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deletedFeb 1
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"psychiatrists are technically neurologists gone weird":-)

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Is Schizophrenia as ontologically defined as the Flu is? There have been plenty of cases of it being misused as a political diagnosis, in the Soviet Union for instance, and even if there's a known ontology it would still be equivocation if it's never clinically tested for and the diagnosis is still only based on symptoms.

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It's necessarily not as ontologically defined, because schizophrenia is a syndrome and the flu is a cause. I think an apples-to-apples comparison would be if it's as well defined as "flulike symptoms", to which the answer is that nobody bothers to define flulike symptoms and they just say "you'll know it when you see it".

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Sounds fake. How do I know that syndromes are even a real class of things, vs a word used to pretend there is a class of things that is conveniently shaped to plug that specific hole in human ignorance.

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To take a wild stab in the dark:

Possibly you could break down a bunch of syndromes into component symptoms, put them in a list, add in other symptoms, collect a huge amount of data from a lot of people as objectively as possible, and see where the clusters are. If infection with the influenza virus is associated with a particular cluster of symptoms, it might make sense to call that cluster "flu-like symptoms" (which may be somewhat different than the cluster we currently call that). If other root causes correlate with that cluster, then it might make sense to take the most common one and use that for the name; it might be "flu", but might theoretically be something else.

Not that we've done that, but it seems like it might be possible?

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I'm sure it's possible. It's just been kind of frustrating to see even celebrated rationalists backslide (or remain?) at the level of showing how a math problem can be solved, not doing the math, then championing a result.

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The mathematician's problem of enjoying the interesting work of proving that a solution exists, but refusing to do the tedious work of coming up with the actual solution? :-)

Practically speaking, I'd worry about falling afoul of HIPAA or an IRB or something, to get that much data.

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Definitely, it's conveniently shaped to plug a specific hole in human ignorance. I think most psychiatrists would probably agree that schizophrenia is a messy concept and it would be great to have less messy concepts, but we're not there yet.

I would encourage you to think of schizophrenia differently, though. I think of syndromes as a way to know who's going to benefit from specific treatments. We have studies showing that, for people who've been diagnosed with schizophrenia, they seem to be less likely to die if they take antipsychotics [1] (modulo a U-shaped dose-response curve, though I suspect reverse causation on the high end, since people with worse schizophrenia tend to end up on higher doses). Obviously, you can disagree with the studies here, but you can disagree with studies about anything; these seem relatively robust compared to a lot of other treatments in medicine.

There are also other benefits to taking antipsychotics in schizophrenia, as well as risks; much ink has been spilled over balancing them, and it's certainly an interesting topic to read about. The same can be said about other treatments for schizophrenia, like psychotherapy or neuromodulation. I will caution that, when interpreting literature in psychiatry, it's important to look at a lot of studies, and look at overall patterns; you will come to incorrect conclusions if you pay too much attention to a single study. But this is a digression.

In other words, schizophrenia is a concept that, among other things, lets doctors find people who will live longer if they give them antipsychotics, and living longer is kind of hard to argue with.

[1] https://academic.oup.com/schizophreniabulletin/article/41/3/656/2375074 - and there are lots of other studies about this question

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When diagnosing a patient, what criteria do you use to decide when to say "this person has schizophrenia", vs "this person has <some different type of brain problem>"?

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https://en.wikipedia.org/wiki/Diagnosis_of_schizophrenia

According to DSM-5, the person has to be experiencing at least two of the following -- either delusions, hallucinations, or disorganized speech -- over much of the time of a period of at least one month.

In other words, by symptoms.

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There's a bit more to it as well, in terms of ruling out other conditions: for example, autoimmune encephalitis can cause symptoms resembling schizophrenia.

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Thank you. Came here to say much the same.

We speak of schizophrenia as if it is a single, well defined pathology (ie. essential nature) when we really still have no basis for such an assertion. The 'diagnosis' being a catch all for a constellation of diverse signs and symptoms with a wide and variable range of expression of largely indeterminate causation(s). (The plurality there - alone- being obvious reason for pause and reconsideration.)

All of which is why we -properly- speak of people having met "criteria consistent with" a diagnosis of schizophrenia. Because, as a matter of fact, we have no warrant to say that they even have the exact same thing. At best we recognize that their particular brain AND mental dysfunctions are being expressed in a recognized and patterned manner.

Dementia is another term often used to describe a clinical presentation with an equally vague and diverse set of conditions yet viewed as somehow being of specific and 'well defined' nature my dint of having been given a name.

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Also, autism is vague in the same way. Or better named "autism spectrum disorder". My daughter is on the spectrum, supposedly, but it took years to get the diagnosis, because she was atypical (as are many girls). I'm still not convinced that that is exactly what is going on with her, but it was a helpful diagnosis for us, since we were then able to get her appropriate therapies, and we could point to her dx to convince people to be more understanding of her differences. Our family participated in the SPARK (genetic) project, but we've never heard from them about any particular gene that they identified in our case. More and more, I am suspecting that the environmental factors that I worried may have caused her disorder, might actually have.

I'm also interested in schizophrenia, since a branch of my family also has several members with that. Scott, have they actually identified the relevant gene/s? How many are there? I'd be interested in getting tested just for curiosity's sake. Are there multiple genes, for example? Could different branches of the family show one or some, and not display the symptoms?

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Im in a similar situation to yours. I have two daughters both w ASD dx, one profoundly so, one much more typically presenting. We did genetic testing on our more effected child revealing no "de novo" or single cause of the ASD. This doesn't mean her condition isn't mostly genetic. It just means the state of genetic counseling is in the practice of finding and communicating very noticeable obvious differences between an effected individual and the general population. Per Wendy Chung (on The Drive with Peter Attia, who was a lead researched in SPARK I believe) says the current guess is there are 1,000 implicated genes in ASD and researchers are maybe 1/3 the way in mapping them all. Interestingly these genes seem to be generalist, which I take to mean if you have an adequate collection of these genes, you're at risk for developing some kind of neurodevelopmental disorder (ASD, ADHD, schizophrenia, depression). The current state of genetic understanding cant yet tell us exactly which condition/s is most likely to develop per se. But I have very little scientific training or understanding so take all that with a grain of salt. Some links that may be of interest:

https://peterattiamd.com/wendychung/

https://www.researchgate.net/publication/358716011_Genome-wide_analyses_of_ADHD_identify_27_risk_loci_refine_the_genetic_architecture_and_implicate_several_cognitive_domains

https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2718628

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I’m surprised that despite a dozen arguments on this list, not one of them is the arguably-correct one: that heritability might be a bad match for human intuitions of what “mostly caused by” means. (e.g. the low concordance probability of schizophrenia in twins, which is counterintuitive. We can respond to this either by saying concordance probabilities are a bad operationalization of “caused by genes,” or by saying the biggest cause of schizophrenia is “shitty luck” or “nonlinear responses to inputs that don’t add up to 1.” Of course, this buys you a whole heck of a lot of other paradoxes instead.)

