Selecting for intelligence feels likely to be banned (unfortunately as this could be hugely beneficial for humanity if widespread) but in theory selecting against disease should also be pro intelligence as both are correlated through mutational load, right?
If they're doing the whole thing for $1400, then they're not doing full sequencing on all the embryos (unless there have been some huge breakthroughs which I missed). They're probably using rna microprobes like 23&me does. This means the ability to select for traits they didn't have in mind will be limited.
To be clear, does a couple doing this with a donor take up additional eggs that could have gone to somebody else, or does it use as many as "traditional" ivf? Neither this post nor the first linked article specified
>Are these tribes based on geography? Are they based on race, ethnic origin, religion, IQ, what TV channels you watched as a kid? I don’t know.
>Some of it is certainly genetic – estimates of the genetic contribution to political association range from 0.4 to 0.6. Heritability of one’s attitudes toward gay rights range from 0.3 to 0.5, which hilariously is a little more heritable than homosexuality itself.
>(for an interesting attempt to break these down into more rigorous concepts like “traditionalism”, “authoritarianism”, and “in-group favoritism” and find the genetic loading for each see here. For an attempt to trace the specific genes involved, which mostly turn out to be NMDA receptors, see here)
The big limiter here is "if you're doing IVF anyway." I doubt anyone would opt for IVF just for the benefit of genetic selection, and I don't think medical providers do the procedure unless natural conception is unsuccessful or inadvisable.
How exactly is this "relative risk reduction" measured ? They say it is "extrapolated from empirical data", but I don't know what that means.
If they mean, "we implanted N embryos, half screened using our algorithm and half at random, and the screened ones had X% less prevalence of genetic diseases in real life", then I might be mildly interested. On the other hand, if they mean, "we obtained a bunch of markers from GWAS, screened all the embryos for them, and assigned a score to each embryo based on its alleles", then I'm almost completely uninterested, because human traits (outside of a few outliers) are so polygenic that you can basically calculate whatever result you want based on how you tweak your model parameters.
I am concerned that we do not understand this well enough. What if, for instance, we find that genes that correlate with disease also correlate with some particular emotion? Or that (the genes we believe increase) intelligence are inversely correlated with empathy? Under a host of horrific hypotheticals, widespread adoption could be catastrophic, creating an entire generation that is missing an attribute, has far different statistical outcomes from the norm, etc. I leave it to those with more imagination than myself to generate better scenarios, and those with more knowledge to figure out if they could actually happen.
This makes Heinlein's Methuselah Project look like it belongs in a high school science fair. This is strong medicine. It will be applied exclusively by the ignorant (since that's all of us, right now) and, also, mostly by idiots who haven't thought about what they are doing.
I strongly suspect it will be done, at least in some if not many places, and I believe the impact will be large. I do not know if it will be positive or negative - or, more likely, both.
"For He knows what we are made of, and that it is dust." But perhaps not for much longer.
Somewhat skeptical of the efficacy of all this when most of the data comes from the company itself. How strictly is something like this regulated? Is there any way to verify that when they for example that there's a 60% lower chance of cancer that the math they're using adds up?
David Plotz wrote a book about the much derided Nobel Prize sperm bank in 2005 by interviewing the children. He was impressed by the offspring, who struck him as on average intelligent and thoughtful (at least the ones who felt like engaging with the man from Slate).
On the other hand, with well over a million children in the US having been conceived via sperm or egg donations, I've never noticed any large scale social effects from the purchasing of selected gametes.
For example, I presume that lesbians, as in the movie "The Kids Are Alright," are much more likely than heterosexuals to have children whose biological fathers were selected from sperm bank catalogs. Do lesbians therefore tend to have super children? I don't know. I've never heard that they do, but maybe they do. Has anybody ever heard of a study?
Here's some background on the validation of polygenic risk scores, pleiotropy, etc.
The effectiveness of polygenic disease risk predictors is tested using tens of thousands of siblings for whom we have genotypes and medical history (they are typically 50-70 years old). We specifically test how well the predictor can pick out a sibling with the condition from a pair:
"Given 1 sibling with normal-range PRS score (< 84 percentile, < + 1 SD) and 1 sibling with high PRS score (top few percentiles, i.e. > + 2 SD), the predictors identify the affected sibling about 70–90% of the time across a variety of disease conditions, including Breast Cancer, Heart Attack, Diabetes, etc."
Risk reduction has been validated using sib data in several independent studies.
Sibling validation of polygenic risk scores and complex trait prediction
We test 26 polygenic predictors using tens of thousands of genetic siblings from the UK Biobank (UKB), for whom we have SNP genotypes, health status, and phenotype information in late adulthood. Siblings have typically experienced similar environments during childhood, and exhibit negligible population stratification relative to each other. Therefore, the ability to predict differences in disease risk or complex trait values between siblings is a strong test of genomic prediction in humans. We compare validation results obtained using non-sibling subjects to those obtained among siblings and find that typically most of the predictive power persists in between-sibling designs. In the case of disease risk we test the extent to which higher polygenic risk score (PRS) identifies the affected sibling, and also compute Relative Risk Reduction as a function of risk score threshold. For quantitative traits we examine between-sibling differences in trait values as a function of predicted differences, and compare to performance in non-sibling pairs. Example results: Given 1 sibling with normal-range PRS score (< 84 percentile, < + 1 SD) and 1 sibling with high PRS score (top few percentiles, i.e. > + 2 SD), the predictors identify the affected sibling about 70–90% of the time across a variety of disease conditions, including Breast Cancer, Heart Attack, Diabetes, etc. 55–65% of the time the higher PRS sibling is the case. For quantitative traits such as height, the predictor correctly identifies the taller sibling roughly 80 percent of the time when the (male) height difference is 2 inches or more.
