Leveraging human genetics to overcome complex diagnostic challenges, evaluation of pan-ancestry polygenic scores to reduce misdiagnosis of narcolepsy and circadian rhythm sleep wake disorders.

利用人类遗传学克服复杂的诊断挑战，评估泛祖多基因评分以减少发作性睡病和昼夜节律睡眠觉醒障碍的误诊。

• 批准号: 10576448
• 负责人: Jacqueline Marie Lane
• 金额: $ 71.61万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-16 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576448
• 关键词: Acceleration; Address; Autoimmune; Awareness; Catalogs; Circadian Rhythms; Clinic; Clinical; Complex; Computer software; Databases; Diagnosis; Diagnostic; Diagnostic tests; Disease; Early Diagnosis; Early identification; European ancestry; Evaluation; Face; Genes; Genetic; Genetic Risk; Goals; Healthcare; Healthcare Systems; Hospitals; Human Genetics; Individual; Inequality; Insurance Coverage; Medicine; Mental Depression; Narcolepsy; Pathogenicity; Patients; Pharmaceutical Preparations; Phase; Phenotype; Population; Primary Care Physician; Process; Rare Diseases; Records; Risk; Risk Factors; Risk Marker; Sleep; Sleep Disorders; Sleeplessness; Testing; Unnecessary Procedures; Variant; Visit; Woman; Work; accurate diagnosis; biobank; circadian; cohort; disorder risk; early screening; exome; exome sequencing; genetic predictors; genetic variant; genome sequencing; genome wide association study; health disparity; health inequalities; improved; large-scale database; medical specialties; novel; people of color; personalized predictions; polygenic risk score; rare variant; repository; risk prediction; risk variant; routine screening; screening; sleep behavior; timeline; trait

Project Summary/Abstract One of the biggest challenges in rare disease is accuracy and timeliness of patient diagnosis. On average it takes 6 years for an accurate diagnosis, delaying treatment and creating substantial burden at the levels of individual, familial and healthcare systems with an estimated $750 billion spent on unnecessary procedures. Misdiagnosis also widens inequalities further, as misdiagnosis is more common among women and people of color. Therefore, there is an urgent need to improve diagnosis. Genetic risk predictions can improve diagnosis, with particular clinical utility in the specific setting where large barriers to diagnosis exist, such as rare sleep disorders. The rare sleep disorders narcolepsy and circadian rhythm sleep wake disorders face large hurdles to diagnosis, where 20% of primary care physicians are unaware that sleep medicine exists as a specialty, routine screening for sleep disorders is nearly absent, diagnostic tests require overnight visits to a limited number of specialized clinics, and insurance coverage for common diagnostic tests is non-existent. In contrast to the current diagnostic landscape for sleep disorders, genetic risk prediction is relatively inexpensive and easily accessible. In order to integrate genetic risk into the diagnosis and treatment pipeline, we must first have genetic predictors of risk applicable across multiple ancestry groups, or we risk widening inequities in healthcare further. To address the challenge of timely patient diagnosis in sleep disorders, we propose to leverage large exome sequence repositories to generate rare variant risk scores, expand the current known common polygenic scores to multiple genetic ancestries, and ultimately test the ability of both the rare and common polygenic scores to predict risk of rare sleep and circadian disorders in a large-scale hospital database with the goal to integrate flags in patient records.

项目总结/摘要 罕见病最大的挑战之一是患者诊断的准确性和及时性。平均而言 准确诊断需要6年时间，延误了治疗，并造成了巨大的负担， 个人、家庭和医疗保健系统，估计有7500亿美元花费在不必要的程序上。 误诊还进一步扩大了不平等，因为误诊在妇女和老年人中更为常见。 颜色.因此，迫切需要改进诊断。遗传风险预测可以改善诊断， 在诊断存在较大障碍的特定环境中具有特别的临床实用性，例如罕见的睡眠 紊乱罕见的睡眠障碍发作性睡病和昼夜节律睡眠觉醒障碍面临巨大障碍 到诊断，20%的初级保健医生不知道睡眠医学是一个专业， 睡眠障碍的常规筛查几乎不存在，诊断测试需要夜间访问有限的 专业诊所的数量不足，普通诊断测试的保险不存在。相比之下 对于目前睡眠障碍的诊断前景，遗传风险预测相对便宜， 轻松抵达为了将遗传风险纳入诊断和治疗管道，我们必须首先 有遗传预测的风险适用于多个祖先群体，或我们的风险扩大不平等， 保健再进一步。为了应对及时诊断睡眠障碍患者的挑战，我们建议 利用大型外显子组序列库生成罕见变异风险评分，扩展目前已知的 共同的多基因得分多个遗传祖先，并最终测试的能力，这两个罕见的， 一家大型医院中预测罕见睡眠和昼夜节律紊乱风险的常见多基因评分 数据库，目标是在患者记录中集成标记。