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author

I thought that was Argument 8.

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Feb 1·edited Feb 3

The concordance is (theoretically) even lower for unrelated people raised in identical environments, so by this logic it makes even less sense to say that it's mostly environmental.

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It's possible for two children in the same environment to have (at least somewhat) different childhoods and traumas, and for one of the children to be more traumatized/abused/neglected than the other(s).

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Polygenic screening doesn't prevent schizophrenia in a meaningful way, though. It just prevents those embryos with high risk from developing into people (modulo your beliefs about when personhood begins).

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That sounds very "meaningful" if you have to select one or two from a dozen one way or another.

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They might each be entitled to an equal probability of selection. It might be immoral to use any method besides RNG to make the choice.

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That seems at odds with how most people would resolve other moral choices.

For instance, in triage situations, it's normally considered good for doctors to treat the person with the best survival chance rather than picking randomly.

Conversely, it's normally considered obligatory for them to treat as many people as they can--it would be pretty weird to have a situation where it's morally obligatory to give an EQUAL survival chance to everyone, but NOT morally obligatory to make that survival chance be as high as you reasonably can. By analogy, it would be weird if you had a free choice about HOW MANY embryos to incubate, but not a choice of WHICH embryos to incubate.

And I have difficulty imagining anyone arguing that you ought to choose the other parent of your child at random, to give all possible potential children an equal chance, instead of having a baby with your spouse. (You could argue that the difference here is that the embryos aren't fertilized yet, and your obligations only start when they are--but that seems to make the objection from the previous paragraph even more acute.)

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If you believe personhood occurs early in embryonic development you shouldn't create superfluous embryos, yes. However, supposing you have already made that error, I don't think assigning equal or near-equal survival chances to each are all that unreasonable. The reductio ad absurdum of your own position would be that if there's some small number of gene combinations that maximize life, all other things being equal ONLY those gene combinations should ever exist. I think most people value hetereogeneity in life to an extent that allows you to leave a large number of QALY's on the table, at which point it's not clear to me that there's an airtight argument for favoring non-schizophrenics over schizophrenics anymore.

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I wasn't trying to promote any specific position, but I notice that the position you have chosen to argue against is "it is OBLIGATORY (not merely permissible) to choose the embryo with more QALYs", and there is plenty of room for that position to be wrong without the "it is obligatory to choose by RNG" position being correct. (Also I'm not sure I buy that your reductio really is absurd, but I don't feel strongly enough to want to defend it right now.)

Re "supposing you have already made that error," imagine a story where, due to some SF/F premise, it is possible to suddenly accidentally create several obviously-fully-developed people, where you meant to create one. In all the stories like this that I can recall, the characters take it as morally obvious that you are now obligated to preserve ALL of the people you created (if possible). I cannot recall a single one where it was suggested that you are morally obligated to choose randomly which one to keep, but are free to discard the rest. I predict that a story where all the characters agreed on that standard would evoke moral disgust in most readers.

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In the absence of some pressing reason why all lives couldn't be preserved, yes, you're right.

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It's possible that RNG selection actually ends up with less heterogeneity in the end! The only acceptable way to choose embryos is to invent metrics of uncertain value or real-world relevance and then laboriously search for the embryo that maximizes all of them (weighted, of course, with the results of your preliminary work to determine how to choose weights without immorally privileging things like general health, QALYs, intelligence, etc).

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I don't know what "entitled" means here.

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Iterate over the possible meanings and choose the one that doesn't lead to you responding to this.

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I'll take a stab at it then: Embryos aren't "entitled" to anything and you can use absolutely any metric you please for determining which ones get to develop and be born.

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This is an argument against polygenetic screening in general, not against screening for the genes that corollate with schizophrenia in particular.

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author

I guess I would phrase that as "it prevents schizophrenia at the family level" or something.

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I'll agree with that. But it is categorically different from preventing lung cancer by banning cigarettes, or preventing car accident deaths by requiring car seats.

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founding

But... why would we care? You can carve reality in an infinity of ways - several infinities, most likely. "it is categorically different" has value only so far as this category pays dividends.

I'm sorry if I'm over-reaching here, but a common argumentation technique is to carve reality at an arbitrary point, they use this categorization as a supporting argument for something else.

In this particular case polygenic testing prevents schizophrenia in future children in all ways that count - pretty much functionally identical with how folic acid or abstaining from smoking and alcohol prevent a bunch of other conditions. We don't use a magnifying glass on how exactly alcohol is bad for you. So why mention that it's categorically different at all?

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> You can carve reality in an infinity of ways - several infinities, most likely.

What would this distinction mean? Usually, you'd come up with a category, like "ways in which it is possible to carve reality", and then consider whether the number of things in the category was finite or not. Clearly it isn't, but since there's only one category, there's only one quantity involved.

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>I'm sorry if I'm over-reaching here, but a common argumentation technique is to carve reality at an arbitrary point, they use this categorization as a supporting argument for something else.

It’s not as arbitrary as you think. You can prevent schizophrenia “at the societal level” by killing everyone who might get schizophrenia. Who could possibly be against this? You will never have to deal with a schizophrenic again! We can create a schizophrenia-free society!

More seriously, I’m not one of those people who believes in objective morality, but if I was, I would be very concerned that IVF clinics are literally Auschwitz.

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To people who are okay with abortion, selecting (and therefore killing) embryos isn't the same thing as killing people who have already been born.

