Should I delay having children to take advantage of polygenic screening?

  Answers
    52 GeneSmith
    18 Scott Alexander
    14 Dagon
    9 Ericf
    8 Srdjan Miletic
    8 Walkabout
    1 David Hugh-Jones
    -2 Bazza
None
4 comments

answer by GeneSmith · 2021-12-21T04:30:46.790Z · LW(p) · GW(p)

TL:DR: If you're female you should consider freezing your eggs and if you're male with a female partner you should consider talking to them about freezing their eggs. You should probably do this regardless of whether you want to wait for the technology to improve. The process will cost about $40k-50k for the first kid with today's prices, and probably $10k/kid after that. The benefit will be at least a year or so of increased life expectancy per kid, a decrease of heart disease, diabetes, and various cancers on the order of 10%-40%, and possibly increased IQ of somewhere between 0 and 10 points even if you don't directly select for it (due to positive pleiotropy).

Here are some more details:

A BASIC PRIMER

So right now we have a bunch of Genome Wide Associate Studies (GWAS) that look at single letters in the genome and how strongly changes in those letters are associated with some trait of interest. These GWAS can usually explain 10-15% of the variance in a given trait, with some notable exceptions such as height, where we can explain >40% of the variance.

I think the two potential benefit of waiting to have kids would be seeing an improvement in the percentage of variance explainable by polygenic scores and having a broader set of traits from which to choose.

WHAT IS AVAILABLE NOW

The only company I know of actually offering polygenic screening available to the general public is Genomic Prediction. Their trait panel is entirely focused on common diseases like heart disease, cancer, diabetes and a couple of others. Let me first give a summary of the cost-effectiveness of this type of "disease reduction" screening.

The implied "variance explained" by the reductions shown in their genomic index is actually quite impressive for some of these diseases. Let's use their original preprint from here: https://www.mdpi.com/2073-4425/11/6/648/htm

I used Carmi et al's code from "Utility of polygenic embryo screening for disease depends on the selection strategy" to estimate the implied variance explained given those reductions and come up with predictors able to explain about 40-50% of variance for Type 2 Diabetes, Heart Attack and Coronary Artery Disease, and slightly lower for Hypertension and the others.

Those are very impressive numbers. Most stand-alone predictors explain less than 15% of variance. This implies that either Genomic Prediction's numbers are wrong, or there's something really amazing going on in genomic indexing: somehow selecting against multiple diseases is straight up better than selecting for a single disease, even if you only care about a single disease.

Part of this might just be a result of sample size: when your coronary artery disease predictor is trained on one population and your hypertension predictor is trained on another, there's probably some kind of pooling effect going on. But given that most of the data for these predictors seems to come from UK Biobank, there's also a more profound implication to the reductions shown in their panel: it seems likely that most of these clinically distinct disease are all manifestations of some underlying "health factor", and that health factor has a strong genetic basis. Some genetic variants increase your risk of many many diseases. If that was not true, you would not see simultaneous reductions of this size across so many diseases. And my bet is there are reductions to diseases not even shown on the panel. What a crazy thing to discover while researching a LessWrong post reply. This is probably worth a whole post.

EDIT: I found a study that replicated the strong positive pleiotropy effect shown in Genomic Prediction's index: https://www.researchgate.net/publication/323614487_Improving_genetic_prediction_by_leveraging_genetic_correlations_among_human_diseases_and_traits

"For six additional phenotypes in the UK Biobank data, we find increases in prediction accuracy ranging from 0.7% for height to 47% for type 2 diabetes, when using a multi-trait predictor that combines published summary statistics from multiple traits, as compared to a predictor based only on one trait."

This is actually incredible. My interpretation is that there's not only a general factor g for intelligence across cognitive tasks, but also an h factor for health across multiple diseasees

Anyways, the implication for you question here is that current DISEASE predictors are already very very strong. Explaining 40-50% of variance from a predictor is incredible. That's probably getting close to the limit of heritability for some of these. So for heart disease, diabetes, and some types of cancer, we're probably nearing the limit of what polygenic predictors can explain and there is not much point waiting for them to get better. Right now you could probably simultaneously decrease the risk of many of these diseases by 70-80% by selecting among 10 embryos.

WHAT ARE THE BENEFITS OF WAITING?

Disease predictors are not nearly as good for non-European populations. I believe they the second best predictors are for South Asian, followed by east asian and then African. If you or your spouse trace your primary ancestor to one or multiple of those groups, it makes more sense to wait. Predictors for those of African ancestry in particular have substantial room for improvement.

