5Polygenic screening is a method for modifying the traits of future children via embryo selection. If that sounds like gobbledygook, then think of it a bit like choosing stats for your baby.
That may sound amazing. It may sound like science fiction. It may even sound horribly dystopian. But whatever your feelings, it is in fact possible. And these benefits are available right now for a price that, while expensive, is within reach for most middle-class families.
On a more serious note, there is limited selection power available with today's technologies, so you will not be able to have a baby Einstein unless you are already a Nobel laureate. But polygenic screening will allow you to decrease your child's risk of common diseases by 10-60%, reduce their risk of mental disorders, and increase their IQ by somewhere between 3 and 8 points. If you are willing to wait a few years, you may be able to increase IQ by up to 13 points. These benefits are available for between $20k-100k depending on how strong of a benefit you want and what kinds of traits you want to select for.
There has been quite a bit of discussion of this topic on LessWrong and adjacent communities but very little concrete advice for would-be parents who are curious whether the benefits are worth the price, particularly for those who have no other reason to do IVF. The purpose of this post is to fill that gap by addressing costs, potential medical complications, choice of clinic, which labs are best, and how age and infertility diagnosis affect the expected benefits.
This is a long post and I expect most people will not want to read the whole thing. If this is you, please use the section selector in the sidebar to navigate to the section you are most interested in. You may want to simply skip to the section titled "The Benefits of Polygenic Embryo Screening".
Background on IVF
Wait, what even is polygenic embryo selection?
Embryo selection is all about picking an embryo to (hopefully) turn into a baby. This occurs during the process of In-Vitro Fertilization, or IVF. In the typical IVF cycle, a couple goes into a fertility clinic because they want to have a baby. Usually this is because they’ve been having trouble conceiving naturally, but couples also seek out IVF when they want to do genetic testing, select the sex of their child, or to preserve fertility for later pregnancy.
The doctor conducts a bunch of medical tests, and if they all check out, the woman begins a hormone regimen that will stimulate an abnormally large number of her eggs to mature all at once.
At the end of the regiment, the doctor extracts a bunch of mature eggs from the woman's ovaries, which are then fertilized using the father's sperm and grown in a lab dish for 4-7 days. When the embryo has finished growing, there are often four or more that can be implanted in the mother. Most couples do not want four children, so a choice must be made about which embryo to pick.
In ye olden days, doctors would often just transfer all the embryos at once in the hope that at least one of them would result in a baby. Sometimes this would work well; one of the embryos would happen to stick and the parents would be very happy. Other times it would work a little too well and more than one of the embryos would implant. This is why twin births are so much more common during IVF than during normal pregnancy.
Transferring multiple embryos at a time is less common nowadays because IVF clinics have figured out how to reduce the odds of failed pregnancy using genetic testing. With a higher chance of live birth from a single embryo transfer, the risk of a failed embryo transfer is outweighed by the risks of a twin pregnancy. The outcomes for twin births are on average worse than for single pregnancies. Twins are more likely to be born preterm, develop health problems, and put excess stress on the mother's body.
This brings us back to embryo selection; the doctor or embryologist has to make a choice about which embryo to transfer first. All clinics have to make this choice, so all practice embryo selection of some kind. But the criteria for selecting the embryo have, until recently, been pretty dumb.
The standard practice is for an embryologist to look at all the embryos under a microscope and pick the one that looks the prettiest. I am not kidding. The embryologist will rank the embryos from best to worst based on their "morphology", which accounts for factors like their rotational symmetry and whether or not they have a dark and rough colored appearance.
To be fair to the embryologists, this method is better than just randomly picking an embryo; embryos with particularly bad morphology gradings do actually have a lower chance of resulting in a live birth. And for a long time, there was simply no other option But times have changed and we can now select embryos by DNA rather than simply the appearance of their cells under a microscope.
But how do they even get an embryo's DNA?
All the best techniques for genotyping rely on destructive sequencing, meaning the cells whose DNA is read must be destroyed. Embryos don't have very many cells. So how do we get information about what's in its genome without destroying it?
It turns out that after roughly five days of development, embryos possess a very interesting property; one may remove up to about 10 cells with little to no measurable impact on the embryo's ability to develop into a healthy child. The embryo can regenerate up to about 10% of its mass! That’s the equivalent of losing and then regrowing both your arms as an adult.
This is very fortunate for us because these cells contain a treasure trove of information. The most common thing IVF clinics look for is aneuploidy, which is a medical term meaning "this embryo has an abnormal number of chromosomes". The term for this type of testing is “PGT-A”, and it’s performed in roughly half of all IVF cycles in the US today.
Human embryos with the wrong number of chromosomes are surprisingly common, both among IVF patients and natural pregnancy. But this wasn’t very well understood before the first use of pre-implantation genetic testing in the late 1980s.
IVF Doctors started wondering why so many transfers were failing to result in pregnancy, or resulting in pregnancy followed by very early miscarriage. They discovered that roughly a third(!) of all pregnancies, both natural and via IVF have chromosomal abnormalities. Most of the time these go undetected because their immediate effect is to result in the arrest of the embryo’s growth, or to cause a very early miscarriage (often before the woman even knows she is pregnant).
IVF clinics began testing embryos for aneuploidy in the early 1980s. But in the late 2000s, something happened that completely changed the landscape of genetic testing.
Why Polygenic Screening wasn't possible before 2015
The cost of sequencing a fixed amount of DNA has declined dramatically since Fred Sanger and his team pioneered the first methods in 1977. There is a kind of "Moore's law of sequencing" in which the cost of sequencing a fixed amount of DNA has declined exponentially over time.
However, something incredibly dramatic happened to DNA sequencing in about 2007. Take a look at this graph:
I don't think I've ever seen a graph that looks like this anywhere else. Between 2007 and 2010, the cost of sequencing a megabase of DNA dropped by a factor of a million! That unbelievable, super exponential drop was made possible by a technology called "Next Generation Sequencing".
By the mid-2010s, you could genotype all the parts of a person’s DNA most likely to differ from other people’s for under $100. At that price point, it became possible to gather genomes from hundreds of thousands of people and assemble them into giant databases that researchers could access.
This was incredibly important, because you NEED hundreds of thousands of samples to make good genetic predictors. It turns out that most of the traits we care about like heart disease risk or intelligence or attractiveness are determined not by a handful of high-impact genes, but by the cumulative effect of thousands of genes, each of which has only a tiny impact.
Take educational attainment. Educational attainment is not the most heritable trait, but because research on it is more politically acceptable in a university environment than the direct study of intelligence, we know quite a bit about its genetic roots. The latest large-scale study of it included data from 2.7 million participants. Among all genes identified, the one with the single largest effect size only increased the amount of time you spent in school by at most 2.8 weeks (see section 3.4). That's it! The average gene has a tiny, tiny impact on how long you spend in school. The predictor used 2,925 genes to explain just 15% of the variance in how many years of school a person completed.
So you actually NEED these gigantic databases to explain more than a tiny fraction of the variance in complex traits. This is why polygenic embryo selection was impossible before about 2016; there just wasn't enough data to figure out which genes did what.
How do they know which genes do what?
Once you have a giant biobank and information about people's traits and diseases, you still need to figure out which genes do what. I mentioned an educational attainment predictor in the section above, but I didn't explain how they created it. So how did they do it?
The answer is actually not too complicated: a researcher will use one of these gigantic biobanks plus a machine learning model to identify which genetic variants are associated with an increase or decrease in a given trait.