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I’m not necessarily opposed to IVF, but I think it’s a relevant consideration to bring up if one is arguing that the objections are stupid. It didn’t even click for me reading the post that we were talking about murdering embryos until we get the right one until I saw the top comment in this chain.

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I thought one of Scott's recent posts shows that not to be true (or at least not as easy as it seems). Nazi Germany tried to kill all schizophrenics, and they have the same rate as countries that did not. IIRC the rate returned to normal extremely fast as well, like the 50s or 60s.

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He's not saying "kill everyone who might get schizophrenia so they won't have kids with schizophrenia" he's saying "kill everyone who might get schizophrenia, then there will be no schizophrenics left in society." Because you killed them all. When more pop up you'll kill them too.

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founding
Feb 1·edited Feb 1

Yes, but in your example the categorization pays dividends immediately and obviously.

My beef isn't with support or condemnation of abortion (for what's worth, I'm European and I find the whole debate strange and exotic, and rather strongly disagree with both extremes). My beef is with sneaking the categorization as an argument for the belief instead of the consequence of the belief.

If OP said "I think we should make a distinction because in one case we're killing embryos and this is bad", this would be owning your position and, agree or not, it's a valid point to make.

Instead, OP suggested in a public forum that it's a categorical difference, with the possible intention of supporting his belief with this categorization. That's circular logic, and it's also use of a Dark Art. Which is ok on Facebook or X, but I thought here should be gently censured.

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author

I'll write a post sometime in the next few weeks about why I don't think it's categorically different from those things at all. If I forget until March, please remind me!

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Please do write on this. Ive been internally grappling with the above thread for some time. My entryway has been Michael Sandel and the ethics chapter from the Walter Isaacson biography of Jennifer Doudna

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In a counterfactual where people did IVF without screening, they'd still be choosing some embryos over others. Some embryos wouldn't develop into people either way. This just affects which embryos are which. But, in a eugenic sense, these embryos-turned-people could in turn reproduce and spread their genes with different risks for schizophrenia, and in different counterfactuals different embryos in the next generation won't exist at all.

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founding

...Who the hell has been saying epilepsy isn't genetic? It's pretty damn obviously genetic. Barring the ones from people getting whacked on the head really hard.

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Feb 1·edited Feb 1

I had never heard that argument either. I have heard there is a drug (lamotrigine) which treats both epilepsy and bipolar, with the latter being closely linked to schizophrenia.

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Most drugs used as mood stabilizers, like lamotrigine, were originally developed as anticonvulsants. (The big exception is lithium, which for decades was the only available mood stabilizer.) Bipolar and schizophrenia are both responsive to treatment with antipsychotics, but I don't know that I'd otherwise describe the disorders as "closely linked."

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There was a major study in the Lancet 'Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis Cross-Disorder Group of the Psychiatric Genomics Consortium'. This identified shared risk loci with cross-effects on 5 disorders including Bipolar and schizophrenia.

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Quoting from Wikipedia's quote of William T. Carpenter:

"Genetic studies do not support the view that schizophrenia, psychotic mood disorders and schizoaffective disorder are distinct etiological entities, but rather the evidence suggests the existence of common inherited vulnerability that increases the risks for all these syndromes. Some susceptibility pathways may be specific for schizophrenia, others for bipolar disorder, and yet other mechanisms and genes may confer risk for mixed schizophrenic and affective [or mood disorder] psychoses, but there is no support from genetics for the view that these are distinct disorders with distinct etiologies and pathogenesis."

https://en.wikipedia.org/wiki/Schizoaffective_disorder#Causes

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OP was responding to Awais Aftab who said

> Take the case of epilepsy. Epilepsy is a recurrent abnormal, excessive, and synchronized electrical discharge in the brain. It has a heritability of 70-88%, at par with schizophrenia. However, epilepsy is not broadly characterized as a genetic disorder. The 2017 ILAE Classification of Epilepsies recognizes six etiologic categories: genetic, structural, metabolic, immune, infectious, and unknown.

I guess his idea was that since most epilepsies don't have a ILAE classification of "genetic", schizophrenia shouldn't be called genetic (but Scott's classification of schizophrenia is not simply "genetic", it's "probably mostly genetic").

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> By comparison, you can very clearly halve your children’s risk of schizophrenia through polygenic selection, which costs only a few hundred dollars if you’re already doing IVF.

Last time I looked into it, polygenic risk scores for schizophrenia were only able explain ~2% of variance of schizophrenia. It’s really hard to recruit enough schizophrenics for variants in a GWAS to reach genome wide significance. And even with GWAS, you can’t measure things like copy number variants or rare variants. I think it’s at least another few decades until we can screen out schizophrenic embryos.

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You can get 40-50% risk reduction with 5 embryos given the current state of PRS models [1][2] (Disclosure: I work at Orchid). I don't have a reference handy but Genomic Prediction has estimated similarly for their models.

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8510582/ external models

[2] https://portal.orchidhealth.com/risk-calculator our simulation

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> And even with GWAS, you can’t measure things like copy number variants or rare variants.

I should also mention, we do WGS so CNV and rare variants get sequenced (with the usual sequencing caveats). That said, the science behind linking rare variants to disease is very much a work in progress so I don't want to claim that has a big impact on Schizophrenia prevention right now.

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Let's assume you are the kind of high-performing family that delays childbearing until after it is normally physically possible and spends multiple tens of thousands of dollars to try to make up for that.

What is the baseline rate of schizophrenia? According to the WHO, the rate of schizophrenia among adults is 0.45%. But it seems likely to me that the rate of eventual schizophrenia among _your_ children would be markedly less. Say it's 0.3%.

Does a 50% risk reduction matter? That would mean that for every 667 children you have, you prevented schizophrenia in one of them. And since it cost a few hundred dollars each time, you spent maybe $170,000 to do it. (Assuming you actually managed to have 667 children, which is an assumption I'm not sure we should overlook.)

It doesn't take a lot to conclude that this is not a cost-effective intervention.

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According to this study [1], schizophrenia is associated with about 10-20 years lower life expectancy. So that would be $8500-$17000 per life year, running with your number of $170,000 to prevent a case of schizophrenia, which most people in North America or Europe would consider to be cost effective - and this is ignoring quality-of-life, which would make that cost-effectiveness look more attractive.