The second caveat is about selecting for non-disease traits. This community has expressed particular interest in selecting for intelligence, though there are obviously other non-disease traits such as conscientiousness or mental energy that are also important.

There is substantial room for improvement in our intelligence predictors. Right now you could likely pay a PHD student <$10,000 to construct an intelligence predictor for you based on the Education Attainment Study #3 that would probably explain about 20% of variance in intelligence. If you had 14 euploid embryos to choose from and 70% of those implant, you would expect your first child to have an IQ about 4-5 points higher than the average of you and your spouse/partner.

Steve Hsu, one of the leading researchers in this field, has estimated that we would be able to explain 50-60% 30-40% of the variance in cognitive ability if the UK biobank simply offered their existing intelligence test to the 90% of BioBank participants who haven't taken it. That would raise the expected IQ gain from selection among 14 embryos to ~9.5 points, which would perhaps be worth waiting for, though it's not clear when or even if UK Biobank will do that. And since most of the biobank participants are European, the benefit might be somewhat smaller for other ethnicities.

So if you and your spouse are both European, you used normal IVF with multiple rounds of egg extractions and improved predictors would be a gain of about 13 IQ points. And since you probably wouldn't select exclusively for IQ (disease are important too), I'd guess a more realistic gain would be about 10 points.

Also paying that PHD student to make the intelligence predictor might get all research into the genetic roots of intelligence banned, so consider that a major possible downside. Though if it wasn't banned you could distribute it to anyone who wanted it and everyone doing IVF could have children 3-10 IQ points above their parents.

Then there's the question of all these other important traits that we don't even have predictors for, like conscientiousness, mental energy, performance while sleep-deprived and whatever else you value. I haven't researched these other traits in depth too much, but it seems like there's a lot of other important stuff that fall into this bucket.

Here's a GWAS looking at neuroticism that found 190 genes associated with the trait at 2.5*10^-5. https://www.nature.com/articles/s41598-021-82123-5#Sec2

Funny anecdote from the study: the associated genes were found to modulate behavioral response to cocaine. The authors don't say what percentage of variance is explained by those 190 genes, but my guess is it's in the neighborhood of 5%. So if you waited 5 years to have kids, these predictors of personality traits would almost certainly improve, probably to somewhere between 15% and 40%.

I can't find a single GWAS on mental energy. Why has no one looked into that yet?

A similar improvement is likely to happen for many of the other predictors, particularly those for which people have already done GWAS.

Of course there's one more question you'd have to answer even if you did have great predictors: which of these personality traits should be selected for and how strongly? All else held equal, more intelligence seems to pretty much always be better, and high disease risk seems to pretty much always be worse. Of course you can't necessarily hold all else equal when selecting a for a finite set of traits, but most of the literature I've read about plieotropy suggests that unless you have extremely powerful selection techniques (i.e. iterated embryo selection, gene editing or whole genome synthesis), these are unlikely to be a concern.

But with personality traits I don't yet have a clear mental model of which traits should be selected for and how strongly. I think most parents mostly want to give their child a happy productive life more than anything else, and besides the no-brainers like reducing predisposition to depression and anxiety, it's not entirely clear how to do that.

WHAT SHOULD I DO?

If you would be willing to pay ~$40k to substantially decrease your child's risk of common diseases and increase their lifespan by ~1 year, you should consider doing freezing eggs and doing IVF. And if you're not ready to have kids yet or you want to wait for polygenic predictors to improve, you should freeze your eggs (or talk with your partner about freezing their eggs).

Why freeze eggs? Well unfortunately a woman's production of chromosomally normal eggs gets substantially lower with age. The percentage of eggs that will be "euploid" (chromosomally normal) first increases in the late teens and early 20's before reaching its max around 25. It then slowly declines starting around 30 and really accelerating after age 35. By the early 40's, 80%+ of eggs produced will be aneuploid. The more euploid eggs available for freezing, the bigger a gain you'll get from polygenic screening.

A woman's capacity to actually carry a pregnancy to term on the other hand, lasts well into the post-menopausal period. The oldest mother to giver birth via donor eggs was 74! So by freezing eggs, you can preserve fertility for as much as 40 years.

