Clinical Implementation of Carrier Testing using NGS

描述(申请人提供)：下一代测序(NGS)技术可以廉价地产生大量的人类基因组序列数据。携带者测试识别携带一种疾病基因变体的一个拷贝的个人，需要表达两个拷贝，是临床实施NGS技术的主要候选方法。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测试的临床实施情况。研究人群将包括要求进行囊性纤维化(CF)携带者状态或其他条件的受孕前测试的妇女及其伴侣。我们提出了三个相互关联的项目。在项目1中，我们将在Kaiser Permanente Northwest(KPNW)健康计划内进行随机临床试验，以测试全基因组测序的临床实施情况以及电子病历(EMR)中该筛查的整合，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目标基因组测试小组的比较结果。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，以确定被认为值得向医生和患者报告的“可操作的变异”。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对返回携带者状态和全基因组测序二次发现的伦理和心理社会影响，并评估下游的医疗利用和成本。该项目将产生深远的影响，并将提供有关从全基因组测序返回先入为主的携带者状态结果的利弊的讨论。携带者检测在所提供的遗传学服务中占很高的比例，这意味着这个计划可以很容易地翻译给大量的患者。我们将重点放在寻求怀孕前携带者状态的患者身上，这将使我们能够快速评估使用NGS作为携带者状态的潜在影响。我们可以接触到真实世界的患者和临床环境，这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.