Monday, October 18, 2021

Embryo Screening and Risk Calculus

Over the weekend The Guardian and The Times (UK) both ran articles on embryo selection.

I recommend the first article. Philip Ball is an accomplished science writer and former scientist. He touches on many of the most important aspects of the topic, not easy given the length restriction he was working with.

However I'd like to cover an aspect of embryo selection which is often missed, for example by the bioethicists quoted in Ball's article.

Several independent labs have published results on risk reduction from embryo selection, and all find that the technique is effective. But some people who are not following the field closely (or are not quantitative) still characterize the benefits -- incorrectly, in my view -- as modest. I honestly think they lack understanding of the actual numbers.

Some examples:
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%
I don't view these risk reductions as modest. Given that an IVF family is already going to make a selection they clearly benefit from the additional information that comes with genotyping each embryo. The cost is a small fraction of the overall cost of an IVF cycle.

But here is the important mathematical point which many people miss: We buy risk insurance even when the expected return is negative, in order to ameliorate the worst possible outcomes.

Consider the example of home insurance. A typical family will spend tens of thousands of dollars over the years on home insurance, which protects against risks like fire or earthquake. However, very few homeowners (e.g., ~1 percent) ever suffer a really large loss! At the end of their lives, looking back, most families might conclude that the insurance was "a waste of money"!

So why buy the insurance? To avoid ruin in the event you are unlucky and your house does burn down. It is tail risk insurance.

Now consider an "unlucky" IVF family. At, say, the 1 percent level of "bad luck" they might have some embryos which are true outliers (e.g., at 10 times normal risk, which could mean over 50% absolute risk) for a serious condition like schizophrenia or breast cancer. This is especially likely if they have a family history.

What is the benefit to this specific subgroup of families? It is enormous -- using the embryo risk score they can avoid having a child with very high likelihood of serious health condition. This benefit is many many times (> 100x!) larger than the cost of the genetic screening, and it is not characterized by the average risk reductions given above.

The situation is very similar to that of aneuploidy testing (screening against Down syndrome), which is widespread, not just in IVF. The prevalence of trisomy 21 (extra copy of chromosome 21) is only ~1 percent, so almost all families doing aneuploidy screening are "wasting their money" if one uses faulty logic! Nevertheless, the families in the affected category are typically very happy to have paid for the test, and even families with no trisomy warning understand that it was worthwhile.

The point is that no one knows ahead of time whether their house will burn down, or that one or more of their embryos has an important genetic risk. The calculus of average return is misleading -- i.e., it says that home insurance is a "rip off" when in fact it serves an important social purpose of pooling risk and helping the unfortunate.

The same can be said for embryo screening in IVF -- one should focus on the benefit to "unlucky" families to determine the value. We can't identify the "unlucky" in advance, unless we do genetic screening!