The dumbest possible way to do this is with a Genome Wide Association Study, or GWAS. It works something like this:
Let's say there's a gene with two different variants commonly present in the biobank population. 96% of participants have an "A" at some particular location in the gene, but 4% have a "T" instead. We want to know whether having a "T" makes you taller.
A GWAS just measures the average height of people with an A and the height of people with a T to see if they're different. Then it uses a statistical significance test to see if the result could have plausibly been the result of random chance. If not, the researchers reason that the gene is having an effect on height. If it passes this test, it is added to the "list of important genes for height".
For such a dumb method, this works remarkably well. Height predictors created using GWAS results correlate with actual height at about 0.55.
The smarter way to do this is to use some kind of machine learning method like LASSO. This will give you a better predictor for the same amount of data. But for some reason I still don't really understand, academia almost exclusively uses GWAS.
Correlation or causation?
"OK", you might say. "That's well and good, but how do we know that these genetic differences are actually CAUSING someone to be taller or smarter rather than just spuriously correlated with height?"
The main reason this is possible is because nature has already conducted a randomized control trial on our behalf. Every time your body produces a sperm or egg cell, your DNA is more or less randomly mixed up and half of it is given to the reproductive cell. This means that, conditional on parental genomes, sibling genomes are randomized!
In turn, this means that if a gene can predict differences between siblings, you can be quite confident that it is in fact CAUSING the difference. This is actually quite a remarkable fact, and one that underpins the entire reason for believing embryo selection should work.
There is one asterisk here; though a sibling GWAS can tell you where the causal variant is, it usually can only narrow down the list of candidates to perhaps 10 distinct variants within a region of very roughly 100,000 base pairs. This is sufficient for embryo selection because that set of 10 base pairs will almost always be inherited together. But if sometime down the line we want to do embryo editing, it will require us to either pinpoint the causal variant precisely or to edit all 10 variants that have a decent chance of causing the observed change.
Another crucial insight from these studies is that nearly all of the genetic differences between humans can be explained by additive effects; there are very few gene-gene interactions going on; If gene A makes you taller, it doesn't depend on gene B being present to work its magic. It's a strong, independent gene that don't need no help.
This fact is extremely important because it makes both evolution and embryo selection possible. There is a common misconception that genes are tied together in a hopelessly complex web and that if we mess with one part of it the whole thing will come crashing down. While that may be true for genes that are universally present in the human population, it is very rarely true for genes that commonly vary between people.
You have the predictors. Now what?
Once you have created genetic predictors using GWAS or LASSO or some other method, you can then feed in the embryo's DNA to the trained model and get a prediction of each embryo's expected trait value. You do this for every predictor you have (or at least those you care about), and then pick an embryo based on the results.
But there's one last question to answer: which traits should you care about? If one embryo has a 20% chance of getting breast cancer and a 10% chance of getting heart disease, is that better or worse than an embryo with a 10% risk of breast cancer and a 20% risk of heart disease? Or how about one that has a high risk of both but is also predicted to have an IQ 5 points above average?
There is no universally agreed-upon method for making the choice about which embryo to implant. My personal hope is that someone (maybe even me!) makes a tool to assess what parents find important and then ranks embryos according to those criteria.
The Benefits of Polygenic Embryo Screening
|Category||Trait||Improvement Range||Publicly Available?|
|Non-disease||Intelligence||+1.6-7.5 IQ points||No*|
|Disease||Basal Cell Carcinoma||3-45%||Yes|
|Disease||Coronary Artery Disease||20-60%||Yes|
|Disease||Inflammatory Bowel Disorder||5-65%||Yes|
|Disease||Type 1 Diabetes||10-55%||Yes|
|Disease||Type 2 Diabetes||20-60%||Yes|
|Mental Disorder||Major Depressive Disorder||5-20%||Yes|
*See the section below for how to get access to these predictors
Ok, enough with the theory. How big of a benefit can you actually get from going through IVF and screening your embryos?
I'll start with the one everyone always asks about: intelligence. How much can you boost your child's IQ with embryo selection?
How much can embryo selection increase my child's IQ?
First, there is no company that publicly offers embryo selection for intelligence. I have heard rumors that there is a group of people offering this service, but I haven't been able to find anything public about them. If you're actually doing IVF, you might want to reach out to Jonathan Anomaly, who knows people working in this space..
I don't know the exact quality of their predictor, but I have a pretty good guess based on publicly available research which they are likely using as their starting point. Assuming they've produced something at least as good as what's available in the Educational Attainment 4 study, I think it's likely that the predictor correlates with measured IQ at about 0.3.
So how big would the gain be? Using some code from Gwern's monster post on embryo selection for intelligence, I'd estimate that if both parents are of European ancestry and you have 10 euploid embryos to pick from, the gain would be about 5 IQ points. It's plausible that you would get up to maybe 40 euploid embryos if the mother is young and you do multiple rounds of egg retrieval. In that case, you could probably get a gain closer to 7.5 points. If the mother is older it will be less. There's also a reduction in benefit if one of the parents is of non-european ancestry, though I'm not sure exactly how much. A safe estimate is that the expected gain in non-Europeans is cut by a third. So if one parent is European and the other is Chinese, for example, the expected IQ gain would be about 4 points.
This is an unfortunate side-effect of the fact that there aren't enough non-Europeans in the large biobanks on which these predictors are trained.
There is significant room for this benefit to improve in the near future. If we simply gave intelligence tests to people who are already participating in existing biobanks, we could increase the IQ gain from embryo selection by about 70% or more. This would imply a gain of 8.5-13 IQ points. Administering these intelligence tests could be done for a few tens of millions of dollars (or perhaps less if you're clever about it).
This future increase in the efficacy of embryo selection has an obvious implication: if you freeze eggs or embryos now, you'll have more embryos to pick from (since egg production declines with maternal age), and if you wait a few years to implant them, the expected gain from selection will be higher. This is my own personal plan.
Unlike intelligence, there actually are several companies that offer polygenic embryo screening for disease risk. For this reason, I can tell you quite a bit about exactly how much you can reduce disease via embryo selection.
There are two main "categories" of disease risk to think about: monogenic disease risk (which includes diseases like Tay Sachs, Cystic Fibrosis etc), and polygenic disease risk, which includes heart disease, alzheimers, schizophrenia, diabetes and most others.
The chance of you and your spouse having a child with a monogenic disease is about 1%. So unless you know that both you and your spouse are known carriers, this is not a reason worth doing IVF and embryo selection.
However, everyone has a non-zero risk of some kind of disease, and embryo selection to reduce polygenic disease risk is already available in clinics.
The first company to offer this was Genomic Prediction. Orchid Health also finally offers polygenic embryo screening, though I believe they charge more per embryo. One other lab in China appears to have recently deployed a similar test, though it looks as though they screened embryos for type 2 diabetes risk exclusively, which is not a very sensible strategy in my opinion.
Since Orchid only recently released their embryo screening product publicly, I haven’t had a chance to read much about it. Because of that, and because I suspect few of my readers would be interested in flying to China to use worse screening technology, I will look exclusively at work done by Genomic Prediction.
They use a pretty straightforward and simple method for determining an embryo's relative ranking: each disease is weighted according to its impact on disability-adjusted lifespan. According to one of their recent papers, selecting embryos in this manner results in a fairly impressive reduction in disease risk across multiple conditions. Here's a graph from one of their latest papers showing the expected reduction in the relative risk of various diseases from selecting the best of five embryos.
The figure above shows disease reductions for selection among 5 "pseudosiblings" of European descent (apparently there are not enough real siblings to train predictors on). My guess is the benefits will be reduced compared to those shown, perhaps by around 20%.
