The Long Life Family Study

摘要 长寿家庭研究(LLFS)是一项以家庭为基础的异常健康的个人队列，有完整的 大多数参与者的基因组测序(WGS)数据，目前正在产生大规模组学 关于其参与者的数据，包括转录组学、全基因组亚硫酸氢盐测序、代谢组学和 蛋白质组学。虽然LLFS目前不会向研究参与者返回任何附带的遗传结果，但LLFS 已经修改了它的同意书，询问参与者是否愿意收到偶然的基因发现 在未来。WGS数据在近4000名LLFS参与者中的可用性以及对 医学上可操作的偶然遗传结果的返回，使LLFS成为解决生物伦理问题的理想位置 与以家庭为基础的队列中遗传结果的返回有关。药物遗传学(PGx)，研究药物的作用。 药物反应表型的遗传变异是基因组科学中一个可以积极影响的领域 关于要测试的特定基因和变种的患者管理和共识指南现在已经 可用。因此，返回具有临床影响并得到以下几项支持的目标PGx结果 国家和国际社会是一个可以用来发展生物伦理的机会 在LLFS中返回偶然遗传结果的框架。我们建议在一个美国野外中心进行一项试点研究 (匹兹堡大学)演示从以下位置返回有限的PGx结果的可行性和可接受性 200名LLFS参与者有三个基因。我们建议在三种情况下确定10种可在医学上操作的PGx变体 来自已在LLFS中可用的WGS数据的基因(CYP2C9、CYP2C19和VKORC1)。我们将确认 在CLIA认证的实验室中观察到的变体，创建一份报告，总结已识别的变体和 受这些变异影响的药物，并建立针对研究的PGx咨询服务，以讨论 根据需要与LLFS参与者一起研究结果。我们建议确定参与者评估的理解力， 决策和对返回PGx结果的满意度(目标1)在两个时间点，即立即和三个时间点 在返回PGx结果几个月后。此外，我们将利用LLFS队列以家庭为基础的结构 评估指数参与者是否与其家庭成员分享他们的PGx结果，并确定 家庭成员对PGx结果返回家庭的理解、决策和满意度 指数研究参与者在返回PGx结果后3个月使用单一电话调查进行(目标 2)。最后，我们还将评估药剂师/医生确定的PGx结果对药物的影响 LLFS参与者确定药剂师评估的影响和参与者评估的影响之间的任何差距 PGx结果(目标2)。在这个项目的最后，我们将解决围绕着 将附带的PGx结果返回给研究参与者，并生成试点数据以支持更广泛的 实施将医学上可操作的偶然基因发现返还给研究参与者。

Abstract The Long Life Family Study (LLFS) is a family-based cohort of unusually healthy individuals that has whole genome sequencing (WGS) data on a majority of its participants and is currently generating large scale -omics data on its participants that includes transcriptomics, whole genome bisulfite sequencing, metabolomics and proteomics. Though LLFS does not return any incidental genetic results to study participants currently, LLFS has modified it’s consent form to ask participants whether they would like to receive incidental genetic findings in the future. The availability of WGS data in almost 4000 LLFS participants along with informed consent for return of medically actionable incidental genetic results, ideally positions LLFS to address bioethical issues related to return of genetic results in family-based cohorts. Pharmacogenetics (PGx), the study of the role of genetic variation in drug response phenotypes, is an area within genomic science that can positively impact patient management and consensus guidelines regarding specific genes and variants to be tested are now available. Thus, return of targeted PGx results that are clinically impactful and are supported by several national and international societies represent an opportunity that can be used to develop the bioethical framework for return of incidental genetic results in LLFS. We propose a pilot study at a single US field center (University of Pittsburgh) to demonstrate the feasibility and acceptability of returning limited PGx results from three genes to 200 LLFS participants. We propose to identify ten medically actionable PGx variants in three genes (CYP2C9, CYP2C19 and VKORC1) from WGS data already available in LLFS. We will confirm the observed variants in a CLIA certified laboratory, create a report summarizing the variants identified and the medications impacted by these variants and establish a study specific PGx consultation service to discuss study results with LLFS participants as needed. We propose to ascertain participant-assessed comprehension, decision making, and satisfaction with return of PGx results (Aim 1) at two time-points, immediately and three months after returning PGx results. In addition, we will leverage the family-based structure of the LLFS cohort to evaluate whether the index participants share their PGx results with their family members and ascertain the comprehension, decision making and satisfaction among family members with return of PGx results to the index study participant using a single telephone survey conducted 3 months after returning PGx results (Aim 2). Finally, we will also assess a pharmacist/physician determined impact of the PGx results on medications the LLFS participants to identify any gaps between pharmacist-assessed and participant-assessed impact of PGx results (Aim 2). At the end of this project, we will have addressed important ethical issues surrounding the return of incidental PGx results to research participants and generated pilot data to support the broader implementation of return of medically actionable incidental genetic findings to research participants.