See also this 2021 review article, to appear in "Genomic Prediction of Complex Traits", Springer Nature book series "Methods in Molecular Biology"
Among other things it discusses pleiotropy and the genetic architecture of disease risks. DNA regions used to predict different risks are largely disjoint. Selection on a risk index (e.g., 10 conditions) has been shown (using sib data) to deliver average risk reduction for all of the diseases in the index.
What is known about the long-term health effects of IVF? My understanding is that people born through IVF are pretty normal as far as we can tell, but the oldest person born through IVF is now 42 so there are possible long-term effects for which we just can't tell. I want to point out the risk that if IVF embryo selection becomes really effective people will start using IVF when not medically necessary, and will eventually suffer long-term health effects that we aren't aware of because nobody with IVF lived that long yet. This risk seems pretty low, though.
Admittingly this kind of concerns me. Some of our most brilliant people have been clinically flawed in some way (like John Nash, Elon Musk Nicola Tesla) and there's good reason speculate that their "bad genes" correlate with or are the cause of their brilliance. Who knows what geniuses we would be depriving ourselves of?
This is messed up on multiple levels. Besides the obvious ethical considerations of having an entire social system based around meritocracy being gamed by innately increasing merit potential and essentially playing God based on unclear and short sighted principles, this is something exclusively available to very wealthy people having children very late in life. At a base it would accelerate wealth inequality and the entitled position that many silicon valley and finance bros have in regard to virtually every other segment of American society. Must be stopped at all costs.
I have three questions someone who is familiar can help me with hopefully.
>There are two ways that an egg may be fertilized by IVF: traditional and ICSI. In traditional IVF, 50,000 or more swimming sperm are placed next to the egg in a laboratory dish. Fertilization occurs when one of the sperm enters into the cytoplasm of the egg. In the ICSI process, a tiny needle, called a micropipette, is used to inject a single sperm into the center of the egg. With either traditional IVF or ICSI, once fertilization occurs, the fertilized egg (now called an embryo) grows in a laboratory for 1 to 5 days before it is transferred to the woman’s uterus (womb).[https://www.reproductivefacts.org/news-and-publications/patient-fact-sheets-and-booklets/documents/fact-sheets-and-info-booklets/what-is-intracytoplasmic-sperm-injection-icsi/]
1. What effect does directly injecting the sperm have? I assume that swimming to reach the egg and penetrate is a test of fitness. But how much does it matter?
2. If there is a substantial negative effect to directly injecting, would making more and more sperm go through an extremely difficult process before fertilizing select for a healthy sperm that would help make a healthy baby?
3. After enough generations of ICSI, do sperm stop swimming enough to get a woman pregnant? Does IVF cause the need for more IVF?
My wife and I went through a couple of cycles of IVF recently, and actually chatted with Genomic Predictions (the name of Prof Hsu's company beofre it changed to LifeView apparently). For us the big challenge was that the fertility clinic we used to harvest the eggs and then implant the embryo was very limiting in what they would allow us to do in terms of selecting embryos. We were already testing for a (mild) genetic defect I have, and their policy was that if any embryo tested positive for it they would refuse to implant it, in spite of the mild expected impact. (On the other hand if we didn't test for the condition they would accept the 50/50 chance an embryo had it and implant any of our embryos.). When we raised the idea of using something like polygenic risk scoring they shut us down immediately. This is a well known clinic affiliated with a top US hospital, but I looked around a bit and got the sense that it would be a struggle to find a clinic (in the US) that would accept this kind of embryo selection process, although the fact that a baby was born using it suggests maybe this wasn't as much of a challenge as I thought. The solution I considered was finding the egg donor in the US and using our normal clinic to harvest the eggs and create the embryos, then having the genetic testing done, then transferring the embryos to an international clinic more willing to allow us to select the embryo using whatever criteria we wanted.
I guess I'm outing myself as a religious conservative, but you wouldn't have to be a religious conservative to see those embryos that don't get chosen with something like compassion.
Granted, an embryo does not suffer, so the unchosen embryo will not know it never even had a chance. And also granted that many embryos don't survive to birth anyway.
I'm a father of five. One of my daughters is autistic, not too severe, but enough that she'll likely not be able to live independently. I am grateful every day that she's part of the world. My youngest child had markers for Down syndrome while my wife was pregnant with him. While we would have loved and cared for him either way, we were grateful that this turned out to be a false alarm. I like children, and would have wanted more, but five kids is already a lot, so you make your choice.
I'm not sure what my point is, but it's something like this: if life is good (and I think it is), then even a life with some pain or sickness may be a life worth having. I guess I'd like to see some sort of organization established to take all these unchosen embryos, and, at some future date, give them a life and a home somewhere. If my vision of the future is right, I could see many happy, not-quite-perfect children growing up in big, beautiful O'Neill cylinders in the sky.
I feel like I might as well chime in with my perspective, as someone who has done pre-conception genetic screening for myself and my partner (through Dor Yeshorim) and is currently 7 months pregnant with (hopefully) my first child after IVF (with ICSI). Upfront: I would not consider polygenic screening of embryos for future pregnancies as the technology stands, and only a few specific improvements would push me to reconsider.