[1] https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(17)30078-0/fulltext

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1. .45% is a global lower bound that's pretty sensitive to classification and the ability of the medical system to diagnose cases. In the US it's 1.2%. So you can use this, but it's pessimistic.

2. I have no particular reason to think a downgrade of the risk to .3% is accurate, but sure.

3. Like a sibling comment mentioned, $170,000 is incredibly cheap for a lifetime of severe disease prevention. Financially, that dwarfs the QALY ROI of most medical interventions from the past 50 years.

And this is harder to quantify, and you are going to just have to take my word from personal experience on this — Schizophrenia has an *incredibly* hard toll on the family of the affected individual. We need to not just count the QALYs of the individual. We need to count the parents, siblings, the entire support network.

4. Either way, (1) and (2) are irrelevant from the perspective of the families that are actively seeking out Schizophrenia PRS; they are seeking it out *because* of a family history. Having an affected brother or sister will tripe your child's risk. Having 2+ affected 1st degree relatives can get the risk up to 9-10%.

Do you think it's an unreasonable intervention if you can spend $17,000 to prevent Schizophrenia? I feel like even you would grant this one.

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Feb 1·edited Feb 1

> Schizophrenia has an *incredibly* hard toll on the family of the affected individual. We need to not just count the QALYs of the individual. We need to count the parents, siblings, the entire support network.

I don't actually believe that, in the case where one couple has 80 kids (assuming odds a bit worse than 1.2%), the schizophrenia of one of those kids is going to take a major toll on the family. They just won't do the things that you expect of a more typical couple with one child who is schizophrenic.

A similar argument scales down; a 0.6% chance that your one child will develop schizophrenia is essentially impossible to distinguish from a 0.006% chance of the same. You can never have enough children for the odds to make an observable difference. Making changes that are not even theoretically detectible is generally a waste of whatever effort you went to to make the change.

Now, the 0.6% difference is perceptible if you are the government. But then your cost-benefit analysis would want to measure different effects; the fact that parents whose existing child develops schizophrenia sink a lot of resources into that child, if they have them, isn't really relevant. What is the benefit of cutting the number of schizophrenics in half on an ongoing basis? Does it exceed an ongoing cost of $250 per birth in the country? (Or... much much more than that, since applying this policy to everyone would mean replacing all natural conception with IVF implantation?)

At the society level, we will see diminishing returns; cutting the population of schizophrenics in half will probably not also cut the problems caused by schizophrenia in half.

I have a very minor amount of personal experience with schizophrenia in that a homeless woman who appeared to be pretty severely detached from reality once visited my home (staying outside and making no attempt to enter) and we had to call the police to have her removed. If there were 50% fewer schizophrenics, we might estimate that that would have had a 50% chance of happening. But it was a one-off event. I will estimate the value of preventing it at $5. She was known to the police and probably had bothered, and still bothers, other people. But I don't believe that the total amount of bother so generated exceeds $170,000, or $42,000 (close to the relevant figure at $250 per birth and a 1.2% pre-filtering rate). The general value of preventing some cases of schizophrenia isn't very high. Most of the value of prevention is specific, captured by the patient and their close relatives.

> Like a sibling comment mentioned, $170,000 is incredibly cheap for a lifetime of severe disease prevention. Financially, that dwarfs the QALY ROI of most medical interventions from the past 50 years.

I will stipulate this, but I don't think it's a good argument that the benefits exceed the costs. I think it's an example of luxury beliefs making society generally worse off. There was an econlog post a while back making the observation that (1) we have a standard for the value of lives saved by medical interventions, and (2) that standard straightforwardly implies that (under some popular assumptions) the benefit of a full halt to all production, if it stopped the spread of covid, exceeded the cost (which is easy to calculate; a loss of all production in some country is equal to that country's GDP), and then (3) that if we actually did halt all production, many more people would die than were believed to be at risk from the fully unimpeded spread of covid.

One obviously correct lesson to draw from that would be that the value of many lives is not a linear multiple of the value of one life; you can't just scale a number of lives saved by a standard "value of saving one life". But another lesson, less popular than the first one, is that our standard VSL is too large. This is unsurprising; the VSL is derived mainly by a process of first choosing how much we want to spend and then seeing how many lives we can attribute to our spending. When the goal is to spend money, prices are likely to be systematically too high.

So, I tend not to agree with the elements of your point (3). Point (4) is perfectly valid. But point (4) is also something of an argument that families without a family history of schizophrenia are *correctly* not filtering their embryos for schizophrenia; it's not an argument that everyone should start doing it.

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> A similar argument scales down; a 0.6% chance that your one child will develop schizophrenia is essentially impossible to distinguish from a 0.006% chance of the same. You can never have enough children for the odds to make an observable difference. Making changes that are not even theoretically detectible is generally a waste of whatever effort you went to to make the change.

Sure, but you're not just selecting against Schizophrenia risk when you do these sorts of selections, you're selecting for/against a hundred different things like it. And on that level if you have a 0.6% chance of *bad thing* for each bad thing for each unselected individual but only a 0.006% chance for each selected individual there's a close to 50% chance of at least one *bad thing* with your child if unselected while you only have a risk of 0.6% of at least one bad thing if you select your embryo.

Now in reality there are tradeoffs because you are limited in the amount of embryos you have to choose from so you can't just independently select on all traits, and therefore you almost certainly won't be able to get the risk of "at least one bad thing" down to 0.6%, but it's perfectly plausible to get the risk down to say 20% instead of 50%, which is most definitely noticably on the individual level.

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I don't think people with low risk should be prioritizing schizophrenia risk when doing their embryo selection. But if you *do* have high genetic predisposition to schizophrenia, as can be easily determined, it makes sense to do some embryo selection to lower that risk. Or at least, it makes more sense than any other preventative measures you might take to prevent schizophrenia.

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Heritability/Variance explained and PGS (polygenic scores) are two different (but not unrelated) things. For embryo selection/gene modification it's the second you care about, not the first. My understanding is for Schizophrenia we have very good PGS score estimates so we can do embryo selection.