Note also that this doesn’t take losses from implantation or miscarriage into account. So you’ll need more like 7 or 8 euploid embryos to achieve gains 20% lower than this. But still, the benefits are reasonably strong.
The most amazing thing to me about the above graph is that selection seems to reduce EVERY disease in the index. One of the major concerns I hear raised about embryo selection is that there might be some "hidden downside" to selection. This graph seems to suggest that, at least so far as diseases go, that's not much of a concern.
Another way of looking at the benefits of disease reduction is to look at how much the quality-adjusted lifespan of an average child born via polygenic screening would increase compared to one born without its benefits. Here's their analysis of this framing:
Keep in mind, this is the pseudosibling benefit, so take what you see on the graph above and multiply it by 0.8 to get a more realistic number. Also, the benefit is not quite as large for non-European groups. It looks like the gain is reduced by about 20-30% for South Asians, 30% for Africans and 35% for East Asians.
Of course, this all kind of ignores the elephant in the room: many of these diseases have an average age of onset of 50-75. In fifty years the world is likely to look incredibly different. If humans are still around, it seems likely that we'll have cures or at least very effective treatments for many of these conditions.
The exceptions are mental disorders like clinical depression and ADHD, which generally have an average age of onset before age 25, and obesity, which is now showing up more and more in childhood.
Other Non-Disease Traits
As with intelligence, there are no companies publicly offering screening for personality traits to the best of my knowledge. Maybe the secret startup I mentioned in the section on intelligence offers screening for personality, but I have yet to find out.
Predictors for personality traits such as conscientiousness and neuroticism are poor. This seems to be partly related to the lack of good data on such traits. A paper published in March of 2022 was able to explain 2% of the variance in conscientiousness and much less for others. There is significant room for improvement here, as most estimates peg the heritability of the big five personality traits at roughly 40-60%.
There are existing third-party services like Genomelink and SelfDecode which provide personality predictors. Unfortunately, they don't have any published data on the quality of the predictors they use, and the anecdotes I've heard suggest that, at least for intelligence predictors, they are very poor. So if you're looking for something that isn't terrible, your best bet is to contact Jonathan Anomaly and hope he knows a group that offers a better predictor.
It would be nice (or possibly dystopian, depending on your views) if you could add physical attractiveness to your embryo selection criteria. More attractive people have higher lifetime income, better dating prospects, and seem to benefit generally from the halo effect.
To the best of my knowledge, no one offers this as a service right now, so unless the super secret startup offers it, you'd probably have to pay a researcher tens of thousands of dollars to develop a predictor for you.
The predictor might be halfway decent, though I don't expect it to be as good as the ones we have for intelligence or most diseases. Here's a meta-analysis of facial feature genetics from 2020 that found 203 genome-wide significant signals. If someone made a predictor using that paper it might be able to predict facial attractiveness reasonably well. However, there is clearly much room for improvement.
Is attractiveness a purely position good? That is to say, if everyone was made attractice, would society be better off? My guess is probably would be a little better off, but I haven’t done enough research into this topic to be sure.
If you want to see what selection on attractiveness looks like in the extreme, take a look at male birds of paradise. Female birds have been selecting mates based on their plumage and dancing ability for thousands of generations, resulting in some very beautiful, but very strange looking birds.
It is worth asking ourselves if dozens of generations of selection for attractiveness might result in similarly strange and pointless features whose sole purpose is to elicit arousal in members of the opposite sex.
And in the shorter run, selection for physical attractiveness probably trades off at least somewhat against selection for other features that have a greater benefit for society as a whole. So for now there is a non-zero cost to making everyone more attractive.
Still, from a purely selfish perspective, some level of selection for attractiveness makes sense. As with intelligence, no company currently offers the ability to select for physical attractiveness, unless you include selection for height, which already works extremely well. Your best bet is contacting Jonathan Anomaly to see if the groups he knows offer something. Or, barring that, you could hire a PHD student for 50k and pay them to develop a predictor for you.
Concrete Advice for Would-Be Parents
If you've read the sections above and you decided you want to do polygenic embryo screening, your primary objective should be to get maximum gain for minimum cost. This section is about how to achieve that goal.
There are two primary inputs that determine the effect size of polygenic screening:
- The power of the polygenic predictors used to select an embryo for implantation.
- The number of "achievable births", meaning the number of children you would have if you implanted all of your embryos one by one.
Number 1 is largely out of your control unless your name is Gwern or you are a research scientist with access to a large biobank.
Number 2 IS within your control, at least to some degree. Here is a list of factors you might be able to change that will influence achievable births:
- How many IVF cycles you go through
- The IVF clinic you choose
- The PGT lab used for aneuploidy testing
- The age of the mother or egg donor at the time eggs are extracted (younger is always better)
- The stimulation protocol used
- The age of the father or sperm donor (younger is better)
- Whether you choose to freeze eggs or embryos
- Routine prenatal care that any good obstetrician will be able to tell you (though see Emily Oster's excellent book if you want more details)
Why do these factors matter? Because at every step of the IVF process from initial consultation to birth, fewer eggs/embryos/pregnancies come out than go in. There's a loss associated with each step, and the factors listed above have a large influence on the size of the loss. Here are some suggestions on how to reduce losses and costs:
Suggestion #1: Reduce uncertainty about how many euploid embryos you will produce
The single most important input into the “gain” equation is the number of mature eggs harvested per retrieval. However, this quantity has a very wide distribution. In conversations an acquaintance of mine had with egg donor clinics, they mentioned that some donors produce as many as 100 eggs per retrieval. A woman in her mid-40s with infertility issues might produce 3.
There are several heuristics you can use to reduce the uncertainty about how many eggs you are likely to harvest during an egg retrieval. Knowing these beforehand can help reduce uncertainty about the exact size of the benefits of polygenic screening.
The easiest heuristic to use is the woman’s age. As a general rule, I wouldn’t do IVF for the purpose of polygenic embryo selection unless the mother is under 38. Beyond age 38, the losses in the IVF funnel are just too steep to justify the pain and expense, unless you plan to use donor eggs.
Another lower-cost but not free thing you can do is assess your likely egg production by undergoing the very first part of IVF; a consultation and ovarian ultrasound. This ultrasound is performed right at the very start of the IVF process and usually costs less than $1000. Ovarian reserve and antral follicle count are strongly correlated with the expected number of mature eggs you or your female partner will produce after hormonal treatments. If you’re willing to do embryo selection in theory if the gain is large enough, this can be a relatively inexpensive way to reduce the uncertainty about the benefits of the procedure.
What is really needed here is a tool that allows one to see the expected gain across a variety of traits given an antral follicle count. The data necessary to do this research is present in the CDC’s NASS database, but I don’t yet have access. I hope to do this for a future research project. Until then, here’s a table showing roughly how your odds vary as a function of antral follicle count.
Suggestion #2: Use my table to pick a clinic
I have spent an embarrassing amount of time on a research project to rank every IVF clinic in the US from best to worst. I compiled this list using data from the CDC’s NASS database, which has information about clinics going back to the mid-90s. I believe I am the first and only person in the world to do this. If you’re curious about a clinic that isn’t on the last, feel free to reach out to me and I can give you the numbers.
A somewhat boring explanation of the research I did (skip this if you just want results)
Clinics are ranked according to their cumulative live birth rate per intended egg retrieval among patients using their own eggs (not donor eggs). In simple English, that means we’re looking at what percentage of women who started hormone treatments actually delivered at least one child.
