Implementation of Whole Genome Sequencing as Screening in a Diverse Cohort of Healthy Infants

在不同健康婴儿群体中实施全基因组测序筛查

• 批准号: 10652609
• 负责人: Robert C. Green
• 金额: $ 123.8万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10652609
• 关键词: Address; African American; African ancestry; Age Months; Age of Onset; Behavioral; Boston; Childhood; Clinical; Clinical Trials; Communication; Communities; Copy Number Polymorphism; Data; Diagnostic; Disclosure; Disease; Distress; Education; Educational Curriculum; Enrollment; Equity; Ethnic Origin; Family; Family history of; Family member; Feedback; Focus Groups; Funding; Future; Genes; Genetic Predisposition to Disease; Genomics; Geographic Locations; Goals; Health Benefit; Health Care Costs; Health Expenditures; Health Personnel; Healthcare; Hispanic; Hispanic ancestry; Iatrogenesis; Infant; Information Management; Infrastructure; Inpatients; Interview; Laboratories; Learning; Life; Light; Longitudinal Surveys; Medical; Medical Records; Mendelian disorder; Methods; Minority Groups; Modeling; Monitor; Morbidity - disease rate; New York City; Newborn Infant; Newly Diagnosed; Outcome; Outpatients; Parent-Child Relations; Parents; Participant; Pathogenicity; Patient Self-Report; Penetrance; Phenotype; Population; Population Heterogeneity; Protocols documentation; Psychological Impact; Psychosocial Assessment and Care; Race; Randomized; Randomized, Controlled Trials; Recording of previous events; Reporting; Research; Resources; Site; Structure; Surveys; Symptoms; Technology; Testing; Training; Underrepresented Minority; Underrepresented Populations; Underserved Population; United States National Institutes of Health; Variant; Vision; arm; behavioral outcome; clinical care; cohort; community engagement; cost; cost effectiveness; design; disorder risk; distrust; economic impact; economic outcome; ethnic diversity; exome sequencing; experience; follow-up; genetic counselor; genome resource; genome sequencing; health care service; health care service utilization; improved; innovation; interest; multidisciplinary; novel; novel strategies; participant enrollment; pediatrician; prevent; primary care setting; programs; psychosocial; racial diversity; recruit; response; retention rate; screening; socioeconomics; two-arm study; underserved community; whole genome

Project Summary/Abstract There is growing societal and scientific interest in using genomic sequencing (GS) as screening to identify genetic predispositions for disease early in life to prevent or mitigate future illness. There is, however, skepticism about the clinical utility of GS in infants and concerns that it could lead to psychosocial harm, unjustified health expenditures, and unnecessary healthcare utilization, with associated iatrogenic morbidity. Over the past five years, within the NIH-funded NSIGHT Consortium, our team launched the “BabySeq Project,” the first randomized controlled trial (RCT) of GS in newborns. We implemented a clinical workflow for whole exome sequencing, created criteria for returnable gene/variant selection and interpretation, curated a list of 1,514 disease-associated genes with favorable validity, age of onset and penetrance; and designed novel reporting formats. We enrolled and randomized 325 families to a family history (FH) arm or a FH+GS arm, completed sequencing in the FH+GS arm, disclosed results to families and placed reports in the infants’ medical record. Our results were striking. Medically, we identified and disclosed unanticipated monogenic disease risks in 11% of infants randomized to GS, and through follow-up testing revealed previously undiscovered signs of underlying disease and unexplored family history in over half of these. We found no increased distress or disruption to the parent-child relationship in response to receiving GS results and no significant increases in downstream healthcare costs. Healthcare providers (HCPs) were able to constructively manage the information reported. The BabySeq Project created a template for studying the psychological impact, medical utility, and cost effectiveness of GS in healthy newborns. However, our BabySeq population was not diverse and thus our findings not generalizable. In order to disseminate this technology equitably, it will be crucial to understand its impact on ethnically and racially diverse populations. The goal of this study is to build on what we learned in BabySeq to study GS as screening in a population of underserved, primarily African American and Hispanic, infants. We will return pathogenic GS and copy number variation results and study the impact on families and HCPs, as well as the medical and economic impact. Through this research we will develop, implement, and evaluate a sustainable approach to GS as screening that leverages underserved community engagement to minimize distrust and maximize benefit. This novel study provides a unique opportunity to determine medical, behavioral and economic outcomes in an under-represented population of infants at three diverse CTSA sites, modeling the vision of GS as a part of healthcare implemented early in childhood. This project is significant because it proposes to generate much-needed evidence of the value of GS infants, innovative in its design as the first RCT to explore the impact of WGS in a diverse population of healthy infants, and feasible because this team of experts has experience in enrolling participants and the infrastructure to rigorously collect and analyze outcomes.