One extreme example to see they are not the same is: consider a gene variant at a locus which is 99.99999999% protective against Schizophrenia, in other words if you carry a copy of this variant you have 99.99999999% reduced risk of Schizophrenia. Such a variant is going to have a very high PGS score. Suppose however this variant is only present in 10 people on the planet, so the total amount of variation in Schizophrenia it explains will be very close to 0.

Now because this variant is so rare you can't use it for embryo slection (with probability very close to 1 no embryo will carry it), but you can use it for e.g. in vivo gene modification. In reality you have lots of loci which are a lot more attuned version of this, so in many cases (including Schizophrenia) you can get pretty good control on the child's risk of developing the disease even if the heritability is low by itslef.

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> One extreme example to see they are not the same is: consider a gene variant at a locus which is 99.99999999% protective against Schizophrenia, in other words if you carry a copy of this variant you have 99.99999999% reduced risk of Schizophrenia. Such a variant is going to have a very high PGS score. Suppose however this variant is only present in 10 people on the planet, so the total amount of variation in Schizophrenia it explains will be very close to 0.

This is a good theoretical example, but in reality won't the PGS score be zero because nobody has ever identified the variant?

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Is Argument #9 even true? Did anyone NOT call epilepsy genetic?

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author

I wouldn't have immediately thought of it as genetic, but I rarely think about epilepsy causes at all.

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Feb 1·edited Feb 1

My late father was epileptic. Today I am the family-tree geek in our extended clan and, with three decades' worth of researching/compiling under my belt, am confident in identifying exactly one person from whom my father may have inherited it: his maternal grandfather. That guy died in 1909 in his late 30s, and from various family lore and old letters and newspaper articles (he'd been a local celebrity) the retroactive diagnosis of epilepsy has decent odds of being correct. Maybe in the range of 75-25.

If that retroactive diagnosis is correct then we have a strong possibility for when/how my great-grandfather became epileptic: in a swimming accident when he was about 20. He was on a group outing at a local swimming hole which was actually an old quarry, a friend started struggling in the water, great-grandpa dove in to help him but had badly misjudged the water depth at the point that he dove in. He slammed his head on a quarry shelf, was knocked unconscious, took days to recover, and was subject to random "episodes" (in the language of the day) for the rest of his life. (All of which is, again, documented both from family lore and a local newspaper article about the incident which occurred in upstate New York.)

I have not found any hints of any epilepsy-type issues among any of that great-grandfather's forebears. Of course that can't conclusively prove a negative but, I do have those folks well-documented in general and going back a good ways.

All of the above leaves me with a question: if we do stipulate that my great-grandfather was epileptic, and that it was caused by that incident rather than a genetic disposition -- then does that enable, or refute, the possibility that my father inherited it from him?

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I'm curious how the part about "schizophrenia is so famously hard to define that we’re not even sure it exists" squares with "studies from 1970s China find exactly the same heritability as Western studies". If it's that hard to define, isn't it likely they're using different definitions in different studies, making direct comparisons pretty hard?

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author

I haven't read the 1970s China study, but I would guess they were using the DSM (given how old it is, probably DSM-1) or some other definition comparable to what Westerners use.

More fundamentally, I don't think that difficulty getting an intensional definition necessarily correlates with trouble picking it out when you see it. Porn is the classic example of "impossible to define but I know it when I see it", and I think there would be very high inter-rater reliability on which art is vs. isn't porn (I'm not saying there aren't ambiguous cases, I'm saying most art is either the Mona Lisa which definitely isn't porn, or Hot Vixens In Your Area which definitely is). Likewise, there's huge debate over what definition we should use for "a woman" and some people can't come up with any definition that really satisfies them, but people basically agree on 99% of cases of who's a woman and who isn't.

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Feb 1·edited Feb 1

I don't know if this is a good comparison, considering the distinctions for those examples aren't particularly meaningful. What's art and what's porn is ultimately just subjective, and I personally consider a lot of stuff to be both. I also think gender is stupid and shouldn't exist, and we really should just be referring to chromosomes when it's relevant for medical and scientific contexts.

But schizophrenia is a consistent condition with a consistent mechanism of action, as far as we're aware, anyways. If completely different brain dysfunctions do cause indistinguishable symptoms, that does complicate things a bit. If that is the case, said conditions should be given different names, and then we can meaningfully judge if each of them is caused by genetics.

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Disagree. In the ontology of https://slatestarcodex.com/2019/12/04/symptom-condition-cause/ , schizophrenia is a condition, like lung cancer. We don't give lung cancer caused by smoking a different name from lung cancer caused by radiation or lung cancer caused by random bad luck. I think we'll find that schizophrenia is a specific cluster of symptoms caused by a specific kind of damage to a specific abstract system, but that many things can be the upstream cause of that damage.

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Feb 1·edited Feb 1

I don't think the distinction you draw between "symptom", something that a patient reports, and "condition", [definition unclear], is useful. Or rather, it's useful to you as a practicing doctor, because you're mostly working off of patient reports. But you definitely can say that "pulmonary edema is a symptom of X", and people do it all the time. They say that because it's caused by X, and that's what "symptom" means. That gives us a simple and useful distinction between symptoms and causes: if you remove a cause, the symptom will go away, but if you remove a symptom, the cause will remain in place and the symptom will come back.

But what's the distinction between a symptom and a condition? A symptom is a state of being that's easy to perceive, and a condition is a state of being that might be hard to perceive? What happens when you can clearly see a symptom visibly present on the surface of the patient, but the patient doesn't report it to you?

The pulmonary edema example looks to me more like a causal chain than a set of three different kinds of things. The pulmonary edema is a cause of breathing difficulty and a symptom of heroin overdose. The breathing difficulty is a symptom of pulmonary edema. The heroin overdose is a cause of pulmonary edema. Where did the concept of a "condition" come into the analysis?

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Regarding argument number 3 specifically, neuroscientist Kevin Mitchell wrote a great book called Innate in which he explains how many mental disorders seem to be caused by non-specific genetic mutations that increase developmental noise. His book is full of insights.

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Highly recommend Kevin Mitchell’s work in general. I’ve been reading his blog for 10+ years and his intuitions as a behavioral geneticists have always made a lot of sense to me.