In an ideal world I’d give you clinic rankings based on the number of expected births per retrieval. But without access to intermediate outcome data from NASS, this is impossible. I plan to apply for access eventually, but in the meantime I think live birth rate is probably quite a good proxy, and clinics with very high live birth rates are likely to be able to produce more achievable births than those with lower live birth rates.
I’ve taken care to control for various factors that could confound the analysis. Some clinics attract a larger proportion of younger patients, who have better prospects than older cohorts. Some clinics attract a large proportion of patients solely interested in freezing eggs or embryos for some later treatment. Some clinics have a very small number of cycles each year and can score very well or very poorly depending on the luck of the draw. I’ve controlled for all of these confounders in my analysis.
The one big thing I didn’t control for was the percentage of patients presenting with a given infertility diagnosis. I attempted to to this in an earlier version of the project but had weeks and weeks of nightmares trying to find some defensible way to deal with the large amount of censored data present in spreadsheets. Supposedly the CDC censors these values to protect patient privacy. This justification is obviously nonsense; they still have uncensored values from before 2018 on their website. I emailed to ask if I could apply for some kind of special access as a researcher and was denied.
I tried to work around these missing vaues but eventually I simply gave up. I had to make too many unjustified assumptions to compute clinic rankings, and ranking was highly variable depending on which assumptions I made.
So this final analysis controls only for maternal age, use of patient’s eggs (vs donor eggs), percentage of retrievals conducted with the intention to freeze embryos or eggs (obviously those people aren’t going to have a baby), and some bayesian averaging sprinkled in on top to differentially bring clinics with low retrievals/year more towards the mean of all clinics.
I plan to actually publish my results in proper academic setting at some point, so this post contains only the headline numbers.
Without further ado, here are the top 25 IVF clinics in the US as of 2020.
The best IVF clinics in the USA
|Clinic Name||Adjusted Live Birth Rate||Clinic State||Phone Number|
|Carolinas Fertility Institute||0.516123||North Carolina||(336) 448-9100|
|The Georgia Center for Reproductive Medicine (no website)||0.490339||Georgia||(912) 352-8588|
|Reproductive Gynecology & Infertility-Westerville (Columbus location)||0.482645||Ohio||(614) 895-3333|
|Reproductive Medicine Associates of New Jersey||0.458511||New Jersey||(973) 971-4600|
|Center for Reproductive Medicine, Advanced Reproductive Technologies||0.457538||Minnesota||(612) 863-5390|
|Missouri Fertility||0.456779||Missouri||(573) 443-4511|
|Spring Fertility (San Francisco location)||0.446066||California||(415) 964-5618|
|CCRM Boston (main center in Chestnut Hill)||0.439929||Massachusetts||(617) 449-9750|
|SpringCreek Fertility (Dayton location)||0.437458||Ohio||(937) 458-5084|
|Duke Fertility Center, Duke University Medical Center||0.419579||North Carolina||(919) 572-4673|
|New Direction Fertility Centers||0.413924||Arizona||(480) 351-8222|
|Shady Grove Fertility Colorado||0.411165||Colorado||(720) 704-8221|
|Center for Advanced Reproductive Medicine||0.409579||Kansas||(913) 588-2229|
|Fertility Center of the Carolinas||0.406704||South Carolina||(864) 455-1600|
|Fertility Center of San Antonio||0.403583||Texas||(210) 692-0577|
|Baystate Reproductive Medicine||0.403039||Massachusetts||(413) 794-1950|
|University of Iowa Hospitals and Clinics, Center for Advanced Reproductive Care||0.401587||Iowa||(319) 356-8483|
|Carilion Clinic Reproductive Medicine and Fertility||0.400715||Virginia||(540) 985-8078|
|Advanced Fertility Center of Chicago||0.399771||Illinois||(847) 662-1818|
|Shady Grove Fertility-Richmond||0.394682||Virginia||(804) 379-9000|
|Fertility Center of Southern California||0.391824||California||(949) 955-0072|
|Northern California Fertility Medical Center||0.390555||California||(916) 773-2229|
|The Nevada Center for Reproductive Medicine||0.390344||Nevada||(775) 828-1200|
|Center for Advanced Reproductive Services (Farmington Location)||0.388567||Connecticut||(844) 467-3483|
For reference, the average adjusted live birth rate for all clinics nationwide was 0.278.
How predictive are an IVF clinic’s past success rates of their future success rates? Here’s a graph showing how well a clinic’s 2019 live birth rates correlated with their 2020 live birth rates after adjusting for the confounders I mentioned above:
It kills me that I can’t show you the correlation between 2017 and 2020 success rates, since that would do a much better job of answering the question “How predictive are 2020 success rates for 2023 outcomes”. But for a bunch of boring reasons I won’t get into, tracking clinic performance over 4 years has been very hard. I’ll try to update this post with the data once I get it.
In the meantime, here’s a graph from AN ENTIRELY DIFFERENT RESEARCH PROJECT I DID AND THEN THREW OUT showing how the performance of the top 50 clinics in the SART database (which also tracks IVF clinic live birth rates) varies over the years.
Suggestion #3: Use a good PGT lab
TL;DR Use Genomic Prediction for aneuploidy testing. They very likely have lower false positive and false negative rates for embryo aneuploidy when compared with other PGT labs, and I believe they have lower per embryo costs than Orchid.
It is a little known fact that there is a significant difference in aneuploidy false positive and false negative rates between PGT labs. To the best of my knowledge, there have been no randomized control trials comparing PGT labs. The best we have are independently conducted retrospective cohort analyses.
Unfortunately most of these analyses do not disclose which labs are being analyzed, making them completely useless for paients. However, I happen to know which clinics are which for one particular study submitted to ASRM in 2021. In this study, clinic A is Igenomix, clinic B is Genomic Prediction, and Clinic C is Cooper Genomics.
There’s a lot of sort of random statistics thrown out in this presentation, but I’d like to focus on those most relevant to achievable births: aneuploidy rates, pregnancy rates and miscarriage rates (which they break up into early and late miscarriages in the study)
If you watch the video, you’ll see that “Lab B” is either as good or significantly better than the other two labs in the study across virtually every metric. If you add up the impact of these metrics, here’s what the expected number of achievable births look like for each clinic from the study:
Caption: Note that Genomic Prediction is labelled as “LifeView” on this graph. LifeView is the name of their PGT platform.
It’s lucky Genomic Prediction’s PGT-A testing is so much better because you don’t have much of a choice other than them or Orchid Health. Those are the only two PGT labs that offer polygenic embryo screening.
Suggestion #4: If possible, freeze embryos instead of eggs
This one is short and sweet: if you have a choice, freeze embryos instead of eggs. At a good storage facility using vitrification, about 90% of eggs will survive cryopreservation. At that same storage facility, 99% of embryos will survive. So if you already know who you want kids with, freeze embryos instead of eggs for an easy 10% boost in achievable births.
Suggestion #5: Freeze eggs or embryos as soon as possible
Since expected gain increases the more achievable births you have, all tips for maximizing it revolve around increasing the number of euploid blastocysts you can produce during IVF. You can pick a good clinic, use a good PGT lab, freeze embryos instead of eggs, and follow good prenatal care guidelines. But at the end of the day, the single biggest input variable into the “gain” equation is the age of the mother.
Here’s a graph from another research project I did showing the relationship between maternal age and number of eggs retrieved at three different clinics
You can see there’s more or less a linear decline in expected egg count per retrieval as a function of maternal age. It’s much the same story for expected zygotes and blastocysts; a linear or even exponential decline as a function of maternal age.
If you decide to do polygenic embryo screening, the sooner you start the process the better.