Re: Dor Yeshorim, my husband and I checked and were deemed “a match” prior to engagement; that is, for a panel of recessive genetic disorders common in Ashkenazi Jewish background, we were mutual carriers for the disease alleles for none (Dor Yeshorim also offers testing for genetic disorders for non-Ashkenazi Jewish backgrounds, and other genetic testing services for those of Jewish background are available and have some advantages). This was something we both strongly believed offered an excellent cost/benefit ratio due to high background risk and severe disease for affected individuals. If we had been mutual carriers for one or more of these disorders, I expect we would have still married and used IVF with pre-implantation genetic screening for whatever we were mutual carriers for. So anyway, I don’t have a general objection to pre-conception genetic screening (which I used) or pre-implantation genetic screening. I ended up doing IVF in my 20s due to infertility.
When you do a round of IVF, you pay a fairly high price for a very limited number of embryos. I was in many ways an ideal candidate for IVF: at 27, young as these things go, good general health, no identified reproductive issues – only male factor infertility had been identified, and was likely the cause of our low fertility. At my fertility clinic, I paid about $20,000 as a flat fee for up to six egg retrieval and fertilization cycles and unlimited embryo transfers, until such time as I gave birth to a living, breathing baby. A single egg retrieval cycle and one or maybe more embryo cycles would have been somewhat cheaper, but two separate rounds of egg retrieval and fertilization ala carte would have been more expensive, and I couldn’t be sure that I’d succeed in a single round. That price doesn’t include the drugs, which are ballpark $3,000-$5,000 and in my case were substantially covered by our insurance. We did extremely well with our egg retrieval and fertilization: 16 eggs retrieved (just about the sweet spot for generating the highest number of good embryos in a single cycle; many more eggs and the overall quality starts to go down as far as I’ve read), 12 of these fertilized, 8 of those grew to five-day blastocyst embryos (all of which were graded highly, that is, they looked morphologically good under the microscope, which to my understanding at best correlates loosely to successful implantation). One cycle, $20,000, eight good embryos – basically the best-case scenario. Now, implantation – what are the odds there? Again, I’m in good general health, age 27, no ovulation or other reproductive cycle problems identified – and each fairly good-looking embryo transferred has slightly under 50% odds to come through as a living baby (slightly over 50% chance to implant, with about the normal rates of miscarriage or pregnancy loss). My first transfer (fresh, during the same cycle as the egg retrieval) didn’t take, my second (“natural cycle” frozen embryo transfer) did, and I’m now seven months pregnant with no major risk factors or complications.
This sets off so many alarm bells for me, but to pick just three issues that I haven't seen in the comments so far, this seems like another step down the road to:
- even more expensive and physically and emotionally grueling norms and expectations foisted on women who want to have children "responsibly"
- even more prejudice against disabled and sick people (for existing) and their parents (for allowing them to exist)
both within the medical establishment and in the broader culture
- even more division and acrimony between the socioeconomic classes...
PRS screens are a perfect scam: no proof that they are effective, and no way to prove that they are ineffective for adult onset diseases like schizophrenia for at least 18 years. Go capitalism!
I've been waiting for this post. Some quick numbers I ran the other day to give a clearer sense of how cost-effective polygenic screening is.
Type 2 Diabetes is one of the more common condition for which we have decent polygenic tests. [One study estimated that 40% of Americans will develop type 2 diabetes at some point in their life](https://www.webmd.com/diabetes/news/20140812/40-percent-of-americans-will-develop-diabetes-cdc-projects). The number of years of life lost to type 2 diabetes varies quite a bit depending on the age at which one develops the condition, but [this study found that even among older men and women, they lost 11.1 and 13.8 Quality Adjusted Life Years respectively.](https://jamanetwork.com/journals/jama/fullarticle/197439). This article suggests the average age of onset of Type 2 Diabetes is [45 years](https://www.medicalnewstoday.com/articles/317375), though the "source" here is just a caption under an image, so take this with a grain of salt. Regardless, let's assume that 15 QALYs is a reasonable estimate for the number of years lost by Type 2 Diabetics.
The value of a QALY varies, but [this article suggests that in the US we value a QALY at somewhere between $50k-$150k. Let's use a fairly conservatie estimate here of $50k.
The average US diabetic in 2013 spent [$85,000](https://pubmed.ncbi.nlm.nih.gov/23953350/) in direct medical costs over a lifetime (about $100,000 in today's dollars).
Add these two up, and Type 2 Diabetes costs the average American diabetic $835,000. With a 4 in 10 chance of getting type 2 diabetes at some point in one's life, the average future American will lose $334k to type 2 diabetes.
Using [Shai Carmi et al](https://github.com/scarmi/embryo_selection)'s code for estimating the relative risk reduction from selecting the two best embryos out of a batch of 10 for a disease with prevalence of 0.4, whose variance we can explain roughly 11% of with polygenic testing, it looks like the first embryo would get an expected risk reduction of 13.7%, while the second would (probably) get a risk reduction of around 10%. At $835,000 of lifetime costs, this works out to a total value of about $200,000 just for Type 2 Diabetes risk. It's possible the 40% lifetime risk I found in the article linked above is high. But even if the risk is only 20%, it's still worth $136k. And the true value is likely to be higher because adding more traits will always increase the expected value.