项目概要/摘要 社会和科学界对使用基因组测序 (GS) 进行筛查以识别疾病的兴趣日益浓厚 生命早期疾病的遗传倾向，以预防或减轻未来的疾病。然而，有 对 GS 在婴儿中的临床效用持怀疑态度，并担心它可能导致社会心理伤害， 不合理的医疗支出和不必要的医疗保健利用，以及相关的医源性发病率。 在过去的五年里，在 NIH 资助的 NSIGHT 联盟内，我们的团队推出了“BabySeq 项目，”新生儿 GS 的第一个随机对照试验 (RCT)。我们实施了一个临床工作流程 全外显子组测序，创建了可返回基因/变异选择和解释的标准，策划了一份清单 1,514 个具有良好有效性、发病年龄和外显率的疾病相关基因；并设计新颖 报告格式。我们招募了 325 个家庭并将其随机分为家族史 (FH) 组或 FH+GS 组， 完成了 FH+GS 组的测序，向家人披露结果并将报告放入婴儿的数据库中 医疗记录。我们的结果是惊人的。在医学上，我们发现并披露了意想不到的单基因 11% 的婴儿被随机分配到 GS，并通过之前的后续测试发现存在疾病风险 其中一半以上有未被发现的潜在疾病迹象和未被探索的家族史。我们发现没有 收到 GS 结果后，亲子关系会更加痛苦或受到干扰，但没有 下游医疗成本显着增加。医疗保健提供者 (HCP) 能够建设性地 管理所报告的信息。 BabySeq 项目创建了一个用于研究心理的模板 GS 对健康新生儿的影响、医疗效用和成本效益。 然而，我们的 BabySeq 人群并不多样化，因此我们的研究结果不可推广。为了 为了公平地传播这项技术，了解其对种族和种族的影响至关重要 不同的人群。这项研究的目标是基于我们在 BabySeq 中学到的知识来研究 GS 作为筛查 在服务不足的婴儿群体中，主要是非裔美国人和西班牙裔婴儿。我们将退回致病性 GS 和拷贝数变异结果，并研究其对家庭和 HCP 以及医疗和健康的影响 经济影响。通过这项研究，我们将开发、实施和评估可持续的方法 GS 作为筛查，利用服务不足的社区参与来最大限度地减少不信任并最大化 益处。这项新颖的研究提供了一个独特的机会来确定医学、行为和经济 三个不同 CTSA 地点代表性不足的婴儿群体的结果，模拟 GS 的愿景 作为儿童早期实施的医疗保健的一部分。该项目意义重大，因为它提出 生成急需的 GS 婴儿价值证据，其设计具有创新性，是第一个探索的随机对照试验 WGS 对不同健康婴儿群体的影响，并且是可行的，因为该专家团队已经 招募参与者的经验以及严格收集和分析结果的基础设施。

项目成果

The evolving role of medical geneticists in the era of gene therapy: An urgency to prepare.

• DOI: 10.1016/j.gim.2023.100022
• 发表时间: 2023-04
• 期刊: GENETICS IN MEDICINE
• 影响因子: 8.8
• 作者: Vockley, Jerry;Brunetti-Pierri, Nicola;Chung, Wendy K.;Clarke, Angus J.;Gold, Nina;Green, Robert C.;Kagan, Stephen;Moroz, Tara;Schaaf, Christian P.;Schulz, Martin;De Baere, Elfride
• 通讯作者: De Baere, Elfride

Delayed diagnosis and racial bias in children with genetic conditions.

• DOI: 10.1002/ajmg.a.62626
• 发表时间: 2022-04
• 期刊: AMERICAN JOURNAL OF MEDICAL GENETICS PART A
• 影响因子: 2
• 作者: Omorodion, Jacklyn;Dowsett, Leah;Clark, Robin D.;Fraser, Jamie;Abu-El-Haija, Aya;Strong, Alanna;Wojcik, Monica H.;Bryant, Allison S.;Gold, Nina B.
• 通讯作者: Gold, Nina B.

Parental Attitudes Toward Standard Newborn Screening and Newborn Genomic Sequencing: Findings From the BabySeq Study.

• DOI: 10.3389/fgene.2022.867371
• 发表时间: 2022
• 期刊: Frontiers in genetics
• 影响因子: 3.7

Proposed criteria for nevoid basal cell carcinoma syndrome in children assessed using statistical optimization.

• DOI: 10.1038/s41598-021-98752-9
• 发表时间: 2021-10-05
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Gold NB;Campbell IM;Sheppard SE;Tan WH
• 通讯作者: Tan WH