“Problems With Using Polygenic Scores to Select Embryos”, Patrick Turley, Michelle N. Meyer, Nancy Wang, David Cesarini, Evelynn Hammonds, Alicia R. Martin, Benjamin M. Neale, Heidi L. Rehm, Louise Wilkins-Haug, Daniel J. Benjamin, Steven Hyman, David Laibson, Peter M. Visscher2021-07-01 (breeding; backlinks; similar)⁠:

Companies have recently begun to sell a new service to patients considering in vitro fertilization: embryo selection based on polygenic scores (ESPS). These scores represent individualized predictions of health and other outcomes derived from genome-wide association studies in adults to partially predict these outcomes.

This article includes a discussion of many factors that lower the predictive power of polygenic scores in the context of embryo selection and quantifies these effects for a variety of clinical and nonclinical traits. Also discussed are potential unintended consequences of ESPS (including selecting for adverse traits, altering population demographics, exacerbating inequalities in society, and devaluing certain traits).

Recommendations for the responsible communication about ESPS by practitioners are provided, and a call for a society-wide conversation about this technology is made.

…Recommendations For Responsible Communication Of Expected Gains From ESPS:

1. Emphasize absolute, not relative, risk reduction.

   Patients have reported greater intention to accept interventions,³² and health care professionals have reported greater willingness to purchase,33 prescribe,^34,35 and view interventions as therapeutically effective,^35,36 when the benefits are presented in terms of relative rather than absolute risk reduction. Given this consistent trend in the literature,^37,38 absolute risk reduction should be the most salient measure of expected gain in tables, figures, and other materials.^39,40 Relative risk reduction associated with embryo selection based on polygenic scores (ESPS) should never be presented in isolation.⁴¹

2. Provide phenotype-specific estimates of expected gains.

   In the phenotypes we assessed, expected gains from ESPS differed widely—from an absolute risk reduction of 0.12% to 8.5% and a relative risk reduction of 15% to 80% in persons of European ancestries. Companies should provide expected estimates of gain for each phenotype for which screening is offered as well as for the screening of multiple phenotypes at once. Expected gains from select phenotypes should not be offered as examples from which consumers and clinicians might improperly generalize.⁴¹ Further, consumers should be aware that “expected gains” for phenotypes that are defined by clinical cutoff points may not be practically meaningful.

3. Provide ancestry-specific estimates of expected gains.

   Currently, ESPS is not nearly as effective for consumers with non-European ancestries. Both the expected gains for each ancestral group and the uncertain gains for those of multiple ancestries should be prominently acknowledged, in plain language. Technical statements buried in fine print, such as “in demographics different from the Caucasian training set, sensitivity will be reduced”,⁴² are inadequate.

4. Provide risk-specific estimates of expected gains.

   Expected gains will differ depending on the lifetime risk of the phenotype in the embryo “population.” This risk, in turn, will depend on family history and on the environment in which the resulting child is expected to be reared.

5. Emphasize that expected gains (and risks) are uncertain.

   Companies should make clear that ESPS predictions have very wide prediction intervals that sometimes cross zero and that pleiotropy presents both risks and uncertainties regarding the other traits that do or might correlate with those the parent is selecting.

6. Avoid exaggerating the benefits of screening additional embryos.

   Claims such as “the more sibling embryos you have to choose from, the greater the relative reduction in risk”⁴¹ are misleading. Even for cases in which the expected gains of ESPS increase largely with each additional embryo for the first 5 embryos, the incremental gains will be smaller with each of the next 5 additional embryos and will slow dramatically thereafter.¹¹ This caution will be especially important if progress in stem-cell technologies makes it possible to create sperm or egg cells from a person’s blood or skin cells, yielding many more embryos, noninvasively, than is possible today.^43,44

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