[CNY sells normal IVF services for $16,000](https://www.cnyfertility.com/ivf-cost/). With a $1400 starting fee and a $400/embryo screening fee (the cost last time I checked in on LifeView), the additional cost from screening would be $5400, bringing the total to $21400. In other words, you could pay $21,400 to get a lifetime benefit of $200,000 for your children. For a life of 85 years, that works out to a 2.7% annual return by the time your children die (though it's likely the return would be somewhat better if we included other diseases).
There's something to be said for the non-fungibility of health. The most expensive medical care in the world can only do a limited amount to extend the lifespans and improve the health of diabetics. And the same is true for nearly all chronic conditions that can be screened for with polygenic testing. So even if you skipped IVF + polygenic screening for your children and invested $21k into index funds, the $6 million valuation it would have by the time your children reached retirement age probably couldn't be turned into an additional 5 years of healthy life.
Your estimate for IQ gain is actually off: using results from [EA3](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985927/), we can explain roughly 10% of variance in intelligence from genetic testing. Using Gwern's own code, we can estimate a gain of 5.5 IQ points when selecting the best of 10 embryos. I suspect Gwern was using results from EA2, which only explained 4.5% of variance. With 34 embryos (the amount the couple in the article you linked had to choose from), we would expect a gain of roughly 7.4.
My overall conclusion is that if we somehow end up banning pre-implantation genetic testing it will be one of the worst decisions we have ever made. The impact would be on-par with a worldwide ban on vaccines or sewage systems. It would likely cost the average person around 5 years of healthy life. In fact I think it will be so bad for the citizens of a country that anyone who can afford to will probably leave to get it done elsewhere, since the cost of the plane flights to get IVF done will be trivial compared to the lifetime benefits of reducing polygenic disease risk.
And the math looks more compelling the further out we extrapolate. There's several research labs working on creating egg cells from induced pluripotent stem cells, which in turn can be created from skin or blood cells. If someone manages to get that working it may eliminate two of the biggest drivers of IVF cost: medication to stimulate egg production and surgical extraction of the eggs by a specialist doctor. Producing and screening embryos at that point would be as simple as submitting a cheek swab and a sperm sample and signing some consent forms. The only remaining necessary procedure would be frozen embryo transfer, which is typically less than $1000.
At that sort of price level I suspect we would see embryo screening become a routine part of pre-pregnancy care. Every generation would have lower chronic disease risks, higher healthy life expectancies and greater intelligence. At least it might continue for a few generations before we hit the singularity. After that who knows what will happen.
Preimplantation genetic diagnosis (PGD) has been in use for years, and many children have been born thanks to it. With that in mind, how is last year's birth of "Aurea Smigrodzki" through preimplantation genetic testing for polygenic (PGT-P) significant?
I've never seen "PGT-P" before, and Google didn't reveal any sources that explained how it was different from PGD.
Full disclosure, I believe human life (and personhood) begins at conception. So the whole concept of deliberately creating lots of people in order to pick one and kill the rest is pretty horrifying to me.
But for the rest of you, consider this issue. What happens when the parents who paid thousands of dollars to pick the "perfect child" discover that their child is just as human and imperfect as the rest of us?
Also, try listening to the adult children of donor conception and IVF. A lot of them do not appreciate being purchased.
Worry about large-scale ill effects of gene screening seems to be based on an assumption that there will be a consensus about what gets screened. My bet is that if there is large-scale screening, there will be a number of organizations doing it and in the nature of things, they won't all be using the same screens. They might even go about screening for the same genes in different ways with different effects. Does this take some of the edge off?
Yes, this is my daughter Aurea's photograph, not stock. Thanks for writing about polygenic testing, this is a revolutionary medical technology and yet many oppose it. Note: I do not have any commercial or professional involvement with PGT-P, my GF and I just happened to be the first couple to successfully use the technology. The more parents know about it, the sooner it becomes standard medical practice, which is a good thing, since (as I see it) it leads to Lake Wobegon, not to GATTACA.
O brave new world, that has such people in 't!
https://www.nejm.org/doi/full/10.1056/NEJMsr2105065?query=recirc_inIssue_bottom_article
Selecting for intelligence feels likely to be banned (unfortunately as this could be hugely beneficial for humanity if widespread) but in theory selecting against disease should also be pro intelligence as both are correlated through mutational load, right?
If they're doing the whole thing for $1400, then they're not doing full sequencing on all the embryos (unless there have been some huge breakthroughs which I missed). They're probably using rna microprobes like 23&me does. This means the ability to select for traits they didn't have in mind will be limited.
To be clear, does a couple doing this with a donor take up additional eggs that could have gone to somebody else, or does it use as many as "traditional" ivf? Neither this post nor the first linked article specified
>Are these tribes based on geography? Are they based on race, ethnic origin, religion, IQ, what TV channels you watched as a kid? I don’t know.
>Some of it is certainly genetic – estimates of the genetic contribution to political association range from 0.4 to 0.6. Heritability of one’s attitudes toward gay rights range from 0.3 to 0.5, which hilariously is a little more heritable than homosexuality itself.
>(for an interesting attempt to break these down into more rigorous concepts like “traditionalism”, “authoritarianism”, and “in-group favoritism” and find the genetic loading for each see here. For an attempt to trace the specific genes involved, which mostly turn out to be NMDA receptors, see here)
(https://slatestarcodex.com/2014/09/30/i-can-tolerate-anything-except-the-outgroup/)
The big limiter here is "if you're doing IVF anyway." I doubt anyone would opt for IVF just for the benefit of genetic selection, and I don't think medical providers do the procedure unless natural conception is unsuccessful or inadvisable.
