Polygenic Embryo Screening: Towards Informed Decision-Making

项目总结 植入前基因检测(PGT)多年来一直被用来避免胚胎植入 具有罕见的单基因致病等位基因或非整倍体的。然而，复杂性状研究的最新进展 遗传学，再加上从单细胞输入产生准确的全基因组基因型别的技术能力， 使从基因上筛选胚胎具有共同的多基因特征和疾病风险成为可能。而当 大众媒体已经提出了“设计婴儿”的幽灵，而私营企业也开始提供 尽管价值值得怀疑，但对多基因胚胎筛查(PES)的实用性进行量化的实证工作很少， 审查其伦理影响，并评估利益相关者的观点。与传统的PGT不同，多基因 风险分数本质上是概率性和多面性的。PES固有的模棱两可需要小心 考虑，以便临床医生、政策制定者和普通公众做出关于 实施多基因胚胎筛查的潜在后果。此外，尽管研究 在过去的几年里，多基因风险得分的势头呈指数级增长，几乎没有 关于以下两个方面的独立经验数据：1)PES在以下两种情况下产生预期结果的潜在能力 各种真实世界的情景；或2)一线临床医生对潜在临床的看法和态度 多基因风险评分的应用，特别是在产前方面。 为了建立一个初步的框架，以考虑道德、法律和社会影响 (ELSI)，有必要建立两组经验参数：一是统计特性，即 将塑造多基因风险评分在产前环境中的潜在应用；第二，态度 以及站在PES一线的临床医生的观点，包括遗传学 咨询师、生殖内分泌学家和产科医生。因此，拟议的研究旨在量化 在不同条件下减少疾病风险的情况下，PES的实际结果范围，使用 模拟数据和真实数据的组合。我们还旨在了解临床医生的观点，这些医生将 潜在地提供PES，使用深入访谈和对生殖临床医生和 遗传学家。在拟议的研究项目中，这两个目标将相互交错并相互提供信息； 统计调查将以利益相关者提出的关切和问题为指导 访谈和调查将根据从我们的 分析。根据我们的结果，我们将对这项快速发展的技术进行伦理分析。

PROJECT SUMMARY Preimplantation genetic testing (PGT) has been utilized for years to avoid implantation of embryos harboring rare monogenic disease-causing alleles or aneuploidies. However, recent progress in complex trait genetics, coupled with the technical ability to generate accurate genome-wide genotypes from single-cell input, has made it possible to genetically screen embryos for common polygenic traits and disease risk. While popular media has raised the specter of ‘‘designer babies,’’ and private industry has begun to offer services of dubious merit, little empirical work has been done to quantify the utility of polygenic embryo screening (PES), examine its ethical implications, and assess stakeholders’ perspectives. Unlike conventional PGT, polygenic risk scores are intrinsically probabilistic and multifaceted. The inherent ambiguities of PES requires careful consideration in order for clinicians, policymakers, and the general public to make informed decisions about the potential consequences of implementing polygenic embryo screening. Moreover, although research momentum for polygenic risk scores has grown exponentially in the last few years, there is almost no independent, empirical data on either: 1) the potential ability of PES to produce desired outcomes under various real-world scenarios; or 2) the perspectives and attitudes of front-line clinicians in the potential clinical application of polygenic risk scores, especially in the prenatal context. In order to build an initial framework for the consideration of the ethical, legal, and social implications (ELSI) of PES, it is necessary to establish two sets of empirical parameters: first, the statistical properties that will shape the potential application of polygenic risk scores in the prenatal setting; and second, the attitudes and perspectives of clinicians who would be at the front lines of administering PES, including genetic counselors, reproductive endocrinologists, and obstetricians. The proposed study therefore aims to quantify the range of realistic outcomes of PES in the context of disease risk reduction under varying conditions, using a combination of simulated and real data. We also aim to understand the perspectives of clinicians who would potentially deliver PES, using both in-depth interviews and a large-scale survey of reproductive clinicians and geneticists. In the proposed research project, these two aims will be interdigitated and mutually informative; statistical investigation will be guided by concerns and questions posed by stakeholders, and stakeholder interviews and surveys will be shaped by the statistical and methodological understanding obtained from our analyses. On the basis of our results, we will perform ethical analysis of this rapidly evolving technology.