Friday, July 02, 2021

Polygenic Embryo Screening: comments on Carmi et al. and Visscher et al.

In this post I discuss some recent papers on disease risk reduction from polygenic screening of embryos in IVF (PGT-P). I will focus on the science but at the end will include some remarks about practical and ethical issues. 

The two papers are 

Carmi et al. 

Visscher et al. 

Both papers study risk reduction in the following scenario: you have N embryos to choose from, and polygenic risk scores (PRS) for each which have been computed from SNP genotype. Both papers use simulated data -- they build synthetic child (embryo) genotypes in order to calculate expected risk reduction. 

I am very happy to see serious researchers like Carmi et al. and Visscher et al. working on this important topic. 

Here are some example results from the papers: 

Carmi et al. find a ~50% risk reduction for schizophrenia from selecting the lowest risk embryo from a set of 5. For a selection among 2 embryos the risk reduction is ~30%. (We obtain a very similar result using empirical data: real adult siblings with known phenotype.)

Visscher et al. find the following results, see Table 1 and Figure 2 in their paper. To their credit they compute results for a range of ancestries (European, E. Asian, African). We have performed similar calculations using siblings but have not yet published the results for all ancestries.

Relative Risk Reduction (RRR): 
Hypertension: 9-18% (ranges depend on specific ancestry) 
Type 2 Diabetes: 7-16% 
Coronary Artery Disease: 8-17% 

Absolute Risk Reduction (ARR): 
Hypertension: 4-8.5% (ranges depend on specific ancestry) 
Type 2 Diabetes: 2.6-5.5% 
Coronary Artery Disease: 0.55-1.1%

Note, families with a history of the disease would benefit much more than this. For example, parents with a family history of breast cancer or heart disease or schizophrenia will often produce some embryos with very high PRS and others in the normal range. Their absolute risk reduction from selection is many times larger than the population average results shown above. 

My research group has already published work in this area using data from actual siblings: tens of thousands of individuals who are late in life (e.g., 50-70 years old), for whom we have health records and genotypes. 

We have shown that polygenic risk predictors can identify, using genotype alone, which sibling in a pair has a specific disease condition: the sib with high PRS is much more likely to have the condition than the sib with normal range PRS. In those papers we also computed Relative Risk Reduction (RRR), which is directly relevant to embryo selection. Needless to say I think real sib data provides better validation of PRS than simulated genotypes. The adult sibs have typically experienced a shared family environment and also exhibit negligible population stratification relative to each other. Using real sib data reduces significantly some important confounds in PRS validation. 

See also these papers: Treff et al. [1] [2] [3]

Here are example results from our work on absolute and relative risk reduction. (Selection from 2 embryos.)

Regarding pleiotropy (discussed in the NEJM article), the Treff et al. results linked above show that selection using a Genomic Index, which is an aggregate of several polygenic risk scores, simultaneously reduces risks across all of the ~12 disease conditions in the polygenic disease panel. That is, risk reduction is not zero-sum, as far as we can tell: you are not forced to trade off one disease risk against another, at least for the 12 diseases on the panel. Further work on this is in progress. 

In related work we showed that DNA regions used to predict different risks are largely disjoint, which also supports this conclusion. See 

To summarize, several groups have now validated the risk reduction from polygenic screening (PGT-P). The methodologies are different (i.e., simulated genotypes vs studies using large numbers of adult siblings) but come to similar conclusions. 

Whether one should regard, for example, relative and absolute risk reduction in type 2 diabetes (T2D) of ~40% and ~3% (from figure above) as important or valuable is a matter of judgement. 

Studies suggest that type 2 diabetes results in an average loss of over 10 quality-adjusted life years -- i.e., more than a decade. So reducing an individual's risk of T2D by even a few percent seems significant to me. 

Now multiply that by a large factor, because selection using a genomic index (see figure) produces simultaneous risk reductions across a dozen important diseases.

