PEStimate: Predicting offspring disease risk after Polygenic Embryo Screening

Area of Science:

• Reproductive medicine and genetics
• Epidemiological modeling and biostatistics
• Bioinformatics and computational biology

Background:

• Polygenic embryo screening (PES) aims to reduce offspring genetic risk for complex diseases by selecting in-vitro fertilization (IVF) embryos with lower genetic predisposition.
• Current PES outcome prediction relies on epidemiological models, often complex and requiring advanced computation, and previously did not account for implantation failure.
• Accurate estimation of PES effectiveness is crucial for informed decision-making by healthcare providers, patients, and policymakers.

Purpose of the Study:

• To develop and present PEStimate, a novel online application for predicting the outcomes of polygenic embryo screening for single-disease risk.
• To introduce an updated epidemiological model for PES that incorporates the possibility of embryo implantation failure, addressing a limitation in previous models.
• To provide a user-friendly tool for exploring the impact of various parameters on PES efficacy and potential risk reduction.

Main Methods:

• Development of a new epidemiological model for PES that includes embryo implantation failure.
• Creation of PEStimate, a freely accessible online application (shiny app) implementing the new model.
• Inclusion of adjustable parameters in PEStimate, such as number of embryos, live birth rate, disease prevalence, heritability, genetic predictor accuracy, selection method, and parental genetic information.

Main Results:

• The study's updated model indicates that previous overestimations of risk reduction associated with PES may have occurred.
• PEStimate provides predictions of offspring disease risk both with and without PES, alongside visualizations of risk reduction.
• The application allows users to explore the sensitivity of PES outcomes to various genetic and reproductive parameters.

Conclusions:

• PEStimate offers a valuable, accessible tool for stakeholders to empirically examine the potential benefits and harms of polygenic embryo screening.
• The inclusion of implantation failure in PES modeling suggests a need for revised expectations regarding the magnitude of disease risk reduction.
• This tool facilitates informed discussions on the clinical utility and societal implications of advanced reproductive genetic technologies like PES.