How exactly is this "relative risk reduction" measured ? They say it is "extrapolated from empirical data", but I don't know what that means.
If they mean, "we implanted N embryos, half screened using our algorithm and half at random, and the screened ones had X% less prevalence of genetic diseases in real life", then I might be mildly interested. On the other hand, if they mean, "we obtained a bunch of markers from GWAS, screened all the embryos for them, and assigned a score to each embryo based on its alleles", then I'm almost completely uninterested, because human traits (outside of a few outliers) are so polygenic that you can basically calculate whatever result you want based on how you tweak your model parameters.
Aurea means "golden" in Latin. Dawn is "aurora."
Also I'm picturing every yuppie mum hiring a lawyer for when Mike isn't 6' and Suzy isn't smart in 20 years and I hope it's entertaining
In extremely related news, the lobster genome is out and it's so fascinating!!! https://advances.sciencemag.org/content/7/26/eabe8290
Aurea looks somewhat shocked - could it be...
a) her parents have just told her she's the first polygenically screened baby
b) she just read the label on her bedding(?) which seems to be about suffocating infants, or
c) she can't believe Scott thinks Aurea means "dawn" when she thought it meant "golden" (gotta update them priors baby 😉)
Vote now!
I am concerned that we do not understand this well enough. What if, for instance, we find that genes that correlate with disease also correlate with some particular emotion? Or that (the genes we believe increase) intelligence are inversely correlated with empathy? Under a host of horrific hypotheticals, widespread adoption could be catastrophic, creating an entire generation that is missing an attribute, has far different statistical outcomes from the norm, etc. I leave it to those with more imagination than myself to generate better scenarios, and those with more knowledge to figure out if they could actually happen.
This makes Heinlein's Methuselah Project look like it belongs in a high school science fair. This is strong medicine. It will be applied exclusively by the ignorant (since that's all of us, right now) and, also, mostly by idiots who haven't thought about what they are doing.
I strongly suspect it will be done, at least in some if not many places, and I believe the impact will be large. I do not know if it will be positive or negative - or, more likely, both.
"For He knows what we are made of, and that it is dust." But perhaps not for much longer.
Somewhat skeptical of the efficacy of all this when most of the data comes from the company itself. How strictly is something like this regulated? Is there any way to verify that when they for example that there's a 60% lower chance of cancer that the math they're using adds up?
Here's a new article in the New England Journal of Medicine:
Problems with Using Polygenic Scores to Select Embryos
https://www.nejm.org/doi/full/10.1056/NEJMsr2105065
Thanks for sharing this. A couple of months ago I wrote this Metaculus question on the same topic: https://www.metaculus.com/questions/7031/first-commercial-polygenic-embryo-screening/ I did it under the assumption that Orchid Health would be the first to come to market with PGS screening. Seems like I missed this kid!
David Plotz wrote a book about the much derided Nobel Prize sperm bank in 2005 by interviewing the children. He was impressed by the offspring, who struck him as on average intelligent and thoughtful (at least the ones who felt like engaging with the man from Slate).
On the other hand, with well over a million children in the US having been conceived via sperm or egg donations, I've never noticed any large scale social effects from the purchasing of selected gametes.
For example, I presume that lesbians, as in the movie "The Kids Are Alright," are much more likely than heterosexuals to have children whose biological fathers were selected from sperm bank catalogs. Do lesbians therefore tend to have super children? I don't know. I've never heard that they do, but maybe they do. Has anybody ever heard of a study?
That is a very cute baby.
Here's some background on the validation of polygenic risk scores, pleiotropy, etc.
The effectiveness of polygenic disease risk predictors is tested using tens of thousands of siblings for whom we have genotypes and medical history (they are typically 50-70 years old). We specifically test how well the predictor can pick out a sibling with the condition from a pair:
"Given 1 sibling with normal-range PRS score (< 84 percentile, < + 1 SD) and 1 sibling with high PRS score (top few percentiles, i.e. > + 2 SD), the predictors identify the affected sibling about 70–90% of the time across a variety of disease conditions, including Breast Cancer, Heart Attack, Diabetes, etc."
Risk reduction has been validated using sib data in several independent studies.
Sibling validation of polygenic risk scores and complex trait prediction
https://www.nature.com/articles/s41598-020-69927-7
We test 26 polygenic predictors using tens of thousands of genetic siblings from the UK Biobank (UKB), for whom we have SNP genotypes, health status, and phenotype information in late adulthood. Siblings have typically experienced similar environments during childhood, and exhibit negligible population stratification relative to each other. Therefore, the ability to predict differences in disease risk or complex trait values between siblings is a strong test of genomic prediction in humans. We compare validation results obtained using non-sibling subjects to those obtained among siblings and find that typically most of the predictive power persists in between-sibling designs. In the case of disease risk we test the extent to which higher polygenic risk score (PRS) identifies the affected sibling, and also compute Relative Risk Reduction as a function of risk score threshold. For quantitative traits we examine between-sibling differences in trait values as a function of predicted differences, and compare to performance in non-sibling pairs. Example results: Given 1 sibling with normal-range PRS score (< 84 percentile, < + 1 SD) and 1 sibling with high PRS score (top few percentiles, i.e. > + 2 SD), the predictors identify the affected sibling about 70–90% of the time across a variety of disease conditions, including Breast Cancer, Heart Attack, Diabetes, etc. 55–65% of the time the higher PRS sibling is the case. For quantitative traits such as height, the predictor correctly identifies the taller sibling roughly 80 percent of the time when the (male) height difference is 2 inches or more.