If you're single and a guy, then there are not really many action items for you. Sperm quality doesn't really seem to decline until about 40, at which point it drops off slowly. The only direct option here would be to get eggs from a donor bank, but if you do that you'd likely have to face the challenges of single parenting. Plus donor eggs cost a few tens of thousands, so it would be quite a bit more expensive.

HOW DO I ACTUALLY DO THIS?

If you're seriously considering doing IVF for polygenic screening, the first step is comparing IVF clinics. Some IVF clinics are 3x the cost of others for essentially the same service. Some IVF clinics have poor implantation cryopreservation and low implantation success rates. So choosing the right clinic will have a big effect on your cost/benefit analysis. Egg retrieval usually takes 3-6 visits from what I've heard, so it may actually be worth flying to another state (or perhaps even another country) to lower the price.

You then have to consider the IVF funnel to figure out how much it's going to cost to achieve a certain reduction in disease risk/increase in healthspan. I really wish there was a tool for this because a lot of factors can substantially affect loss rates. But the basic gist is this: at each step in the IVF process, fewer eggs/embryos come out than go in. The three most important factors affecting the number of embryos you have to choose from are the IVF clinic, the genetic testing company, and the age of the mother.

Here are all the steps that have to be done.

• Medication is taken stimulating egg production

• Eggs are extracted

• Eggs are frozen and unfrozen at a later date (optional but necessary for polygenic screening)

• Eggs are fertilized, turning them into embryos

• Embryos grow to day 5 blastocysts, at which point they are biopsied

• Day 5 blastocysts are biopsied for polygenic screening (and to see if they're chromosomally normal)

• The euploiod embryo with the highest polygenic score is implanted.

• A baby is born

At every single one of these steps, fewer eggs/embryos come out than went in.

If you're 23-28 you'll probably get around 15 eggs per cycle of IVF. According to some random news articles I looked up, 40%-50% of those will grow to day 5 blastocysts (this might be higher if you go to a good clinic and/or don't have fertility issues)

If you're 23-28, about 80% of the embryos that reach this stage will be euploid, meaning they have the potential to implant and turn into a healthy child. The others will either result in miscarriage or have a condition like Down Syndrome if implanted.

When you choose an embryo to implant, there's a roughly 70% chance it will lead to a live birth (lower if you have fertility issues).

So roughly 30% of eggs extracted will lead to a live birth (though it should be noted that the above numbers may not be accurate since my numbers might be wrong a bunch of factors influence the percentage).

That means you need 3-4x as many eggs extracted as you want to select from. At 15 eggs per IVF cycle in good conditions, that's 2-3 rounds of egg extraction if you want 10 embryos to choose from (taking implantation rates into account).

I think egg freezing is about $6k/cycle with genetic testing included. So for 3 cycles, that's about $20k. Then IVF itself is I think like $15k. So maybe $35k-45k all-in cost not including the cost of childbirth, which is stupidly exensive but usually covered by insurance.

It should be noted that there's actually a pretty big gain from selecting from just 2 embryos. Going up to 10 increases the benefit by about 80%, but the gains are still pretty noticable from any selection at all.

Anyways, I hope this was helpful. Let me know if you want me to write a more in-depth post about how to do IVF for polygenic selection.

answer by Scott Alexander · 2021-12-20T03:17:05.962Z · LW(p) · GW(p)

There's polygenic screening now. It doesn't include eg IQ, but polygenic screening for IQ is unlikely to be very good any time in the near future. Probably polygenic screening for other things will improve at some rate, but regardless of how long you wait, it could always improve more if you wait longer, so there will never be a "right time".

Even in the very unlikely scenario where your decision about child-rearing should depend on something about polygenic screening, I say do it now.

answer by Dagon · 2021-12-19T18:57:41.075Z · LW(p) · GW(p)

How old are you, and how long do you propose delaying?  There may be some good reasons to delay having children until late 20s or maybe even early 30s (especially if your economic or social-support structures are likely to improve).  But also pretty strong evidence that earlier is better (especially the mother's age matters statistically for success of pregnancy and health of the child).

Generally, if you're in a position to consider "definitely want kids, unsure whether now or later", the answer is "now".  

answer by Ericf · 2021-12-19T19:09:07.959Z · LW(p) · GW(p)

If you are rich enough to afford a full time nanny, and pay for surrogacy then sure, freeze some gamete and have kids when you can get the genetic testing and have genetically superior offspring.

