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 aleady 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!

Saturday, October 16, 2021

Dune 2021

I have high hopes for this new version of Dune.


Below, a re-post with two Frank Herbert interviews. Highly recommended to fans of the novel. 

The interviewer is Willis E. McNelly, a professor of English (specializing in science fiction). Herbert discusses artistic as well as conceptual decisions made in the writing and background world building for Dune. Highly recommended for any fan of the book.

See also Dune and The Butlerian Jihad and Darwin Among the Machines.
The Bene Gesserit program had as its target the breeding of a person they labeled "Kwisatz Haderach," a term signifying "one who can be many places at once." In simpler terms, what they sought was a human with mental powers permitting him to understand and use higher order dimensions.

They were breeding for a super-Mentat, a human computer with some of the prescient abilities found in Guild navigators. Now, attend these facts carefully:

Muad'Dib, born Paul Atreides, was the son of the Duke Leto, a man whose bloodline had been watched carefully for more than a thousand years. The Prophet's mother, Lady Jessica, was a natural daughter of the Baron Vladimir Harkonnen and carried gene-markers whose supreme importance to the breeding program was known for almost two thousand years. She was a Bene Gesserit bred and trained, and should have been a willing tool of the project.

The Lady Jessica was ordered to produce an Atreides daughter. The plan was to inbreed this daughter with Feyd-Rautha Harkonnen, a nephew of the Baron Vladimir, with the high probability of a Kwisatz Haderach from that union. Instead, for reasons she confesses have never been completely clear to her, the concubine Lady Jessica defied her orders and bore a son. This alone should have alerted the Bene Gesserit to the possibility that a wild variable had entered their scheme. But there were other far more important indications that they virtually ignored ...
"Kwisatz Haderach" is similar to the Hebrew "Kefitzat Haderech", which literally means "contracting the path"; Herbert defines Kwisatz Haderach as "the Shortening of the Way" (Dune: Appendix IV).

Another good recording of Herbert, but much later in his life.

Saturday, October 09, 2021

Leo Szilard, the Intellectual Bumblebee (lecture by William Lanouette)


This is a nice lecture on Leo Szilard by his biographer William Lanouette. See also ‘An Intellectual Bumblebee’ by Max Perutz.
Wikipedia: Leo Szilard was a Hungarian-American physicist and inventor. He conceived the nuclear chain reaction in 1933, patented the idea of a nuclear fission reactor in 1934, and in late 1939 wrote the letter for Albert Einstein's signature that resulted in the Manhattan Project that built the atomic bomb.
How Alexander Sachs, acting on behalf of Szilard and Einstein, narrowly convinced FDR to initiate the atomic bomb project: Contingency, History, and the Atomic Bomb

Szilard wrote children's stories and science fiction. His short story My Trial as a War Criminal begins after the USSR has defeated the US using biological weapons.
I was just about to lock the door of my hotel room and go to bed when there was a knock on the door and there stood a Russian officer and a young Russian civilian. I had expected something of this sort ever since the President signed the terms of unconditional surrender and the Russians landed a token occupation force in New York. The officer handed me something that looked like a warrant and said that I was under arrest as a war criminal on the basis of my activities during the Second World War in connection with the atomic bomb. There was a car waiting outside and they told me that they were going to take me to the Brookhaven National Laboratory on Long Island. Apparently, they were rounding up all the scientists who had ever worked in the field of atomic energy ...
This story was translated into Russian and it had a large impact on Andrei Sakharov, who showed it to his colleague Victor Adamsky:
A number of us discussed it. It was about a war between the USSR and the USA, a very devastating one, which brought victory to the USSR. Szilard and a number of other physicists are put under arrest and then face the court as war criminals for having created weapons of mass destruction. Neither they nor their lawyers could make up a cogent proof of their innocence. We were amazed by this paradox. You can’t get away from the fact that we were developing weapons of mass destruction. We thought it was necessary. Such was our inner conviction. But still the moral aspect of it would not let Andrei Dmitrievich and some of us live in peace.

See also The Many Worlds of Leo Szilard (APS symposium). Slides for Richard Garwin's excellent summary of Szilard's work, including nuclear physics, refrigeration, and Maxwell's Demon. One of Garwin's anecdotes:
Ted Puck was a distinguished biologist, originally trained in physics. ‘With the greatest possible reluctance I have come to the conclusion that it is not possible for me personally to work with you scientifically,’ he wrote Szilard. ‘Your mind is so much more powerful than mine that I find it impossible when I am with you to resist the tremendous polarizing forces of your ideas and outlook.’ Puck feared his ‘own flow of ideas would slow up & productivity suffer if we were to become continuously associated working in the same place and the same general kind of field.’ Puck said, ‘There is no living scientist whose intellect I respect more. But your tremendous intellectual force is a strain on a limited person like myself.’
Puck was a pioneer in single cell cloning, aided in part by Szilard:
When Szilard saw in 1954 that biologists Philip Marcus and Theodore Puck were having trouble growing individual cells into colonies, he concluded that “since cells grow with high efficiency when they have many neighbors, you should not let a single cell know it’s alone”. This was no flippant excursion into psychobiology. Rather, Szilard’s idea to use a layered feeder dish worked, while the open dish had not (Lanouette, 1992: 396–397).
After the war Szilard worked in molecular biology. This photo of Jacques Monod and Szilard is in the seminar room at Cold Spring Harbor Lab. Monod credits Szilard for the negative-feedback idea behind his 1965 Nobel prize.
“I have … recorded” in my Nobel lecture, said Monod, “how it was Szilard who decisively reconciled me with the idea (repulsive to me, until then) that enzyme induction reflected an anti-repressive effect, rather than the reverse, as I tried, unduly, to stick to.”


Friday, October 01, 2021

DNA forensics, genetic genealogy, and large databases (Veritasium video)


This is a good overview of DNA forensics, genetic genealogy, and existing databases like GEDmatch (Verogen).
@15:35 "Multiple law enforcement agencies have said that this is the most revolutionary tool they've had since the adoption of the fingerprint."
See Othram: the future of DNA forensics (2019):
The existing FBI standard (CODIS) for DNA identification uses only 20 markers (STRs -- previously only 13 loci were used!). By contrast, genome wide sequencing can reliably call millions of genetic variants. 
For the first time, the cost curves for these two methods have crossed: modern sequencing costs no more than extracting CODIS markers using the now ~30 year old technology. 
What can you do with millions of genetic markers? 
1. Determine relatedness of two individuals with high precision. This allows detectives to immediately identify a relative (ranging from distant cousin to sibling or parent) of the source of the DNA sample, simply by scanning through large DNA databases. 
More Othram posts.

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