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

项目概要/摘要 使用基因组测序（GS）作为筛选以鉴定具有遗传缺陷的人的基因组的方法越来越受到社会和科学的关注。 在生命早期对疾病的遗传倾向，以防止或减轻未来的疾病。然而， 对GS在婴儿中的临床效用持怀疑态度，并担心它可能导致心理社会伤害， 不合理的卫生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联盟中，我们的团队推出了“BabySeq 项目，“第一个随机对照试验（RCT）的GS在新生儿。我们实施了临床工作流程， 全外显子组测序，为可返回的基因/变体选择和解释创建标准，策划了一个列表 1，514个疾病相关基因，具有良好的有效性，发病年龄和发病率;并设计了新的 报告格式。我们招募了325个家庭，并将其随机分配到家族史（FH）组或FH+GS组， 完成了FH+GS组的测序，向家庭披露了结果，并将报告放在婴儿的 病历我们的结果是惊人的。在医学上，我们发现并披露了意外的单基因 11%的婴儿随机分配到GS，并通过后续测试显示， 其中一半以上存在未发现的潜在疾病迹象和未探索的家族史。我们没有发现 收到GS结果后，父母与子女关系的痛苦或破坏增加， 下游医疗成本大幅增加。医疗保健提供者（HCP）能够建设性地 管理上报的信息。BabySeq项目创建了一个模板，用于研究 GS在健康新生儿中的影响、医疗效用和成本效益。 然而，我们的BabySeq人群并不多样化，因此我们的发现不可推广。为了 公平地传播这项技术，至关重要的是要了解它对民族和种族的影响， 不同的人群。这项研究的目标是建立在我们在BabySeq中学到的基础上，将GS作为筛选研究。 主要是非洲裔美国人和西班牙裔婴儿。我们将把致病性GS 和拷贝数变异结果，并研究对家庭和HCP的影响，以及医疗和 经济影响。通过这项研究，我们将开发，实施和评估一种可持续的方法， GS作为筛选，利用服务不足的社区参与，最大限度地减少不信任， 效益这项新的研究提供了一个独特的机会，以确定医疗，行为和经济 在三个不同的CTSA地点，代表性不足的婴儿人群的结果，模拟GS的愿景 作为儿童早期医疗保健的一部分。该项目意义重大，因为它建议 产生急需的GS婴儿价值的证据，其设计创新，作为第一个RCT探索 WGS在不同健康婴儿人群中的影响，并且是可行的，因为这个专家团队 在招募参与者和基础设施方面的经验，以严格收集和分析结果。

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.