Raising kids, especially toddlers, is exhausting work best done by the young but mature. So, in the 25-35 age range.

answer by Srdjan Miletic · 2021-12-22T02:42:03.886Z · LW(p) · GW(p)

Are you already committed to a specific person to have children with?

The reason I ask is that who you have children with will have a drastically larger impact on the quality of children you get vs even 100% accurate polygenic screening. If waiting 10 years gets you better polygenic screening but makes finding a good partner (genetics + character/culture etc...) somewhat less likely, then the tradeoff may not be worth it.

(It's still smart to freeze eggs/sperm anyway)

answer by Walkabout · 2021-12-20T15:38:58.212Z · LW(p) · GW(p)

One issue nobody has raised yet is the effects of structural racism.

The GWAS studies used to create the polygenic risk scores generally have a very pronounced sampling bias towards people of European ancestry. See for example the GWAS Diversity Monitor, which is a dashboard meant to monitor the sampling practices used by GWAS studies. In addition to selecting people to sample by ethnicity, an accepted practice is to look at the genomes after sampling and try to identify and exclude "ethnic outliers".

If you or your partner don't have ethnicities that would make your genomes look typical among the samples used to train the scoring algorithm, it's an open question whether any particular score instrument is going to be usefully predictive for you or your potential child. See for example Generalization and dilution of association results from European GWAS in populations of non-European ancestry: the PAGE study, which found that, while many GWAS hits generalize from a very restricted sample, a substantial fraction don't. See also Current clinical use of polygenic scores will risk exacerbating health disparities, which discusses polygenic risk scores in particular, and their accuracy falloff when used on people who the score developers would have excluded from their training set.

Note also that even the papers complaining about this problem are still breaking down their results by very abstract discrete dimensions like "5 continental populations", which sweep a lot of people under a very large rug. If you and your partner have different ethnicities, you get to be on the wrong end of fun lines like this one, from that last paper:

Related to stratification, most PRS methods do not explicitly address recent admixture and none consider recently admixed individuals’ unique local mosaic of ancestry; further methods development is needed.

answer by David Hugh-Jones · 2021-12-19T13:01:06.514Z · LW(p) · GW(p)

In my opinion, as of 2021, no.

1. Our polygenic scores are predictive, not causal. That is, we estimate them by maximizing predictive power in a non-causal setting. They do have some causal effects. For example, about half a score for educational attainment's correlation with EA is causal. The other half is correlated environments, genetic nurture etc.
   In future, sibling-based designs may lead to truly causal scores. I don't know how long that will take. 
2. Scores typically have low predictive power. The R2 of scores for EA is IIRC about 10%. By definition, they will never go above the heritability of EA which is only about 40%. Unless you're prepared to pump out tons of eggs, test them all, and pick the best, you are probably not going to do much to change the phenotype. Again, with larger sample sizes this will eventually change.
3. Polygenic scores are, well, polygenic. They sum up many different genes. We don't know what else they correlate with. You are in effect giving your child a pill with unknown side effects. 
   Maybe in future that won't be true. I don't know how long that will take, but I suspect it will be long because there is a lot we don't know.
4. Having children involves risks. Your child might end up with a terrible disease. Even with all the genetic testing in the world, your child might be hit by a bus and end up quadriplegic. Or they may mature into smart, healthy adults... and embrace values that you find deeply wrong.
   That's not to say you should be casual about those risks. It is to say that you have to accept some risk. Delaying childrearing because in future you might be able to avoid some of this risk suggests that you may not have internalized that. (I only say "suggests". I don't know you!)

If you do want to delay childrearing so you can screen using reliably causal polygenic scores with high predictive power and no risk of side effects, I think you should be prepared to wait 10 years (and maybe more). If so, consider freezing your/your partner's eggs.

There are some good general reasons to delay childrearing:

• Older parents tend to be richer
• Older parents might be wiser 

Both those things benefit children (pace Robert Plomin!) The benefits of older parents are visible in the data (within families, so controlling for obvious differences between early- and late-parenting families). But of course that depends how old, wise and rich you and your partner are now.

answer by Bazza · 2021-12-20T02:38:57.967Z · LW(p) · GW(p)

Selection of embryos based on polygenic scoring is a cute idea but is decades away at best.

Your ability to pick an appropriate partner to conceive a child with has been honed over 100,000's of years (actually, more like 'since sexual reproduction began'). However, it's far from perfect and there are some gross genetic failings (existing and de novo) that genetic screening can recognise that aren't obvious at the everyday scale of day to day living.