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: 9538816
• 负责人: Pui-Yan KWOK
• 金额: $ 384.52万
• 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/9538816
• 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 Diseases; Genetic Predisposition to Disease; Genetic screening method; Genomics; Goals; Health; Health Personnel; Healthcare Systems; 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; 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; rare condition; recruit; 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.

先天畸形和发育障碍影响 3-5% 的活产婴儿和儿童。 尽管产前和产后治疗都取得了进步，但基因检测在诊断病因方面的效用 令人沮丧的是，为指导管理层而对这些条件进行分析的能力十分有限。传统遗传 使用特定的基因测试，甚至基因组进行测试，只能在一小部分病例中起到诊断作用。最近的 下一代测序 (NGS) 的技术进步带来了测序和解释的能力 整个外显子组的检测速度相对较快，可诊断 25-30% 或更多的发育障碍病例 当其他基因测试没有得出结果时。 尽管全外显子组测序 (WES) 在改进诊断方面具有巨大的希望，从而带来更好的结果 尽管临床结果不同，但在确定如何最好地应用和利用序列数据方面仍然存在挑战。履行 鉴于某些人的怀疑，WES 的承诺还需要对 ELSI（道德、法律、社会）问题进行调查 研究将使他们受益的社区；最终决定获得和使用的经济因素 公平使用 WES；以及与家庭和整个医疗保健系统分享临床遗传学结果的需要 以便更好地预测和管理社区环境中的罕见疾病。 我们在 UCSF 提出了一个产前和儿科基因组测序 (P3EGS) 项目来检查 WES 的诊断和临床应用。 P3EGS 将招募并研究受影响的个人及其父母， 包括胎儿已确认存在结构异常的妊娠以及先前患有该病的儿童 可能由遗传病因引起的未确诊的发育障碍。经同意并收集 标准化表型数据后，这些家庭将接受 WES 作为临床护理的一部分。为了实现多样性， 患者确定和招募将在 UCSF 的四个站点进行，这些站点为广泛的欠缺人群提供服务 代表少数群体（目标为 75%），涵盖整个社会经济领域，包括服务不足的群体。 我们的具体目标是：1）检查 WES 的临床效用，包括评估各种 1100 名未确诊个体（300 名产前者、800 名儿童）的健康相关和生殖结果 0-17）； 2) 解决向基因组测序结果提供过程中的伦理、社会和经济问题 通过（2.1）混合方法、纵向实证研究对祖先和经济多样化的人群进行研究 临床相互作用和经验，（2.2）保险范围、价格和经验的经济分析 报销多基因测试，以及 (2.3) 建立道德咨询委员会以应对新出现的问题 问题和建立真正的利益相关者参与； 3) 试行用户友好的基于网络的 患者/提供者应用程序将基因组和临床数据整合为共享证据基础以支持 结果沟通、解释和临床决策；该应用程序将基于 “Bioscreen”模型在加州大学旧金山分校创建并成功实施。