A compendium of other advice
- When choosing a clinic, there’s several things you need to ensure they are OK with before you agree to become a patient
- You need to be able to send your embryo’s biopsies to a lab of your choosing
- They need to be willing to implant an arbitrary embryo of your choice.
- Make sure that the clinic you choose either has reasonable embryo storage costs or will let you ship your frozen embryos to a facility that does. Some clinics charge up to $1500/year for embryo storage and will raise the price on you as time goes on. Cheaper clinics charge under $1000/year for storage (some as little as $500)
- Read Emily Oster’s excellent book about the things you should and shouldn’t do before, during and after pregnancy. Seriously, Oster is excellent and enjoyable to read. Ex: gardening is dangerous for pregnant women due to soil microbes but <3 drinks per week seems to be completely fine.
- If you’re a older man (>40) planning to go through this process, freeze your sperm unless you plan on starting the IVF process fairly soon.
The IVF Loss Funnel
Ok, if we put together all the data above, how many live births can you get per egg retrieval?
Naively interpreted, the above graph would imply that an average IVF cycle would only yield a single achievable birth on average. This is true! The average IVF patient is a 36 year old woman with significant fertility issues, so it’s not particularly common for such individuals to have more than one birth per egg retrieval. In fact, over half of IVF cycles do not result in live birth. The average is dragged up somewhat by the fact that some women are able to have multiple children from a single egg retrieval.
But what if you choose a better IVF clinic and a better PGT lab than average? What if you and your partner have no known infertility issues and your female partner is younger than the average 36 year-old IVF patient (say 32 for this example).
In that case, we'd expect the graph to look something like this:
Looking better! With a younger mother, a top-tier clinic, and no history of infertility, roughly 5 achievable births per retrieval is possible.
How about in the best case scenario? Assume the following:
- The mother is at peak fertility (early to mid 20s)
- Egg retrieval is performed using conventional IVF hormone treatment
- The father is young-ish (under 40)
- Neither parent has any infertility issues
- The parents use a top-tier clinic that is very good at culturing eggs into blastocysts
- They use a top-tier PGT clinic with a very accurate aneuploidy test
- The eggs are fertilized immediately and the resulting blastocysts were frozen
In that case, things start to look A LOT better.
The numbers above are based on a combination of sources including SART data on miscarriage and transfer loss rates, podcast episodes, publicly available data from egg donor clinics, and my own knowledge of the IVF industry. I suspect that it may be somewhat conservative for couples without infertility since I have used the infertile transfer and miscarriage rates. But they should nonetheless give a fairly accurate view of the loss funnel.
One last topic I shoud address; how much will all of this cost?
How much does IVF and PGT cost?
IVF is expensive. To do polygenic embryo screening you’ll need to pay for a consultation, ultrasounds, transportation to and from the clinic, IVF services like lab techs, medication, pre-implantation genetic testing, and data analysis services to select for non-disease traits.
I’ve called a couple of dozen top-tier IVF clinics on the phone to ask about prices. I’ll give you a general cost estimate based on those calls:
|Service||Price Range||Modal Price|
|Egg retrieval (not including transfer)||$6000-20,000||$14,000|
|PGT-P||$1500-5000||$1000 + $400/embryo|
|Selection for intelligence, height, etc||???||Best guess: $20,000. But I am highly uncertain here.|
|Total||$9000-$35000||$26,500 + intelligence screening|
This process is not cheap. If you want to do two egg retrievals and select for intelligence you’re looking at a minimum of $50k and possibly much higher depending on how much the secret startup charges for their services. This is one of the things I hope we can fix in the coming years.
Polygenic embryo selection can currently increase your child's quality-adjusted life expectancy by 1-4 years, decrease their risk of various chronic diseases by 10-60%, increase their IQ by 2-7.5 points, increase height by up to 2.25 inches, and moderately improve other traits. The exact gain you can expect to get for each of these traits varies depending on the genetic correlation between the traits, the number of embryos you have to choose from, and the strength of the predictor used to select embryos, as well as simple luck. Subsequent children will see a somewhat smaller but still positive benefit, though for every child to benefit you will need at least 3x the number of euploid embryos as you want children.
To get these benefits, you will have to go through IVF and genetic testing of your embryos, which will cost $20k-$60k (and perhaps more depending on whether you want custom testing) and require the female partner to take 2-6 weeks off work.
You can increase the expected gain by choosing a good IVF clinic, choosing a good PGT Lab, freezing embryos instead of eggs, and beginning the process as soon as possible since younger mothers produce significantly more eggs than older mothers.
The IVF process is not particularly pleasant, and is expensive to boot, if you and your partner are willing to put up with the discomfort and expense it you can give your children advantages that are impossible to get any other way.
If you freeze embryos now, the expected gain will increase over time as the genetic predictors used to select embryos improve, and the panel of traits which you can select for will also increase.
There are technologies on the horizon that will allow for significantly greater gains across all heritable traits, making possible gains of 4 or more standard deviations across multiple traits simultaneously.
If AI doesn't destroy the world first, the next 30 years will likely see the greatest crop of geniuses and athletes the human species has ever produced. If we are wise and select for traits like kindness, altruism, and happiness in addition to health, attractiveness and intelligence, the children born with these benefits may be able to guide the human species through the incredible upheaval and instability we are likely to see over the next century.
Thank you, this is a great post. A few questions:
Yes. My understanding is he knows some groups that have a working IQ predictor and are accepting customers.
Genomic Prediction no longer offers an intellectual disability predictor. They got huge blowback when they first released that predictor and removed it from their traits as a result.
I do not believe that you'd expect to get much of an IQ bump from selecting against disease risk either. My guess is less than 1 point from 10 achievable births.
Sorry, I should really go back and edit the post to make this clearer. To the best of my knowledge Genomic Prediction (and possibly Orchid) are the only companies that can genotype your embryos with reasonably good quality and will give you the raw data. This is the part that (probably) costs about $1000 + 400 per embryo.
You then have to take that raw data to a third-party service (probably one of the groups that Jonathan knows) and ask them to predict the IQ and/or other traits. I don't know anything about the groups, but I'd be shocked if they're doing this for free. So they will charge an additional amount, which is where my estimate of $20k came in. I don't actually know anything about their prices so that's a complete shot in the dark for what it costs.
But given it's a low-volume service at this point, my guess is it's quite expensive.
Great post. Thank you. Fertility doctor here and a supporter of ART (assisted reproductive technologies) in general. A few thoughts (although you touched on a few of these below, worth emphasizing in my opinion):
I made my reply to your comment into a standalone post
My partner and I put some effort into benefits from polygenic screening, but alas weren't able to make it work.
Quick details: we had IVF embryos created and screened for a monogenic disease, (1) this didn't leave us with enough embryos to choose anything, (2) our embryos were created and stored by UCSF clinic, and any screening would have required transferring to another clinic which would have been time consuming and expensive. Unfortunately two rounds of IVF implantation were unsuccessful, so notwithstanding the monogenic disease risk (unclear how bad it'd be), we'll be trying the natural route.
My guess is the whole process goes better if you plan it from the start and choose a clinic accordingly, unlike us who used UCSF without realizing the impact that'd have.
Sorry to hear your IVF process didn't work out. UCSF was in the top 59% of clinics nationwide in 2020 and the top 38% in 2019, so while the clinic you chose may not have been the best, you at least didn't pick a bad clinic.
Your experience is unfortunately fairly common among IVF patients. Most parents using the procedure are just hoping for at least one child through the process, and many don't have enough embryos to even consider polygenic screening.
