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PEStimate: Predicting offspring disease risk after Polygenic Embryo Screening
Liraz Klausner1, Ateret Revital1, Todd Lencz2,3,4,5
1Braun School of Public Health and Community Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Insights
Polygenic embryo screening (PES) can estimate offspring disease risk, but new models show potential risk reductions may be overestimated. The PEStimate app helps evaluate the impact of PES, considering factors like implantation failure.
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.
Motivation:
Polygenic embryo screening (PES) is a new technology in reproductive medicine, whereby human in-vitro fertilization (IVF) embryos are screened for their genetic risk of complex, polygenic diseases. PES aims to reduce the burden of polygenic diseases in offspring by prioritizing the selection of low-risk embryos. However, given that polygenic diseases are usually late-onset, PES outcomes cannot be evaluated empirically and must be estimated by epidemiological modeling. The commonly used liability threshold model has been previously used to predict PES outcomes. However, predictions rely on complex sets of equations, some of which require numerical integration or simulation. Further, previous models failed to account for the possibility that the selected embryo will not be born.
Results:
Here, we present PEStimate, a freely available online app for predicting PES outcomes when screening for a single disease. PEStimate predicts the offspring risk with and without PES, as well as plots of the risk reduction vs key parameters. Users can adjust the number of available embryos, the live birth rate, the disease prevalence and heritability, the accuracy of the genetic risk predictor, the embryo selection method, and the genetic risk and disease status of the parents and other relatives. Our new model for PES, which includes the possibility of embryo implantation failure, shows that risk reductions have been previously overestimated. PEStimate provides geneticists, healthcare professionals, patients, policymakers, and other stakeholders a necessary tool for examining the impact of PES and weighing its potential benefits against expected personal and societal harms.
Availability And Implementation:
PEStimate is freely available at: https://polygenicembryo.shinyapps.io/pestimate. The source code is available at: https://github.com/Lirazk/PEStimate.
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