recruitment as well as consideration of the effects of heterogeneity during analysis. For example, our preliminary data show striking dissociations in suicide risk as influenced by polygenic scores. Notably, these opposing associations are apparent only when gender diversity status (i.e., cisgender; gender-diverse) is modeled, underscoring the imperative to parsing the heterogeneity of such associations by both sex and gender. These results suggest value in genomic research for gender minority groups to understand both innate risk and resilience. The promise of genomic research informed by designated sex, gender, and their interaction (i.e., gender diversity) depends on the ability to rigorously and equitably include and characterize individuals across the spectra of designated sex and gender. Currently, biomedical research relies on checklist or write-in gender identity descriptors, which do not capture the continuous and simultaneous nature of dimensional binary and nonbinary gender experiences and result in statistically underpowered analytics with far too few individuals within each gender self-descriptor category. This perpetuates the exclusion of gender and its intersection with designated sex in genetic research. We propose to close this gap by calibrating and genetically characterizing the Gender Self-Report (GSR), a novel and broadly disseminable method for obtaining multidimensional gender for genomic research and broader research applications. First, we will facilitate partnership between scientists and gender diverse community stakeholders, and reduce paternalistic tendencies in this ethically complex field of research, by building on our established community partnerships with a purposively recruited stakeholder panel (N=50) to provide a final version of the GSR itemset. Next, to advance the dimensional characterization of gender identity and gender diversity in a genomic research context, we will validate the stakeholder-refined GSR in a large sample (N=10,000) of genotyped neurotypical and neurodivergent adults, enriched across broad experiences of gender diversity. Finally, to demonstrate proof-of-principle for how designated sex, gender, and gender diversity contextualize patterns of association with polygenic scores, we will measure key health outcomes (both mental and physical), in a large, genetically informed sample enriched for neurodiversity (e.g., autism) and broad gender diversity. The proposed research will provide value to gender minority groups by seeking a better understanding of how polygenic scores apply specifically to them, and not just the cisgender proportional majority.

抽象的 多基因分数 - 基因组对生物医学特征的风险和弹性的贡献的摘要 - 临床风险评估和个性化医学的新兴和有希望的方法。少数群体， 例如性别少数族裔，目前并不从通过对多基因评分的研究获得的见解中受益 因为这些群体在这项研究中尚未充分包含或表征。这种差异必须 在招募期间纳入以及考虑的影响 分析过程中的异质性。例如，我们的初步数据表明，自杀风险中的罢工分离为 受多基因评分的影响。值得注意的是，仅当性别多样性时，这些相反的关联才会显而易见 状态（即cisgender;性别多样性）是建模的，强调了解析异质性的必要性 性别和性别的关联。这些结果表明性别基因组研究的价值 少数群体了解先天风险和韧性。基因组研究的希望 指定的性别，性别及其互动（即性别多样性）取决于严格和严格的能力 公平地包括并在指定性别和性别的整个光谱中表征并表征个体。 目前，生物医学研究依赖于清单或写入性别认同描述符，但不会捕获 维度二进制和非二进制性别经验的连续和简单性质，并导致 在每个性别自我描述符类别中，统计学不足的分析能力较少。 这使性别的排除及其与遗传研究中指定性别的交集的延续。我们 通过校准和遗传表征性别自我报告（GSR）来缩小这一差距的提议，这是一种小说 以及广泛的可忽视方法，用于获得基因组研究的多维性别和更广泛的性别 研究应用。首先，我们将促进科学家与性别潜水员社区之间的伙伴关系 利益相关者，并通过以我们的为基础来减少这一具有道德上复杂的研究领域的家长式倾向 与普遍招募的利益相关者小组（n = 50）建立了社区合作伙伴关系，以提供最终 GSR项目集的版本。接下来，提高性别认同和性别的维度表征 在基因组研究环境中的多样性，我们将在大型样本中验证利益相关者精制的GSR （n = 10,000）基因分型神经型和神经异常成年人，在广泛的经验中丰富 性别多样性。最后，为指定性别，性别和性别的指定证明证明 多样性将与多基因分数的关联模式与情境化，我们将衡量关键健康 在富含神经多样性的大型，遗传知情的样本中，结果（精神和身体）的结果（例如， 自闭症）和广泛的性别多样性。拟议的研究将为性别少数群体提供价值 寻求更好地了解多基因分数如何专门应用它们，而不仅仅是顺格 比例多数。