I really hope someone does a clinical trial of embryo splitting soon. There's a roughly 50% chance of success using the process in animals. I bet with research we could get it up to 80-90%, which would make it viable for increasing live birth rates among parents who don't have many embryos. That's the type of procedure which would have improved the odds of success for parents like yourselves.
I’ve been wanting a LW article on polygenic screening for some time now, so thank you so much for writing it. I’ll be going through it in detail later. For now, I’d just suggest rewording this:
“The average gene has a tiny, tiny impact on how long you spend in school. The predictor used 2,925 genes to explain just 15% of the variance in how many years of school a person completed.”
Instead of talking about the average gene, consider pointing out that “the most important gene” has only a tiny tiny impact on how long you spend in school. Of course, with 20-25,000 genes, the average gene was never going to be very impactful even if a single gene controlled 100% of educational attainment.
The point about 2925 genes controlling 15% of variance in years of schooling doesn’t support a candidate gene hypothesis - it supports a limited role for genes in controlling educational attainment. Even if just one gene was responsible for all of the genetic component in educational attainment, adding in the other 2924 genes would result in the same 15% of variance explained.
Thanks for the suggestion. I've edited the post.
It may not have saved, it still reads the same way to me (on a different device, so it's not just cached or anything like that).
I think Widen et al. (2022) uses actual sibling pairs/trios (unless I'm misreading?), but a few other studies use simulated embryos such as Lencz et al. (2021)  and Turley et al. (2021) .
 "Utility of polygenic embryo screening for disease depends on the selection strategy"
 "Problems with Using Polygenic Scores to Select Embryos"
If you look at the discussion section they say "Specifically, we validated this index in selection experiments using unrelated individuals and sibling pairs and trios from the UK Biobank."
The graph of relative risk reduction I placed in the post shows reductions among groups of five. They state elsewhere in the paper that there were 969 trios available in UK Biobank, the source of data for the paper. There is simply no way they could have produced confidence intervals as tight as those shown in the graph from real families of five siblings. I would be surprised if there were more than 100 such families in all of UKBB.
Hence I concluded they must be using pseudosiblings.
My estimates for the expected reduction we'd see moving from pseudosiblings to real siblings are pretty rough, but it's based on Figure 7 in the paper where they show the relative risk reduction size between siblings and unrelated individuals. There's a lot of variance in the chart, but it looks like there's maybe a roughly 20% reduction in RRR when moving from pseudosiblings to siblings.
Curated. This post is a feat of scholarship, well-written, and practical on a high impact topic. Thank you for not just doing the research, but writing it up for everyone else's benefit too. As someone who's personally tried for polygenic screening for IQ, etc., I wish I'd had access to this guide last year.
Sorry I couldn't get it out earlier! I meant to release this in June of last year but the research project into which IVF clinics are best turned out to be quite a bit more difficult than I anticipated.
Hi, you suggested freezing embryos instead of eggs. However, a recent study found that frozen embryo babies are 2.5 times more likely to develop cancer. At the same time, a review article on IVF comes to the following conclusion (likely due to epigenetic factors):
This makes me want to consider two points:
Thank you for leaving such a thought-provoking comment. I've spent a couple hours reading through the study you posted tonight as well as others linked to by the authors.
I don't see the claim about a 2.5x increased risk of cancer anywhere though. From the findings section:
So the risk of cancer was 8% higher in those born after ART, and 59% higher for frozen embryos vs fresh embryos.
I think the generally higher disease prevalence among IVF couples probably explains the 8% increase for ART in general, though the 59% increase they see for frozen embryo transfer is surprising.
Looking more into the study it looks like about a quarter of the effect is driven by the higher rates of twin births in IVF, which are much less common nowadays.
This study uses data that is also quite old; they include cycles going all the way back to 1984 or 1994 for some countries. The rate of embryo freezing at that time were quite low, as evidence by the huge difference between hazard ratios for all ART and frozen embryo transfer. If frozen embryos made up a higher proportion of the births you would see a smaller difference between all ART relative to spontaneous conception and frozen embryo transfer relative to spontaneous conception.
Here's another study that found higher risk of neoplasms among embryos that were transferred fresh. Granted, this was a smaller study, so I'd lean towards believing your study.
There's also a graph in the study which seems to show the relative cancer risk for frozen embryos declining over time:
Though this could just reflect fewer twin births. And the confidence interals are such that it's hard to be certain the effect is real.
Another possible confounder here is maternal age. The average age of mothers in ART were older than those in the spontaneous conception group by about 4 years. You can see in this study that maternal age is significantly associated with higher childhood cancer risk. So this could explain another 5-10%, particularly if the age of mothers in the frozen embryo group was higher (I didn't see a comparison in the study but I could have missed it).
Still, there remains a chance that freezing embryos does increase childhood cancer risk. The absolute risk increase is still quite small: about 0.2% up to age 18. Though I suppose the increase in risk for adults could be higher?
Overall I'm just not sure what to think. This is one study and my experience with these "association studies" is they never control for confounders. Like what are the indications for embryo freezing and could those potentially account for this difference? Was childhood cancer risk the only thing the authors tested for, or are there other associations they didn't report? I guess I'll update my priors in favor of frozen embryo transfer increasing childhood cancer risk a bit?
Yes, this one seems like a no-brainer to me, regardless of whether or not the effects we see are caused by IVF or merely associated with it by virtue of the parents that need it having higher polygenic risk scores for disease. The fact that PGT-P isn't already universal in IVF is kind of a tragedy. You can avoid like $200k in future medical expenses for like $3-5k. Not to mention the improvement in quality of life that comes with lower risk of obesity, clinical depression, type 1 diabetes and other early onset conditions.
If the effect is indeed real, I would happily take a .2% increase in childhood cancer risk for +5 IQ points. I don't think that level of increased risk is really much of an issue for most parents. The much bigger issue is the cost of doing IVF. At $30k minimum, this is an expensive procedure.
I'm relatively confident there are at least a few tens of thousands of parents in the US who would do IVF for the purposes of these benefits if they knew this was possible. But for the time being with the benefits being relatively minor, the vast majority of parents will of course opt for natural birth.
With a better predictor capable of +5-13 IQ points I think that number will expand significantly. And if we can lower the cost of IVF I expect it to expand much farther. But we have to start somewhere.
It's probably morally imperative that all parents who have the financial means to do this do it.
I think it’s morally important that we make this choice increasingly accessible, and fight any bigotry against children born with this method and bigotry against their parents. It would take a pretty niche moral stance and cost benefit analysis to make this morally imperative.
I suspect bigotry against children born this way would not work, just because they would be impossible to identify. (Presumably most of them would not even know themselves).
Although a future world where someone says: "phwa! You are only smarter and hotter because of gross polygenic screening your parents cheated into you." Reply: "But, I am a lonely child selected from 4 embryos, you have 4 less successful siblings, so you are more selected than I am."
Yes, I might write later about how to make this cheaper. Though what I would write may have limited relevance, as I expect gene editing methods to surpass simple embryo selection within the next ten years.
I'm not quite sure I would agree with this yet, though I can see the case being made for it.
I think it mostly comes down to how much you think you can improve worldwide outcomes by increasing the abilities of those at the top vs bringing up those with the least.
Iodine supplementation in the developing world, for example, is probably the single most cost-effective way of increasing average IQ per capita worldwide. It also helps prevent other problems like hypothyroidism.
So if just increasing IQ per capita is your goal, polygenic embryo selection is not going to come anywhere close to iodine supplementation.
Of course, iodine supplementation is not going to give you any more geniuses, and geniuses per capita has an incredibly strong impact on human progress.
