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: 10359980
• 负责人: Pui-Yan KWOK
• 金额: $ 186.27万
• 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 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10359980
• 关键词: Address; Affect; Area; Child; Childhood; Clinical; Congenital Abnormality; Data; Databases; Decision Making; Deposition; Diagnosis; Diagnostic; Economics; Enrollment; Ethics; Ethnography; Etiology; Family; Fetus; Funding; Genes; Genetic Predisposition to Disease; Genomics; Goals; Healthcare Systems; Individual; Infant; Investigation; Manuscripts; Medical Genetics; Outcome; Parents; Patient Recruitments; Patients; Physicians; Population Heterogeneity; Pregnancy; Publications; Site; Structural defect; Underrepresented Minority; arm; clinical sequencing; community based participatory research; community setting; data integration; developmental disease; effectiveness study; ethical legal social implication; exome; exome sequencing; follow-up; genetic information; genetic testing; genome sequencing; health economics; improved; medically underserved; next generation sequencing; prenatal; prognostic; programs; rare condition; recruit; social; socioeconomics; sound; tool

Project Summary/Abstract 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. 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. Although exome sequencing (ES) has improved diagnosis and led 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. The Program in Prenatal and Pediatric Genomic Sequencing (P3EGS) at UCSF has been examining the diagnostic and clinical utility of WES. We have recruited and studied 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. We recruited patients from four UCSF sites that serve a broad range of underrepresented minorities (75%) and span the full socio-economic spectrum, including the underserved. We are on-track to meet our goal of enrolling 849 cases (566 pediatric cases and 283 prenatal cases) and performing exome sequencing of these cases by May 31, 2021. However, we will need at least an additional year to complete the 6-month follow-up of the last 80 or so cases enrolled since December, organize and deposit the data into databases, analyze the data collected, and prepare manuscripts (both for our project and for CSER Consortium-wide projects) for publication. Accordingly, we are requesting funding to keep a small team together to finish the most exciting part of the project: carefully analyze the data and draw sound conclusions regarding the many aspects of clinical sequencing. Specifically, our team will analyze the data in three main areas: 1. Exome sequencing data of prenatal and pediatric cases from a diverse population. 2. Ethnographic studies of patients offered exome sequencing from the prenatal and pediatric arms of the study. 3. Health economics study of payer decision making on exome/genome sequencing coverage.

项目概要/摘要 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。最新技术 下一代测序（NGS）的进步带来了对整个序列进行测序和解释的能力 外显子组相对较快，可以诊断 25-30% 或更多的发育障碍病例。 尽管外显子组测序 (ES) 改善了诊断并带来了更好的临床结果，但仍面临挑战 仍然在确定如何最好地应用和利用序列数据。履行 WES 的承诺还需要 鉴于一些社区对研究是否会产生怀疑，对 ELSI（道德、法律、社会）问题进行调查 使他们受益；最终决定 WES 的获取和公平使用的经济考虑因素；和一个 需要与家庭和整个医疗保健系统分享临床遗传学结果，以便更好地 社区环境中罕见疾病的预测和管理。 加州大学旧金山分校的产前和儿科基因组测序项目 (P3EGS) 一直在研究 WES 的诊断和临床实用性。我们招募并研究了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。我们从四个 UCSF 招募了患者 为广泛的代表性不足的少数群体 (75%) 提供服务并涵盖整个社会经济领域的网站 频谱，包括服务不足的地区。我们正在实现入组 849 例病例（566 例儿科病例）的目标 病例和 283 例产前病例），并在 2021 年 5 月 31 日之前对这些病例进行外显子组测序。 然而，我们至少还需要一年的时间来完成最后80个左右的6个月的随访 12月份以来入组的病例，整理数据存入数据库，分析收集到的数据， 准备手稿（包括我们的项目和 CSER 联盟范围内的项目）以供出版。因此， 我们正在请求资金来让一个小团队聚集在一起，以完成该项目最令人兴奋的部分：仔细 分析数据并就临床测序的许多方面得出合理的结论。 具体来说，我们的团队将分析三个主要方面的数据： 1. 来自不同人群的产前和儿科病例的外显子组测序数据。 2. 对患者进行的人种学研究提供了来自产前和儿科部门的外显子组测序 学习。 3. 付款人外显子组/基因组测序覆盖率决策的卫生经济学研究。

项目成果

Clinical Genetics Lacks Standard Definitions and Protocols for the Collection and Use of Diversity Measures.

临床遗传学缺乏多样性测量的收集和使用的标准定义和协议。

• 发表时间: 2020-07-02
• 影响因子: 9.8
• 作者: Popejoy, Alice B;Crooks, Kristy R;Fullerton, Stephanie M;Hindorff, Lucia A;Hooker, Gillian W;Koenig, Barbara A;Pino, Natalie;Ramos, Erin M;Ritter, Deborah I;Wand, Hannah;Wright, Matt W;Yudell, Michael;Zou, James Y;Plon, Sharon E;Bustamante
• 通讯作者: Bustamante

Private payer coverage policies for exome sequencing (ES) in pediatric patients: trends over time and analysis of evidence cited.

儿科患者外显子组测序 (ES) 的私人付款人覆盖政策：随时间的趋势和引用的证据分析。

• 发表时间: 2019
• 作者: Douglas, Michael P;Parker, Stephanie L;Trosman, Julia R;Slavotinek, Anne M;Phillips, Kathryn A
• 通讯作者: Phillips, Kathryn A

Emergence of Hybrid Models of Genetic Testing Beyond Direct-to-Consumer or Traditional Labs.

超越直接面向消费者或传统实验室的基因检测混合模型的出现。

• 发表时间: 2019
• 作者: Phillips, Kathryn A;Trosman, Julia R;Douglas, Michael P
• 通讯作者: Douglas, Michael P

The difficulties of broad data sharing in genomic medicine: Empirical evidence from diverse participants in prenatal and pediatric clinical genomics research.

基因组医学广泛数据共享的困难：产前和儿科临床基因组学研究不同参与者的经验证据。

• 发表时间: 2022-02
• 作者: Norstad, Matthew;Outram, Simon;Brown, Julia E H;Zamora, Astrid N;Koenig, Barbara A;Risch, Neil;Norton, Mary E;Slavotinek, Anne;Ackerman, Sara L
• 通讯作者: Ackerman, Sara L

Multicancer Screening Tests: Anticipating And Addressing Considerations For Payer Coverage And Patient Access.

多种癌症筛查测试：预测和解决付款人覆盖范围和患者访问的考虑因素。

• 发表时间: 2022-03
• 作者: Deverka, Patricia A;Douglas, Michael P;Phillips, Kathryn A
• 通讯作者: Phillips, Kathryn A