Genomic sequencing to aid diagnosis in pediatric and prenatal practice: Examining clinical utility, ethical implications, payer coverage, and data integration in a diverse population.

基因组测序有助于儿科和产前实践中的诊断：检查不同人群的临床效用、伦理影响、付款人覆盖范围和数据整合。

• 批准号: 9327452
• 负责人: Pui-Yan KWOK
• 金额: $ 309.54万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-04 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9327452
• 关键词: AIDS diagnosis; Address; Affect; Age; Bioethics; California; Caring; Child; Childhood; Clinical; Clinical Data; Clinical Informatics; Collaborations; Collection; Communication; Communities; Congenital Abnormality; Consent; Counseling; Data; Diagnosis; Diagnostic; Early Diagnosis; Economics; Effectiveness; Ethics; Etiology; Evaluation; Family; Family health status; Fetus; General Hospitals; Genes; Genetic Predisposition to Disease; Genetic screening method; Genomics; Goals; Health; Health Personnel; Healthcare Systems; Hereditary Disease; Hospitals; Individual; Infant; Informatics; Insurance Coverage; Investigation; Life; Measures; Medical Genetics; Mendelian disorder; Methods; Minority Groups; Mission; Modeling; Molecular Genetics; Online Systems; Other Genetics; Outcome; Parents; Patients; Pediatric Hospitals; Physicians; Population; Population Heterogeneity; Pregnancy; Price; Provider; Recruitment Activity; Research; Research Infrastructure; San Francisco; Site; Specialist; Speed; Standardization; Structural defect; Study Subject; Testing; Underrepresented Minority; Universities; Variant; Visit; Woman; base; clinical care; clinical decision-making; community setting; cost; data integration; design; developmental disease; ethical legal social implication; evidence base; exome; exome sequencing; experience; follow-up; genetic information; genome sequencing; genomic data; health economics; improved; improved outcome; medically underserved; next generation sequencing; patient population; phenotypic data; prenatal; prognostic; programs; reproductive; social; socioeconomics; targeted treatment; therapy outcome; tool; underserved minority; user-friendly

Congenital abnormalities and developmental disorders affect 3-5% of live born infants and children. Despite advances in both pre- and post-natal treatment, the utility of genetic testing in diagnosing the etiology underlying such conditions in order to guide management has been frustratingly limited. Traditional genetic testing with specific gene tests, or even gene panels, is diagnostic in only a small percentage of cases. Recent technological advances in next generation sequencing (NGS) have led to the ability to sequence and interpret the entire exome relatively quickly, allowing a diagnosis in 25-30% or more of cases of developmental disorders when other genetic tests have not yielded a result. Although whole exome sequencing (WES) holds great promise for improved diagnosis leading to better clinical outcomes, challenges remain in determining how best to apply and utilize sequence data. Fulfilling the promise of WES also requires investigation of ELSI (ethical, legal, social) concerns, given skepticism in some communities that research will benefit them; economic considerations that ultimately determine access to and equitable use of WES; and a need to share clinical genetic results with families and across health care systems to enable better prognostication and management of rare conditions in community settings. We propose a Program in Prenatal and Pediatric Genomic Sequencing (P3EGS) at UCSF to examine the diagnostic and clinical utility of WES. P3EGS will recruit and study affected individuals and their parents, including pregnancies in which the fetus has a confirmed structural anomaly and children with previously undiagnosed developmental disorders that are likely of genetic etiology. Following consent and collection of standardized phenotypic data, the families will undergo WES as part of clinical care. To achieve diversity, patient ascertainment and recruitment will occur at four UCSF sites that serve a broad range of under- represented minorities (target of 75%) and span the full socio-economic spectrum, including the underserved. Our specific aims will: 1) examine the clinical utility of WES, including assessment of a variety of health-related and reproductive outcomes, in 1100 undiagnosed individuals (300 prenatal, 800 children ages 0-17); 2) address ethical, social and economic issues in the delivery of genomic sequencing results to ancestrally and economically diverse populations through (2.1) a mixed methods, longitudinal empirical study of clinical interactions and experiences, (2.2) an economic analysis of insurance coverage, price and reimbursement of multigene tests, and (2.3) creation of an Ethics Advisory Board to respond to emerging issues and establishment of authentic stakeholder engagement; and 3) pilot a user-friendly web-based patient/provider application integrating genomic and clinical data as a shared evidence base to support result communication, interpretation and clinical decision making; the application will be based on the “Bioscreen” model created and successfully implemented at UCSF.

先天性异常和发育障碍影响3-5％的活生生和儿童。 尽管产前和产后治疗都取得了进步，但基因检测在诊断学中的实用性 为了指导管理的基本条件受到了令人沮丧的限制。传统遗传 使用特定基因测试甚至基因面板进行测试，仅在一小部分病例中是诊断性的。最近的 下一代测序（NGS）的技术进步已导致了顺序和解释的能力 相对较快的整个外显子组，可以在25-30％或以上的发育障碍病例中进行诊断 当其他基因检测未产生结果时。 尽管整个外显子组测序（WES）具有改进诊断的巨大希望 临床结果，在确定如何最好地应用和利用序列数据的过程中仍然存在挑战。实现 韦斯的承诺还需要对某些人怀疑的Elsi（道德，法律，社会）关注的投资 研究的社区将使他们受益；经济考虑最终决定访问和 公平使用WES；并且需要与家庭和跨卫生保健系统共享临床遗传结果 为了更好地预测和管理社区环境中的罕见状况。 我们提出了一个在UCSF的产前和小儿基因组测序（P3EG）的程序，以检查 WES的诊断和临床实用性。 P3EG将招募和研究受影响的个人及其父母 包括胎儿具有确认的结构异常的怀孕，以前患有儿童 可能具有遗传病因的未诊断发育障碍。遵循同意和收集 标准化的表型数据，家族将作为临床护理的一部分进行WES。为了实现多样性， 患者的确定和招聘将发生在四个UCSF站点，这些地点范围广泛 代表少数民族（目标为75％），跨越了全部社会经济谱，包括服务不足。 我们的具体目的将：1）检查WES的临床实用性，包括评估各种 与健康有关和生殖结果，1100个未诊断的人（300个产前，800名儿童年龄 0-17）; 2）解决基因组测序结果的道德，社会和经济问题 通过（2.1）一种混合方法，纵向经验研究在祖先和经济上多样化的种群 临床互动和经验，（2.2）对保险，价格和 补偿多基因测试，以及（2.3）创建道德咨询委员会以应对新兴 问题和建立真实的利益相关者参与； 3）驾驶基于用户友好的网络 患者/提供者的应用集成基因组和临床数据作为支持的共享证据基础 结果交流，解释和临床决策；该应用程序将基于 在UCSF创建并成功实施的“ Bioscreen”模型。