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

项目摘要/摘要 使用基因组测序(GS)作为筛查以识别 在生命早期具有疾病的遗传倾向，以预防或减轻未来的疾病。然而，存在这样的问题， 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， 不合理的医疗支出和不必要的医疗保健使用，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，“第一个新生儿GS的随机对照试验(RCT)。我们为以下项目实施了临床工作流程 整个外显子组测序，创建了可回收基因/变体选择和解释的标准，策划了一个列表 1,514个与疾病相关的基因，具有良好的有效性、发病年龄和外显性；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臂的测序，向家人披露了结果，并在婴儿的 医疗记录。我们的结果令人震惊。在医学上，我们确定并披露了意想不到的单基因 11%的婴儿被随机分配到GS，并通过先前揭示的后续测试发现了疾病风险 在这些人中，超过一半的人有潜在疾病的未发现迹象和未探索的家族史。我们没有发现 在收到GS结果和没有结果的情况下，增加对亲子关系的痛苦或破坏 下游医疗成本大幅增加。医疗保健提供商(HCP)能够建设性地 管理上报的信息。BabySeq项目创建了一个研究心理学的模板 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种群并不多样，因此我们的发现不能一概而论。为了 公平地传播这项技术，了解它对种族和种族的影响将是至关重要的 不同的人群。这项研究的目标是以我们在BabySeq学到的知识为基础来研究GS作为筛查 在一个服务不足的人群中，主要是非裔美国人和西班牙裔婴儿。我们将退回致病GS 和复制数量变化的结果，并研究对家庭和HCP的影响，以及医疗和 对经济的影响。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 AS筛查，利用服务不足的社区参与来最大限度地减少不信任和最大化 利益。这项新颖的研究提供了一个独特的机会来确定医疗、行为和经济 在三个不同的CTSA地点对代表性不足的婴儿人群的结果，模拟GS的视觉 作为儿童早期实施的医疗保健的一部分。这个项目意义重大，因为它提出了 为GS婴儿的价值产生亟需的证据，其设计创新成为第一个探索的RCT WGS对不同健康婴儿人群的影响，而且是可行的，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.