Clinical Implementation of Carrier Testing using NGS

描述（由申请人提供）：下一代测序（NGS）技术可以低成本地产生大量人类基因组序列数据。携带者检测是临床应用NGS技术的主要候选者，可识别携带一种需要表达两种拷贝的疾病基因变体拷贝的个体。我们将研究使用全基因组测序来辅助成人生殖决策的携带者检测的临床实施。研究人群将包括要求孕前检测囊性纤维化（CF）携带者状态或其他情况的女性及其伴侣。我们提出三个相互关联的项目。在项目1中，我们将在Kaiser Permanente Northwest （KPNW）健康计划中进行一项随机临床试验，以测试全基因组测序的临床实施情况，以及将这种筛查整合到电子病历（EMR）中，并从患者和医生的角度衡量结果。我们将评估添加基因组测序与常规护理或与靶向基因组检测组的比较结果。在项目2中，我们将对实验室测试样本进行基因组测序，包括对已识别的变异进行验证和解释，以确定值得向医生和患者报告的“可操作变异”。这将包括使用结果返回委员会（RORC）。在项目3中，我们将评估扩大携带者筛查的伦理和社会心理影响，以返回携带者状态和全基因组测序的次要发现，并评估下游医疗保健利用和成本。该项目将产生深远的影响，并将为讨论从全基因组测序中返回孕前携带者状态结果的利弊提供信息。携带者检测在提供的遗传学服务中占很大比例，这意味着该项目可以很容易地转化为大量患者。我们对寻求孕前携带者状态的患者的关注将使我们能够快速评估使用NGS检测携带者状态的潜在影响。我们对真实世界患者和临床环境的接触将使我们的研究具有广泛的普遍性。

DESCRIPTION (provided by applicant): Next generation sequencing (NGS) technologies can produce large volumes of human genome sequence data inexpensively. Carrier testing identifying individuals who carry one copy of a variant in a gene for a disease that requires two copies to be expressed is a prime candidate for clinical implementation of NGS technology. We will investigate the clinical implementation of carrier testing using whole genome sequencing to aid reproductive decision-making in adults. The study population will include women and their partners requesting pre-conception testing for cystic fibrosis (CF) carrier status, or other conditions. We propose three interrelated projects. In Project 1, we will conduct a Randomized Clinical Trial within the Kaiser Permanente Northwest (KPNW) health plan to test clinical implementation of whole genome sequencing and the integration of this screening within the electronic medical record (EMR), as well as measure outcomes from patient and physician perspectives. We will evaluate the comparative outcomes of adding genome sequencing versus usual care or versus a targeted genomic test panel. In Project 2, we will perform genome sequencing of the laboratory test samples, including validation and interpretation of the identified variants to identify "actionable variants" deemed worthy of reporting to doctors and patients. This will include using a Return of Results Committee (RORC). In Project 3, we will evaluate the ethical and psychosocial implications of expanded carrier screening for the return of carrier status and secondary findings from whole genome sequencing, and evaluate the downstream healthcare utilization and costs. This project will have a far-reaching impact and will inform discussions about the advantages and disadvantages of returning preconception carrier status results from whole genome sequencing. Carrier testing represents a high proportion of genetics services delivered, meaning this program can be readily translated to a large number of patients. Our focus on patients seeking preconception carrier status will allow us to rapidly assess the potential impact of using NGS for carrier status. Our access to real world patients and clinical settings will make our research broadly generalizable.