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个体队列研究， 大多数参与者的基因组测序（WGS）数据，目前正在产生大规模的组学 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目前不向研究参与者返回任何偶然的遗传结果， 已经修改了它的同意书，询问参与者是否愿意接受偶然的基因发现 在未来近4000名LLFS参与者的WGS数据沿着知情同意书的可用性， 医学上可操作的偶然遗传结果的返回，理想地使LLFS能够解决生物伦理问题 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），研究的作用， 药物反应表型中的遗传变异，是基因组科学中的一个领域，可以积极影响 患者管理和共识的指导方针，关于特定的基因和变异进行测试，现在是 available.因此，返回具有临床影响力的靶向PGx结果，并得到多个 国家和国际社会提供了一个机会，可以用来发展生物伦理 在LLFS中返回偶然遗传结果的框架。我们建议在一个美国现场中心进行试点研究 （匹兹堡大学），以证明返回有限PGx结果的可行性和可接受性， 200名LLFS参与者的三个基因。我们建议在三个方面确定十种医学上可操作的PGx变体 基因（CYP 2C 9，CYP 2C 19和VKORC 1）来自LLFS中已有的WGS数据。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，总结所识别的变体和 受这些变体影响的药物，并建立研究特定的PGx咨询服务， 根据需要与LLFS参与者进行研究。我们建议确定参与者评估的理解， 决策，并在两个时间点（立即和三个时间点）返回PGx结果（目标1）的满意度 在返回PGx结果后几个月。此外，我们将利用LLFS队列的家庭结构 评估指数参与者是否与家人分享PGx结果，并确定 家庭成员对PGx结果的理解、决策和满意度 在返回PGx结果后3个月，使用单一电话调查的索引研究参与者（Aim 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）。在这个项目结束时，我们将解决围绕 将偶然的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 向研究参与者退还可采取医学行动的偶然遗传发现。

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.