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Schizophrenia serves an important social function by generating people who assert and act according to blatantly false ideas for non-predatory reasons:

* Based function: This allows sociopaths to prototype new con games while scapegoating non allied persons who act similarly enough to be confused for them

* Woke function (theoretical): This allows neurotypicals to discern deeply entrenched con games and the people who play them

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I don't think you would get very far testing con games on schizophrenics.

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You don't test them on schizophrenics. You watch the schizophrenics do crazy things and you see which ones have unanticipated effects while taking notes from a distance. Then you make a hypothesis about why it had those effects, and try to deploy those same behaviors to selective intentional effect. Schizophrenics will consistently find and exceed the boundaries of human social life even at personal cost, and more prudent people have the opportunity to observe and selectively learn from these tests, which are unlikely to occur otherwise.

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So if society thinks that if you insult Zeus, then he'll strike you with lightning, but a schizophrenic insults Zeus all the time and remains un-electrified, then we might start to suspect that we can get away with the same behavior?

That sounds plausible as a useful side-effect, but I'm dubious that evolution would select for it? There's also a bunch of sayings about how God protects fools and madmen, which I'd guess would be a memetic immune response, basically "don't try this at home, kids".

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More likely the first person to tell someone not to insult a metaphor or concrete bad things would happen, and have people believe them, had something wrong with them, but it worked, and leaders noticed it worked, and that's how you ended up with that particular religious tradition at all.

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It does seem evolutionarily implausible because it would probably only operate on a group selection basis. I don't really have an answer to that. I just have a theory that fits my observations at the moment. I guess this should make me happy because it is weak evidence group selection is possible which gets me further away from nightmare world interpretations and closer to Kropotkin mutual aid as fitness stuff.

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I'm generally fine with group selection as an abstract mechanism; my main problem with it is that it's very easy for people to come up with Just-So stories about how something is adaptive, in ways that it's hard to investigate scientifically. But it's not on the same level as perpetual motion machines.

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I think historically we see the opposite. Schizophrenic delusions are often religious and it's more likely people see schizophrenics worried about how Zeus is going to strike them with lightning at anytime and end up believing the same than the opposite.

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The only schizophrenic I knew claimed to have experiences of this general type, but was not the sort of person who would inspire anyone to believe what she said. Maybe that's just my WEIRD mindset, though. Perhaps in a pre-rational ancestral habitat, she'd have had higher status and a better life, and have been treated as something of an oracle.

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That's not plausible as a useful side effect of schizophrenia just because people curse the gods all the time. By definition, it is their fault when something bad happens to you!

There is always a distinction drawn between offending the gods and doing something that sure sounds like it falls into the same category as what offends the gods.

Here's a classic scene from the Iliad (Perseus's edited version of Samuel Butler's prose translation):

> When they had thus armed, each amid his own people, they strode fierce of aspect into the open space, and both Trojans and Achaeans were struck with awe as they beheld them. They stood near one another on the measured ground, brandishing their spears, and each furious against the other. Alexander aimed first, and struck the round shield of the son of Atreus, but the spear did not pierce it, for the shield turned its point. Menelaos next took aim, praying to Father Zeus as he did so. "King Zeus," he said, "grant me revenge on Alexander who has wronged me; subdue him under my hand that in ages yet to come a man may shrink from doing ill deeds in the house of his host."

> He poised his spear as he spoke, and hurled it at the shield of Alexander. Through shield and cuirass it went, and tore the shirt by his flank, but Alexander swerved aside, and thus saved his life. Then the son of Atreus drew his sword, and drove at the projecting part of his helmet, but the sword fell shivered in three or four pieces from his hand, and he cried, looking towards Heaven, "Father Zeus, of all gods you are the most spiteful; I made sure of my revenge, but the sword has broken in my hand, my spear has been hurled in vain, and I have not killed him."

> With this he flew at Alexander, caught him by the horsehair plume of his helmet, and began dragging him towards the Achaeans. The strap of the helmet that went under his chin was choking him, and Menelaos would have dragged him off to his own great glory had not Zeus' daughter Aphrodite been quick to mark and to break the strap of oxhide, so that the empty helmet came away in his hand.

Alephwyr's premise is flawed; every boundary is going to be tested by a non-schizophrenic whose personality happens to lean in that direction before it gets tested by a schizophrenic. Schizophrenics are too rare for it to be otherwise.

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Honestly the much more plausible theory would seem to be just be that some of the genes for schizophrenia are evolutionarily useful *in moderation* , but not when they manifest as full schizophrenia. Since schizoaffective disorder is much easier to explain evolutionarily. I know there was a slatestarcodex article on the idea before. IIRC the article also mentioned how both autism and schizophrenia have a component of both de novo harmful mutations and genes that run in families (which must have some trade off to stick around)

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Genes running in families could be genes that were de novo a few generations ago and just haven't had time to disappear yet.

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I'm assuming you're trying to say that schizophrenia was naturally selected for? In which case, you're probably wrong, because the genetic conditions responsible for schizophrenia seem to be heritable. If it was a product of natural selection, the genes responsible would be endemic among humanity, with the condition activating due to epigenetic factors instead. This is how homosexuality seems to work, as far as I'm aware.

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If you think "how are the most common forms of neurodivergence as common as they are" is a mess, boy, you'll find "how is primary or exclusive homosexuality as common as it is" an even worse one.

(This is because gay people know full well that when we identify clear-enough genetic causes for any form of being weird, society starts to salivate about eradicating it and damn the knock-on effects, don't you want to prevent the worst-case scenario, how heartless are you for not wanting that?, and gay people have more class consciousness and access to social power than autistic or schizotypal people, so prevent doom by bringing this up any time people research the causes of homosexuality hard enough.)

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>and gay people have more class consciousness and access to social power than autistic or schizotypal people,

I think this is the only reason that being gay is socially acceptable but being schizophrenic isn't.

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The frequency of schizophrenia seems to be around 1%, which is near the limit of where you can expect something caused by de novo mutations. Homosexuality is closer to 3%, which is indeed harder to explain. My understanding is that it's among the least heritable behavioral traits though.

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A beautiful example of the classic "hot take" format, complete with buzzwords and historical illiteracy. You even got the substack author to bite, absolute top tier posting.

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Sorry for having a question made of popular words

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Turkheimer … didn't he write something similar about the intelligence not being genetic either?

