Polygenic Embryo Screening: Towards Informed Decision-Making - 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. Polygenic embryo screening (PES), unlike conventional PGT, is intrinsically probabilistic and multifaceted. The inherent ambiguities of PES require careful consideration in order for clinicians, patients, policymakers, and the general public to make informed decisions about the potential consequences of implementing this technology. During the prior funding period (see Progress Report), our statistical genetics work demonstrated that relative risk reductions approaching 50% for complex adult-onset diseases are plausible, but absolute risk reductions depend on disease prevalence. Interviews and surveys demonstrated considerable interest amongst patients and the public, but more reticence amongst clinicians. The programmatic goal of our work is to provide independent (i.e., not commercially conflicted), transparent data enabling a rigorous ethical evaluation of this technology. This competing renewal application is based on the premise that the principles of beneficence and nonmaleficence are at the heart of medical ethics, and these cannot be adequately evaluated as abstractions. While our published results to date describe generalized/idealized PES scenarios, the range and complexity of available PES options has expanded considerably over the last four years, and feedback from diverse stakeholders has indicated: 1) that it is critical to examine PES under realistic, specific clinical scenarios; and 2) it is necessary to incorporate increasingly diverse perspectives and backgrounds into all analyses. The proposed study therefore aims to calculate relative and absolute risk reductions across varying use cases, incorporating a broad range of realistically derived clinical parameters, such as expected live birth rates, carrier status, and family history, and to survey reproductive physicians as to how they would evaluate these clinical trade-offs. We also aim to use interview and survey methods to determine the potential impact of PES on persons living with conditions (PLC) that might be screened by PES. Finally, we will perform a policy Delphi study to develop guidance for patients and clinicians in the form of criteria for consideration when deciding whether to use or offer PES. Our deliverables are designed to meet the needs of professional societies, policymakers, patient advocates, and other relevant stakeholders as they evaluate the potential risks/benefits of PES and develop guidance for its real-world use.