I really, really wish we could just ban AI improvements and focus on enhancing human intelligence and morality for a few decades. The reason I originally became interested in embryo selection was that I thought that genetic engineering might be a potential solution to the alignment problem (not to mention many of the other problems the human species faces). But it's going to take at least 20 years to work (and realistically more like 30-40) to have a large impact. I'd put the odds of us getting to AGI before that at like 90%. The only path I can see now involves a worldwide ban on AI capabilities improvements.
Suppose a family values the positive effects that screening would have on their child at $30,000, but in their area, it would cost them $50,000. Them paying for it anyway would be like "donating" $20,000 towards the moral imperative that you propose. But would that really be the best counterfactual use of the money? E.g. donating it instead to the Against Malaria Foundation would save 4-5 lives in expectation. Maybe it would be worth it at $10,000? $5,000?
Although, this doesn't take into account the idea that an additional person doing polygenic screening would increase its acceptance in the public, incentivizing companies to innovate and drive the price down. So maybe the knock-on effects would make it worth it.
Okay, I've heard that this scale of donations to short-termist charities is actually a lot more complicated than that, but this is just an example.
I mostly agree with this perspective with regards to the "moral imperative".
But apart from that, it seems to me that a good case can be made if we use personal health spending as a reference class.
Even if we only consider currently achievable DALY gains, it is quite notable that we have a method to gain several healthy life-years for a price of maybe $20,000/healthy year (and actually these gains should even be heritable themselves!).
I do not know the numbers for common health interventions, but this should already be somewhat comparable.
update: Quick estimate: US per capita health spending in 2019 was $11,582 according to CDC. If the US health spending doubles life expectancy compared to having no health system, this is comparable to $20,000/healthy year.
This may be an overstatement. I think the moral minimum looks more like "bring children into the world in a way that's consistent with the value system you plan to teach them and hope that they live by".
If you want to teach a value system of global optimization, where every dollar should be spent to have the maximum possible impact to global quality of life, you're probably adopting rather than conceiving anyways... but this great an investment into a single individual is likely inconsistent with those values.
If you want to teach a value system of local optimization, where every person ought to first do what's best for themself and their loved ones before attempting to intervene in the lives of strangers, then it might be inconsistent to gamble with a family member's lifetime wellbeing when you could instead have stacked the odds in their favor.
I think this is incorrect. Behaviors and talents are to a large degree heritable. If you want future people to share your values, one of the best ways to do that is to have kids who are disproportionately likely to share those values.
And while you can of course attempt to teach your kids your values, genetics plays a major role in determining what kinds of values we adopt.
This is one of the major reasons why "not having kids because of climate change" is not just ineffective but actively counterproductive; it ensures there are less people in the future that will be willing to make large sacrifices for the good of the whole.
I agree that many behaviors are heritable, but I model that inheritance as emerging from the intersection of genetic and environmental factors. I hadn't previously considered generalizing from genetic behavioral proclivities to what values people hold.
Could you point me toward the data from which you've drawn this conclusion? I imagine that there are enough adoptee studies in the world to point at a link pretty conclusively if one exists, but I'd also like to skip straight to the most applicable ones if you could recommend them.
Political attitudes seem to be about 30-70% heritable. Interestingly, people's genetics seem to have a stronger effect on their attitudes the more politically engaged they are.
"Moral imperatives" is not a category that relies upon financial means. Moral imperatives in traditional Kantian framework are supposed to be universal, no? Just because some action could be personally and socially very beneficial doesn't make it morally compulsory. The benefits would have to be weighed against opportunity cost, uncertainty, game theoretic considerations, and possible contrary moral systems being correct.
A great overview, thanks for writing it! I think it will help a lot of people. I suggest a few corrections though:
SNP genotyping doesn't use next generation sequencing, it uses microarrays. (Also it's more properly called genotyping not sequencing)
I should note, in some cases embryos with aneuploid cells in the trophectoderm actually have a mixture of aneuploid and euploid cells, and the euploid cells can successfully grow into a healthy embryo. So an aneuploid trophectoderm biopsy doesn't necessarily mean the embryo is not viable. (Although it does provide some evidence for that.)
Thanks for the correction
Sorry I may have deleted your response to my mosaicism comment when I merged it with this one. I agree that it's controversial.
Given that this is still fairly underground with all the secret startups, contact Jonathan etc, how should this impact on deciding to do this sooner rather than later? From reading this, it seems like this is not particularly difficult to do in 2023, providing you know where to look, and will likely get easier in the next few years.
My concern is that as this becomes more widespread, sociopolitical pushback will cause it to become more difficult/costly/less effective, either through social pressure or regulation. You have mentioned already that companies have removed certain predictors; I suspect that this is just the beginning, and more obstacles will appear as this becomes more widely known among the public.
From this perspective, I would argue that people should plan to do this in the next few years, while it is comparatively unknown/unregulated.
I actually see things going the other way: about 30% of Americans already support gene editing for intelligence enhancement, and almost 50% support embyro selection. My prediction is this tech will gain widespread acceptance.
IVF was pretty unpopular when it first came out, but over time as people came to see that the children born via the process were normal, it became much more acceptable to the point where nowadays it's kind of weird to view IVF as immoral.
Embryo selection for health, intelligence and happiness is completely consistent with our existing values. And it's not scary in the way eugenics is because you don't need top-down government control of reproduction for it to work.
If we just ignore AI for the moment (or assume progress slows down a lot due to regulations/restrictions), I predict the fight is going to shift towards cost and access. People are going to be upset that rich people are securing an advantage for their children that they can't afford.
But regardless of whether it becomes popular or causes a backlash, it makes sense to freeze embryos NOW. Female age is the single biggest predictor of gain for a fixed price, so the sooner you go through the process the better.
Do you mean "natural pregnancy?" Aneuploidy generally results in miscarriage, which we don't call a "natural birth."
Yes, thanks for the correction
Thanks for this awesome post. Biggest update for me is "there might be a way to get screening for traits not advertised by Genomic Prediction", but I still have no idea of the cost or the probability of success :-) Would be great to hear from people who have more info on this.
I recently weighed the pros and cons of IVF vs old-fashioned conception and went old-fashioned because:
1. This article claims "different embryo culture media give rise to different birthweights and growth patterns in children" and "children born after ART have altered epigenetic profiles". I'm not an expert but I read it and found it quite plausible that there are ways that IVF can cause worse health outcomes. Very hard to tell without randomized trials, and all trials on IVF vs non-IVF are going to be heavily confounded.
2. My child would be only 1/4 European ancestry and as you note the current predictors perform worse on non-Europeans. If we had good predictors for my child's ancestry mix, then I'd probably go with IVF despite the possible downsides I noted above. Hopefully the new bio-banks you cited will enable that soon.
I wrote the section on cost to give you a better idea of the prices involved. Hopefully that's helpful.
But I take your point that what is really needed is a “calculator” of some sort where you can input relevant variables and see your expected gains and costs. I am working on something like this at the moment but it may be several months until it's finished.
Apart from the randomized control trial looking at different embryo media, I find all the studies presented in this paper to be highly suspect. For example they cite showing that fresh embryo transfer is associate with preterm birth. But the study THEY cite doesn’t even control for the differences in maternal age between parents that do IVF and those that don’t!
And surprise surprise, there is a major difference in PTB rates between women in their late 20s and early 30s and those in their late 30s to early 40s.
Perhaps I am wrong about this, but my best guess right now is that the downsides of doing IVF are very minor and are massively outweighed by the upsides of embryo selection. The cost is still a big barrier, so I can understand if you don't do it for that reason.