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Turkheimer used to be very influential in behavior genetics (wrote a paper about the "3 rules of behavior gen."), then he felt guilty over his career and tried to deny everything about it.

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There's definitely something weird going on with Turkheimer, but I had never heard the details before Is the story written up somewhere?

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I don't think so. I just noticed that he wrote more critical stuff later on in his career and a few people commented on that.

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The rumor was that there was a cancellation attempt but that's all it is, a rumor, so far as I know. I have a post in drafts about how he has essentially been bullied into abandoning his old work but it feels a little too personal to publish, I dunno.

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*sigh* Is it really so hard to live with the truth, no matter how horrible it might be? Refusing to accept reality isn't going to change it.

...And honestly, reading what his research was about, the implications of the results don't even seem to be that bad. The main point seemed to be that, while intelligence is genetic, being raised in a shitty environment is so awful for intelligence that it makes the genetic variance completely irrelevant. The only real implication is that we're throwing away a lot of potential value by letting children grow up in poverty.

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theres two problems humans are vulnerable to:

1. the idea that some men are made of gold, some of silver, some of bronze; some are destined to rule, and some serve

2. certain traits make you a better more important person. intelligence isn't just a force multiplier, intelligent people are more worthy.

genetic/hereditarian ideas can wind up boosting these old sins and even here people are painfully unaware of it. its not like humanity accepts difference as "each man's gift from God," but will sort people into worthy masters and destined slaves, no matter how smart they think they are.

like they will still see obesity as a moral failing even if its genetic. thats why its so dangerous. youd need to be a saint to avoid it while holdng the belief

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...And why would you consider those to be sins in the first place? Human lives obviously don't have equal practical value, and some are more replaceable than others. Pretending otherwise is just incredibly inefficient. When you have limited resources to be allocated, you want to allocate them in a way that offers the most returns. That applies to both resources being invested in people as well as the people themselves.

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the fun thing is people who say this always think they are the allocators and the irreplaceable ones deserving of resources. The idea they might be shut out never occurs to them. Or that people might be selfish or evil and define "most returns" as to what goes to me and mine.

we arent saints. equality is needed as medicine, cs lewis said. we don't take it, we get sicker as a society. it may be a good thing to make it inefficient to put chains on others, or to be evil

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Oh, reading the post (and knowing nothing of the subject) I kept thinking that this discussion is happening because schizophrenia and genes is right next door to intelligence and genes. And we can't talk about the later...

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Funny, when I was reading this I was thinking, "these seem like the kind of specious arguments IQ/sex/race/evolutionary psychology deniers use."

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I see that much of the discussion about causation in this context is still based on verbal arguments and common sense. On the other hand I keep hearing that DAGs and the other machinery developed by Pearl and others is widely applied to epidemiology. Did anyone try to throw a bunch of potential risk factors, genetic or not, into a causal discovery framework to see what happens?

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I don't think the debate about whether they're "causal" is in the sense where the opposite of that is "correlational". For example, in the omnipresent virus situation in Argument 6B, the genes would still be "causal" in a Pearlian sense.

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I see. But in general are people using causal discovery (as opposed to just doing inference on a given DAG) in epidemiology at all? I could not find much at a cursory glance to the main journals. It is interesting to me because I would like to see a real world application of causal discovery on actual data: I am trying to do that on astronomical data and it would be cool to have a model from other disciplines.

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Indeed, people do use causal DAGs and causal inference to interrogate and improve GWAS methodology. However causal discovery problems are notoriously unidentifiable problem in genetics, so most researchers in epidemiology do not use causal discovery in the GWAS and rightly so. In fact, just finding putative genetic instruments for mendelian randomization is often fraught with problems because everything tends to be related to everything else. It makes a lot more sense in perturbational genomics.

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Could you expand on “causal discovery problems are notoriously unidentifiable”? Why is that?

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The other environmental risk factors for schizophrenia are equally hard to change. Poverty? Okay, don’t be poor, thanks for the important life advice. Social defeat? “Doctor, are you saying I have to never let anyone defeat me?” “Yes, it’s my official medical recommendation that you become invincible.”

Keep writing paragraphs like that.

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Poverty is not that hard to change. You work hard, seek an education in a field with reasonably high pay, do your job well without missing days, don't have kids without a partner. Keep looking for higher-paying jobs once you get on the ladder. People do all of these things constantly.

Not being defeated is impossible, but being defeated less often and winning more often are both quite doable.

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Except that getting an education in a field with reasonably high pay is highly IQ-dependent and IQ is largely genetic

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It certainly helps to be smart, but anyone who ever had a varied career could probably tell you that the middle managers are fairly often a bit dense. It is however true that someone with an IQ below 85 or so is going to have tremendous difficulty getting a high-paying job. Even there, however, the ones who get married and stay married can usually get up to $20 an hour or more (minimum wage in Seattle), eventually, if they are reliable and hard-working, and with a partner that puts their combined income at around $80,000 a year.

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I would hesitate to call a couple making $80,000 in Seattle meaningfully above poverty – I would also question how likely it is that a couple, both with IQs well below 100, would purposefully relocate to Seattle based off of this logic.

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I don't think you're right about that. A two-bedroom apartment in Seattle or, say, Mill Creek, a "nice" (heartless wicked sterile) area in Shoreline where I used to do deliveries, can be had for about $1700-$2000 a month. A one-bedroom on Capitol Hill can be found for $1600/month. And $5,670 is the estimated after-tax income of this couple (I used ChatGPT for this calculation, I confess), leaving them approximately $3,700 a month in after-tax income after paying rent.

Nor is Seattle very expensive. I visit every summer, and if you know where to shop, neither food nor clothes nor furniture is expensive (dining out is expensive, but that's all). The Grocery Outlet on MLK Way will sell you just about everything for less than most people pay in the rest of the country.

Only Americans could consider $3700 a month income after tax and rent "poverty." It really shows how delusional the country has become about its affluence.

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Re 6B: A good analogy might be peanut allergies. Is it meaningful to argue the anaphylaxis was caused by peanuts instead of the allergy?

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author

Yeah, this is what I was trying to get at in Footnote 3, but your example is better.