See also this 2021 review article, to appear in "Genomic Prediction of Complex Traits", Springer Nature book series "Methods in Molecular Biology"
Among other things it discusses pleiotropy and the genetic architecture of disease risks. DNA regions used to predict different risks are largely disjoint. Selection on a risk index (e.g., 10 conditions) has been shown (using sib data) to deliver average risk reduction for all of the diseases in the index.
https://arxiv.org/abs/2101.05870
What is known about the long-term health effects of IVF? My understanding is that people born through IVF are pretty normal as far as we can tell, but the oldest person born through IVF is now 42 so there are possible long-term effects for which we just can't tell. I want to point out the risk that if IVF embryo selection becomes really effective people will start using IVF when not medically necessary, and will eventually suffer long-term health effects that we aren't aware of because nobody with IVF lived that long yet. This risk seems pretty low, though.
Admittingly this kind of concerns me. Some of our most brilliant people have been clinically flawed in some way (like John Nash, Elon Musk Nicola Tesla) and there's good reason speculate that their "bad genes" correlate with or are the cause of their brilliance. Who knows what geniuses we would be depriving ourselves of?
What would we call this? Neonatal gene editing? Prenatal?
Here's a beautiful article about how maybe we shouldn't eradicate DOWNS -- maybe there's actually a lot of happiness we're missing out on.
https://www.thenewatlantis.com/publications/at-home-with-down-syndrome
"In theory, you're not supposed to use polygenic screening to produce designer babies."
Is that law? The company's policy? Your ethical opinion? Some people's ethical opinion?
This is messed up on multiple levels. Besides the obvious ethical considerations of having an entire social system based around meritocracy being gamed by innately increasing merit potential and essentially playing God based on unclear and short sighted principles, this is something exclusively available to very wealthy people having children very late in life. At a base it would accelerate wealth inequality and the entitled position that many silicon valley and finance bros have in regard to virtually every other segment of American society. Must be stopped at all costs.
I have three questions someone who is familiar can help me with hopefully.
>There are two ways that an egg may be fertilized by IVF: traditional and ICSI. In traditional IVF, 50,000 or more swimming sperm are placed next to the egg in a laboratory dish. Fertilization occurs when one of the sperm enters into the cytoplasm of the egg. In the ICSI process, a tiny needle, called a micropipette, is used to inject a single sperm into the center of the egg. With either traditional IVF or ICSI, once fertilization occurs, the fertilized egg (now called an embryo) grows in a laboratory for 1 to 5 days before it is transferred to the woman’s uterus (womb).[https://www.reproductivefacts.org/news-and-publications/patient-fact-sheets-and-booklets/documents/fact-sheets-and-info-booklets/what-is-intracytoplasmic-sperm-injection-icsi/]
1. What effect does directly injecting the sperm have? I assume that swimming to reach the egg and penetrate is a test of fitness. But how much does it matter?
2. If there is a substantial negative effect to directly injecting, would making more and more sperm go through an extremely difficult process before fertilizing select for a healthy sperm that would help make a healthy baby?
3. After enough generations of ICSI, do sperm stop swimming enough to get a woman pregnant? Does IVF cause the need for more IVF?
My wife and I went through a couple of cycles of IVF recently, and actually chatted with Genomic Predictions (the name of Prof Hsu's company beofre it changed to LifeView apparently). For us the big challenge was that the fertility clinic we used to harvest the eggs and then implant the embryo was very limiting in what they would allow us to do in terms of selecting embryos. We were already testing for a (mild) genetic defect I have, and their policy was that if any embryo tested positive for it they would refuse to implant it, in spite of the mild expected impact. (On the other hand if we didn't test for the condition they would accept the 50/50 chance an embryo had it and implant any of our embryos.). When we raised the idea of using something like polygenic risk scoring they shut us down immediately. This is a well known clinic affiliated with a top US hospital, but I looked around a bit and got the sense that it would be a struggle to find a clinic (in the US) that would accept this kind of embryo selection process, although the fact that a baby was born using it suggests maybe this wasn't as much of a challenge as I thought. The solution I considered was finding the egg donor in the US and using our normal clinic to harvest the eggs and create the embryos, then having the genetic testing done, then transferring the embryos to an international clinic more willing to allow us to select the embryo using whatever criteria we wanted.
I guess I'm outing myself as a religious conservative, but you wouldn't have to be a religious conservative to see those embryos that don't get chosen with something like compassion.
Granted, an embryo does not suffer, so the unchosen embryo will not know it never even had a chance. And also granted that many embryos don't survive to birth anyway.
I'm a father of five. One of my daughters is autistic, not too severe, but enough that she'll likely not be able to live independently. I am grateful every day that she's part of the world. My youngest child had markers for Down syndrome while my wife was pregnant with him. While we would have loved and cared for him either way, we were grateful that this turned out to be a false alarm. I like children, and would have wanted more, but five kids is already a lot, so you make your choice.
I'm not sure what my point is, but it's something like this: if life is good (and I think it is), then even a life with some pain or sickness may be a life worth having. I guess I'd like to see some sort of organization established to take all these unchosen embryos, and, at some future date, give them a life and a home somewhere. If my vision of the future is right, I could see many happy, not-quite-perfect children growing up in big, beautiful O'Neill cylinders in the sky.
