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.

PROJECT NARRATIVE 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. However, little empirical work has been done to quantify the utility of polygenic embryo screening (PES), examine its ethical implications, and assess stakeholder perspectives. The proposed study is designed to provide the necessary empirical basis for informed ethical discussion.