Yes, this is still a problem. For IQ gain in particular though the difference is not that big. I believe east and south asians, for example, have an expected IQ gain of about 75% that of Europeans (so like 3.5-4 points vs 5). Maybe that's a big enough difference for it to not be worth it, but it's not a huge reduction.
I think you should mention that traits tend to be correlated. Genomic Prediction has a company policy of not telling you the polygenic scores for height, education attainment, or even cosmetic traits like the eye color of the embryo (this last one can be nearly 100% accurate). Understandably, they don't want to be accused of being an eugenics shop. However, there's strong correlation between height, education attainment, and lower mental disease risk. If you optimize for lower disease risk and height, you will get high education attainment as a by product.
Explicitly screening for IQ is what we want. I don't know when this will happen without all the associated baggage from people who won't even accept the very concept of behavior genetics.
Hm. I wonder if there are people who simultaneously say that genes don't affect behavior, and also say that genetic screening is bad. Seems like a near-contradiction, but I suspect there are such people.
You're right. I'll edit the original post. I originally didn't include it because i couldn't quantify it that well, but it's worth at least mentioning.
Again, if you read the post I believe there are probably groups doing this right now. If you're interested in using the service right now you can talk to Jonathan Anomaly as he seems to know how to get in contact with them.
I should note, in many cases embryos with aneuploid cells in the trophectoderm actually have a mixture of aneuploid and euploid cells, and the euploid cells can successfully grow into a healthy embryo. So an aneuploid trophectoderm biopsy doesn't necessarily mean the embryo is not viable. (Although it does provide some evidence for that.)
Yes, I thought about mentioning mosaicism but it's such a can of worms with so much debate in the PGT research field that I just left it out.
My reading of the research suggests that mosaicism is far less common than the average PGT test would suggest. Here's a well done study from 2021 in which the authors took apart 942 embryos and found the true rate of mosaicism to be 3%.
Most PGT labs diagnose mosaicism at far higher rates: 5-15% at most labs. My impression is this is mostly an artefact of noisy, low-density NGS sequencing technology and/or contaminated samples.
It's also worth noting that we have a single digit number of examples of "mosaicism" in actual people, which suggests to me that there's either differential apoptosis of aneuploid cells during embryonic development, or that mosaicism is almost always lethal.
As a newbie to this intriguing topic, I have various questions:
There's about 4-5 million letters in the genome where at least one percent of humans have a different letter at that location. That's compared to 3 billion letters overall.
Another way to look at genetic differences is to pick a random pair of humans and ask how much they are likely to differ. The answer is by about 3 million base pairs.
That's not my impression from reading the literature. There was some giant analysis of educational attainment done last year which found literally zero gene-gene interactions. But I'm not a deep expert on this subject.
For intelligence? You can probably get to 1/3rd of variance explained just using SNP arrays like they collect for 23&Me. With whole genome sequencing and more samples you could probably get up to 45%, maybe higher.
Gwern has written quite extensively about this.
This is not a theoretical assertion but an empirical one. We have studies on educational attainment with like 3 million participants now that have shown ZERO gene-gene interactions. They definitely exist, (at least for other traits) but according to the authors I guess you need an even larger sample size to identify them. Given how little they expect to improve the predictors power by increasing the sample size, one can infer that these interactions, if they exist (and they surely do to some extent), just don't explain very much of the variance. (Ctrl+F for "epistatic interactions" in this paper)
Ok. I guess that, for two random humans, you expect almost all 20000 genes to differ at least on a letter, right?
Ok, but this shows that your models do not see the non-additive effects, not that there aren't any. I don't know exactly how analyses are done, but assuming they look at interactions with a model like y=β0+β1x1+β2x2+β12x1x2, then they would not pick up the α term in my example because of the hash (the "hash" stands for any very granular and nonlinear function).
But actually I think that it would be very weird to have such "stenographic" interactions only, without also simpler ones, so I'm satisfied with your answer.
Many of the differences between human genomes are actually in "promoter" regions. For a gene to be synthesized into a protein a little enzyme has to come over and bind to a spot next to the gene and transcribe the sequence into mRNA.
Other differences are in regions that don't seem to affect traits at all. There's a lot of leftover DNA in our genomes from endoviruses, transposons and other events in our evolutionary history. Sometimes the DNA in those regions randomly mutates into something useful and evolution will start acting on it.
One thing I didn't see on perusal was a reference to the length of time some of these paths might take.
I know this could vary extremely according to each person's desired timeline w/r/t keeping embryos frozen and determining the right time for implantation, etc.
But from a naive standpoint, saying that someone wanted to have children quite soon otherwise, how long might one expect to spend going through the "average" or "optimal" path doing this?
There's generally a waiting time of 1-3 months for initial consultations, and another 1-2 months of checkups, hormone treatments and transfers. So 2-5 months before you can actually transfer an embryo, and another 9 months until birth.
EDIT: An earlier draft of the post failed to account for the cost of medications in the price of IVF and subsequently understated the expected cost of IVF by $4000. The costs table has been updated to reflect the changes.
Well this certainly opens a window I hadn't really thought about before. Very intriguing stuff (have only had time to read over the "Concrete Advice" section, but it was a great overview). Not sure I would totally utilize this at the moment (the cost being a major factor), but I have no doubt this kind of thing will get more prevalent and less expensive as time goes on.
I'm wondering if others are having a bit of cognitive dissonance like myself with the taint of eugenics lingering in the air? This quote
definitely reminded me of some of the complications of this kind of thing in practice...
Yes, I agree that cost and disparities in predictor strength between genetic ancestry groups are probably the biggest issues with polygenic screening at the moment. I didn't mention this in the post, but the issue with disease predictor disparity should improve significantly in the next year or two. There are two large biobanks coming online with significant numbers of non-European participants; The Taiwan Biobank and the "All of Us" biobank in the USA. These should at least reduce the disparity in disease predictor strength, though it remains to be seen whether either one will actually collect data on cognitive phenotypes.
I think we need a new term to describe "genetic improvement" that includes embryo selection and people choosing who to reproduce with but not state-sponsored sterilizations or genocide. The fact we use one word to describe both of those is crazy. It's like using "stuff" to refer to both food and excrement.
"Oh yeah the stuff I got at the restaurant was good, but stuff isn't always good so eating there made me a bit nervous"
Aella girl has suggested the term "epilogenics". "epilogi" is the greek word for "choice", so we can use that instead of "eu" which means "good". I quite like this term and will be using it from now on.
So yes, I strongly oppose many types of eugenics but I am strongly in favor of epilogenics.
Yeah I tried to invoke the notion I had that there was this almost ephemeral, tenuous connection between this "stuff" and eugenics. Not trying to imply a direct line of similarity by any means. And I agree that new terminology is needed to distinguish and make useful which aspects society is willing and able to allow vs. not.
I'm glad more biobanks are coming online! I could imagine this increasing by an OOM over the next 5-10 years?
Do you have a source for the misconception being common?
No. This is drawn from my own personal experience reading comments by otherwise knowledgeable academics or professionals in the ART industry. It's also something I read online a lot in forums such as reddit. Inevitably one of the top comments on most articles about human genetic engineering is along the lines of "we don't understand anywhere close to enough about genetics to make the proposed changes".
If this is really important to you I can probably find some examples.
Neither of Einstein's parents were Nobel laureates;
his father was a salesman, his mother was a pianist (among other talents).
This is not meant as a literal statement. I'm just trying to convey that the magnitude of benefits is still rather small.
There are obviously many examples of geniuses who didn't come from unusually impressive families.
Shouldn't this be triplet birthrates? Twin birthrates look pretty stable in comparison.