Finally, polygenic predictors are improving rapidly as more genomic and health record data become available for machine learning. All of the power of modern AI technology will be applied to this data, and risk reductions from selection (PGT-P) will increase significantly over time. See this 2021 review article for more.

Practical Issues 

Aurea, the first polygenically screened baby (PGT-P), was born in May 2020.
See this panel discussion, which includes 

Dr. Simon Fishel (member of the team that produced the first IVF baby) 
Elizabeth Carr (first US IVF baby) 
Prof. Julian Savalescu (Uehiro Chair in Practical Ethics at the University of Oxford) 
Dr. Nathan Treff (Chief Scientist, Genomic Prediction)
Dr. Rafal Smigrodzki (MD PhD, father of Aurea) 

Astral Codex Ten recently posted on this topic: Welcome Polygenically Screened Babies :-) Many of the comments there are of high quality and worth reading. 

Ethical Issues 

Once the basic scientific results are established, one can meaningfully examine the many ethical issues surrounding embryo selection. 

My view has always been that new genomic technologies are so powerful that they should be widely understood and discussed -- by all of society, not just by scientists. 

However, to me it is clear that the potential benefits of embryo PRS screening (PGT-P) are very positive and that this technology will eventually be universally adopted. 

Today millions of babies are produced through IVF. In most developed countries roughly 3-5 percent of all births are through IVF, and in Denmark the fraction is about 10 percent! But when the technology was first introduced with the birth of Louise Brown in 1978, the pioneering scientists had to overcome significant resistance. There may be an alternate universe in which IVF was not allowed to develop, and those millions of children were never born.
Wikipedia: ...During these controversial early years of IVF, Fishel and his colleagues received extensive opposition from critics both outside of and within the medical and scientific communities, including a civil writ for murder.[16] Fishel has since stated that "the whole establishment was outraged" by their early work and that people thought that he was "potentially a mad scientist".[17]
I predict that within 5 years the use of polygenic risk scores will become common in some health systems (i.e., for adults) and in IVF. Reasonable people will wonder why the technology was ever controversial at all, just as in the case of IVF.

This is a very complex topic. For an in-depth discussion I refer you to this recent paper by Munday and Savalescu. Savalescu, Uehiro Chair in Practical Ethics at the University of Oxford, is perhaps the leading philosopher / bioethicist working in this area. 
Three models for the regulation of polygenic scores in reproduction 
Journal of Medical Ethics
The past few years have brought significant breakthroughs in understanding human genetics. This knowledge has been used to develop ‘polygenic scores’ (or ‘polygenic risk scores’) which provide probabilistic information about the development of polygenic conditions such as diabetes or schizophrenia. They are already being used in reproduction to select for embryos at lower risk of developing disease. Currently, the use of polygenic scores for embryo selection is subject to existing regulations concerning embryo testing and selection. Existing regulatory approaches include ‘disease-based' models which limit embryo selection to avoiding disease characteristics (employed in various formats in Australia, the UK, Italy, Switzerland and France, among others), and 'laissez-faire' or 'libertarian' models, under which embryo testing and selection remain unregulated (as in the USA). We introduce a novel 'Welfarist Model' which limits embryo selection according to the impact of the predicted trait on well-being. We compare the strengths and weaknesses of each model as a way of regulating polygenic scores. Polygenic scores create the potential for existing embryo selection technologies to be used to select for a wider range of predicted genetically influenced characteristics including continuous traits. Indeed, polygenic scores exist to predict future intelligence, and there have been suggestions that they will be used to make predictions within the normal range in the USA in embryo selection. We examine how these three models would apply to the prediction of non-disease traits such as intelligence. The genetics of intelligence remains controversial both scientifically and ethically. This paper does not attempt to resolve these issues. However, as with many biomedical advances, an effective regulatory regime must be in place as soon as the technology is available. If there is no regulation in place, then the market effectively decides ethical issues.
Dalton Conley (Princeton) and collaborators find that 68% of surveyed Americans had positive attitudes concerning polygenic screening of embryos.

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