I feel like I might as well chime in with my perspective, as someone who has done pre-conception genetic screening for myself and my partner (through Dor Yeshorim) and is currently 7 months pregnant with (hopefully) my first child after IVF (with ICSI). Upfront: I would not consider polygenic screening of embryos for future pregnancies as the technology stands, and only a few specific improvements would push me to reconsider.
Re: Dor Yeshorim, my husband and I checked and were deemed “a match” prior to engagement; that is, for a panel of recessive genetic disorders common in Ashkenazi Jewish background, we were mutual carriers for the disease alleles for none (Dor Yeshorim also offers testing for genetic disorders for non-Ashkenazi Jewish backgrounds, and other genetic testing services for those of Jewish background are available and have some advantages). This was something we both strongly believed offered an excellent cost/benefit ratio due to high background risk and severe disease for affected individuals. If we had been mutual carriers for one or more of these disorders, I expect we would have still married and used IVF with pre-implantation genetic screening for whatever we were mutual carriers for. So anyway, I don’t have a general objection to pre-conception genetic screening (which I used) or pre-implantation genetic screening. I ended up doing IVF in my 20s due to infertility.
When you do a round of IVF, you pay a fairly high price for a very limited number of embryos. I was in many ways an ideal candidate for IVF: at 27, young as these things go, good general health, no identified reproductive issues – only male factor infertility had been identified, and was likely the cause of our low fertility. At my fertility clinic, I paid about $20,000 as a flat fee for up to six egg retrieval and fertilization cycles and unlimited embryo transfers, until such time as I gave birth to a living, breathing baby. A single egg retrieval cycle and one or maybe more embryo cycles would have been somewhat cheaper, but two separate rounds of egg retrieval and fertilization ala carte would have been more expensive, and I couldn’t be sure that I’d succeed in a single round. That price doesn’t include the drugs, which are ballpark $3,000-$5,000 and in my case were substantially covered by our insurance. We did extremely well with our egg retrieval and fertilization: 16 eggs retrieved (just about the sweet spot for generating the highest number of good embryos in a single cycle; many more eggs and the overall quality starts to go down as far as I’ve read), 12 of these fertilized, 8 of those grew to five-day blastocyst embryos (all of which were graded highly, that is, they looked morphologically good under the microscope, which to my understanding at best correlates loosely to successful implantation). One cycle, $20,000, eight good embryos – basically the best-case scenario. Now, implantation – what are the odds there? Again, I’m in good general health, age 27, no ovulation or other reproductive cycle problems identified – and each fairly good-looking embryo transferred has slightly under 50% odds to come through as a living baby (slightly over 50% chance to implant, with about the normal rates of miscarriage or pregnancy loss). My first transfer (fresh, during the same cycle as the egg retrieval) didn’t take, my second (“natural cycle” frozen embryo transfer) did, and I’m now seven months pregnant with no major risk factors or complications.
-1/2-
This sets off so many alarm bells for me, but to pick just three issues that I haven't seen in the comments so far, this seems like another step down the road to:
- even more expensive and physically and emotionally grueling norms and expectations foisted on women who want to have children "responsibly"
- even more prejudice against disabled and sick people (for existing) and their parents (for allowing them to exist)
both within the medical establishment and in the broader culture
- even more division and acrimony between the socioeconomic classes...
https://www.statnews.com/2021/07/01/researchers-raise-concerns-genetic-risk-scores-pick-healthier-embryos/?utm_content=bufferd4781&utm_medium=social&utm_source=twitter&utm_campaign=twitter_organic
To pay for the treatment it should be legal for potential parents to borrow the money and obligate their future child to pay back the loan.
If you search on YouTube or look on his blog information processing Steve has some good talks on the ability to predict IQ.
Personally, I think that's far from the most important thing. The ability to select against things like disposition to have depression could be huge!
PRS screens are a perfect scam: no proof that they are effective, and no way to prove that they are ineffective for adult onset diseases like schizophrenia for at least 18 years. Go capitalism!
I've been waiting for this post. Some quick numbers I ran the other day to give a clearer sense of how cost-effective polygenic screening is.
Type 2 Diabetes is one of the more common condition for which we have decent polygenic tests. [One study estimated that 40% of Americans will develop type 2 diabetes at some point in their life](https://www.webmd.com/diabetes/news/20140812/40-percent-of-americans-will-develop-diabetes-cdc-projects). The number of years of life lost to type 2 diabetes varies quite a bit depending on the age at which one develops the condition, but [this study found that even among older men and women, they lost 11.1 and 13.8 Quality Adjusted Life Years respectively.](https://jamanetwork.com/journals/jama/fullarticle/197439). This article suggests the average age of onset of Type 2 Diabetes is [45 years](https://www.medicalnewstoday.com/articles/317375), though the "source" here is just a caption under an image, so take this with a grain of salt. Regardless, let's assume that 15 QALYs is a reasonable estimate for the number of years lost by Type 2 Diabetics.
The value of a QALY varies, but [this article suggests that in the US we value a QALY at somewhere between $50k-$150k. Let's use a fairly conservatie estimate here of $50k.
The average US diabetic in 2013 spent [$85,000](https://pubmed.ncbi.nlm.nih.gov/23953350/) in direct medical costs over a lifetime (about $100,000 in today's dollars).
Add these two up, and Type 2 Diabetes costs the average American diabetic $835,000. With a 4 in 10 chance of getting type 2 diabetes at some point in one's life, the average future American will lose $334k to type 2 diabetes.
Using [Shai Carmi et al](https://github.com/scarmi/embryo_selection)'s code for estimating the relative risk reduction from selecting the two best embryos out of a batch of 10 for a disease with prevalence of 0.4, whose variance we can explain roughly 11% of with polygenic testing, it looks like the first embryo would get an expected risk reduction of 13.7%, while the second would (probably) get a risk reduction of around 10%. At $835,000 of lifetime costs, this works out to a total value of about $200,000 just for Type 2 Diabetes risk. It's possible the 40% lifetime risk I found in the article linked above is high. But even if the risk is only 20%, it's still worth $136k. And the true value is likely to be higher because adding more traits will always increase the expected value.
[CNY sells normal IVF services for $16,000](https://www.cnyfertility.com/ivf-cost/). With a $1400 starting fee and a $400/embryo screening fee (the cost last time I checked in on LifeView), the additional cost from screening would be $5400, bringing the total to $21400. In other words, you could pay $21,400 to get a lifetime benefit of $200,000 for your children. For a life of 85 years, that works out to a 2.7% annual return by the time your children die (though it's likely the return would be somewhat better if we included other diseases).
There's something to be said for the non-fungibility of health. The most expensive medical care in the world can only do a limited amount to extend the lifespans and improve the health of diabetics. And the same is true for nearly all chronic conditions that can be screened for with polygenic testing. So even if you skipped IVF + polygenic screening for your children and invested $21k into index funds, the $6 million valuation it would have by the time your children reached retirement age probably couldn't be turned into an additional 5 years of healthy life.
Your estimate for IQ gain is actually off: using results from [EA3](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985927/), we can explain roughly 10% of variance in intelligence from genetic testing. Using Gwern's own code, we can estimate a gain of 5.5 IQ points when selecting the best of 10 embryos. I suspect Gwern was using results from EA2, which only explained 4.5% of variance. With 34 embryos (the amount the couple in the article you linked had to choose from), we would expect a gain of roughly 7.4.
My overall conclusion is that if we somehow end up banning pre-implantation genetic testing it will be one of the worst decisions we have ever made. The impact would be on-par with a worldwide ban on vaccines or sewage systems. It would likely cost the average person around 5 years of healthy life. In fact I think it will be so bad for the citizens of a country that anyone who can afford to will probably leave to get it done elsewhere, since the cost of the plane flights to get IVF done will be trivial compared to the lifetime benefits of reducing polygenic disease risk.
And the math looks more compelling the further out we extrapolate. There's several research labs working on creating egg cells from induced pluripotent stem cells, which in turn can be created from skin or blood cells. If someone manages to get that working it may eliminate two of the biggest drivers of IVF cost: medication to stimulate egg production and surgical extraction of the eggs by a specialist doctor. Producing and screening embryos at that point would be as simple as submitting a cheek swab and a sperm sample and signing some consent forms. The only remaining necessary procedure would be frozen embryo transfer, which is typically less than $1000.
At that sort of price level I suspect we would see embryo screening become a routine part of pre-pregnancy care. Every generation would have lower chronic disease risks, higher healthy life expectancies and greater intelligence. At least it might continue for a few generations before we hit the singularity. After that who knows what will happen.
Preimplantation genetic diagnosis (PGD) has been in use for years, and many children have been born thanks to it. With that in mind, how is last year's birth of "Aurea Smigrodzki" through preimplantation genetic testing for polygenic (PGT-P) significant?
I've never seen "PGT-P" before, and Google didn't reveal any sources that explained how it was different from PGD.
As I haven't seen it linked elsewhere here is a recent review of the limitations and misunderstanding of PRS from Lior Pachter: https://liorpachter.wordpress.com/2021/04/12/the-amoral-nonsense-of-orchids-embryo-selection/
tl/dr PRS is usually misunderstood, as are the percent reduction in complex traits.
Full disclosure, I believe human life (and personhood) begins at conception. So the whole concept of deliberately creating lots of people in order to pick one and kill the rest is pretty horrifying to me.
But for the rest of you, consider this issue. What happens when the parents who paid thousands of dollars to pick the "perfect child" discover that their child is just as human and imperfect as the rest of us?
Also, try listening to the adult children of donor conception and IVF. A lot of them do not appreciate being purchased.
Worry about large-scale ill effects of gene screening seems to be based on an assumption that there will be a consensus about what gets screened. My bet is that if there is large-scale screening, there will be a number of organizations doing it and in the nature of things, they won't all be using the same screens. They might even go about screening for the same genes in different ways with different effects. Does this take some of the edge off?
https://m.youtube.com/watch?v=HE5ADe7BgdM
https://www.ivfbabble.com/on-the-40th-anniversary-of-the-first-ivf-in-the-usa-the-first-baby-elizabeth-jordan-carr-looks-at-how-science-today-has-produced-a-new-world-first-baby-aurea
Yes, this is my daughter Aurea's photograph, not stock. Thanks for writing about polygenic testing, this is a revolutionary medical technology and yet many oppose it. Note: I do not have any commercial or professional involvement with PGT-P, my GF and I just happened to be the first couple to successfully use the technology. The more parents know about it, the sooner it becomes standard medical practice, which is a good thing, since (as I see it) it leads to Lake Wobegon, not to GATTACA.
Should I delay having children to take advantage of polygenic screening?
x-post: https://www.lesswrong.com/posts/tg2fzDSjzyEgo2QFr/should-i-delay-having-children-to-take-advantage-of