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"This is both totally antithetical to the spirit of real clinical medicine as it’s practiced, and ethically odious to anyone who has witnessed the side effects of antipsychotics first-hand. "

You've perhaps already written it, but an essay on side effects of psychiatric drugs (or even of drugs in general) would be interesting and useful, and a good counterweight to "just take some pills, it's no big deal" thinking.

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Every drug is different enough that I'm not sure anything short of a book would be helpful. I don't think there are a lot of people who say "it's no big deal" for antipsychotics in particular - these are very big deals (although there are maybe some exceptions - Seroquel at sleeping pill doses probably doesn't count as a real antipsychotic, although it still has horrible metabolic effects, and I'm still unsure how often it's okay to use low-dose Abilify for depression). I think the "it's no big deal" perspective makes much more sense with antidepressants, although of course it's never great to trivialize side effects for anything and there are a few ways they can be very big deals if things go wrong.

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Spontaneous song-and-dance seems like quite a big deal: https://www.youtube.com/watch?v=OG6HZMMDEYA

Think about the dancing plague of 1518!

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low dose(5mg) abilify saved my life. it totally stopped my recurring depressions that ssri, snri and ndri' had failed to improve, and it fixed my delayed sleep phase disorder.

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And what is considered an effect and what is a side effect also varies with intent.

The most famous and salient example is probably Viagra, which was first trialled as a medication against angina (or so?), but is now more famous for a side effect they noticed during that trial.

Less memetic, but probably more important is all.the weird side effects of aspirin. It started as a pain killer, but apparently is also helps with preventing heart attacks and cancer.

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And what is considered an effect and what is a side effect also varies with intent.

The most famous and salient example is probably Viagra, which was first trialled as a medication against angina (or so?), but is now more famous for a side effect they noticed during that trial.

Less memetic, but probably more important is all.the weird side effects of aspirin. It started as a pain killer, but apparently is also helps with preventing heart attacks and cancer.

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The author's arguments against GWAS are not very convincing. It's a god of the gaps situation, where he says that in lack of a definitive list of genes, we should assume that its not genetic. This assertion falls flat because many traits are, in fact, highly polygenic, and for those where we have sufficient data the "definitive list" has in fact been produced. Polygenic scores for height explain nearly 80% of variance, which is essentially what the heritability studies would suggest. We even have mathematical theorems that describe the number of samples we'd need to capture the heritability of other traits, including schizophrenia, as well (Steve Hsu's compressed sensing).

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https://www.pgscatalog.org/score/PGS000758/

A polygenic score for height with r^2 of .71, after accounting for sex.

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This is mostly based on the same twin argument I think I debunked at https://www.astralcodexten.com/p/some-unintuitive-properties-of-polygenic

It also mentions that the genes have to be of small effect to be missed by GWASs. I plan to have a post next week on why this has to be true and we shouldn't find it suspicious.

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Ooh! Let me predict why individual genes that cause schizophrenia must have at most a small effect:

Schizophrenia is terrible for reproduction, so a gene with large effect (in the more-schizophrenia direction) would be wiped from the gene pool near-instantaneously.

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I more or less agree with all of your arguments presented here, but I disagree with the conclusion. I don't think the solution is to assert that "genetics cause schizophrenia", but rather as a society we should be a whole lot more careful about using the word "causes" in scientific research (including smoking/lung cancer).

I understand your frustration with applying a different bar to smoking and psychological diseases, but one has to start *somewhere* to enact societal change in the level of confidence that scientists imply when they are speaking with the lay public. If someone is a psychology researcher they probably will start with psychology stuff. A cancer researcher may simultaneously be pushing back against the "smoking causes lung cancer" narrative in a way that you don't see because your day job doesn't involve following prominent cancer researchers who are labelled (possibly inappropriately) as Big Tobacco puppets.

There are some things that scientists are quite confident about (nearly all of mathematics, most of physics, a lot of chemistry, some molecular biology, etc.), and there are some things that we have really good correlational data on but don't fully understand (nearly all of psychology, etc.). For the latter set of things, it is very likely that one day, as you suggest in this article, we'll find that "computational center" and it will all make causal sense. At that time, we'll find that genetics were not causal, just risk factors like in your kidney example, and we'll be able to create a very clear causal chain for each specific instance of schizophrenia. If we say "genetics cause schizophrenia" today, then when that future day comes we'll have to say, "sorry, we were dumbing it down for you, but now we know for sure what causes it" and no one will believe you (fool me once, shame on you, fool me twice, shame on me).

I personally find that way too many scientists are far too eager to assign causation long before they should. IMO, we shouldn't say we know causation until we can predict future outcomes with near 100% certainty (like we can with all of mathematics, most of physics, etc.) At the moment, our predictive capacity for both lung cancer and schizophrenia is appallingly low and doesn't get anywhere near reaching the bar where I think using the word "causal" is appropriate.

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What word would you like to use for "provides explanatory power sufficient for correct prediction 70% of the time and has a clear and plausible mechanism"? Not to say genes necessarily fit that for schizophrenia but it's important we have a way to communicate that concept.

Until we have such a word, "cause" is the right one as long as you couch it in the nuance that things can have multiple causes and each can have not bear 100% predictive power.

Btw you're also wrong about how often harder sciences are willing to use "cause" by convention in this way - it's normal practice to use cause this way and equally normal practice for everyone to understand "cause" means "has predictive power and a logic-consequence-linked mechanism"

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"Predicts".

Try saying "genetics predicts schizophrenia", or "smoking predicts lung cancer". That's what Granger causality boils down to, for that matter.

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Seems fair enough.

Very well then.

Schizophrenia is primarily predicted by genetics.

Schizophrenia is a primarily genetic disorder

Works for me.

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I like "predicts" too!

> Btw you're also wrong about how often harder sciences are willing to use "cause" by convention in this way - it's normal practice to use cause this way and equally normal practice for everyone to understand "cause" means "has predictive power and a logic-consequence-linked mechanism"

While I am skeptical that it is well understood by scientists that "cause" actually means "has a moderate amount of predictive power", I won't challenge that at the moment since I think that is less important than what laymen think when they see an "X causes Y" statement.

Gravity cause objects to fall.

Genes X+Y+Z cause Schizophrenia.

These two statements are wildly different in terms of their predictive power, but if we use the same terminology for both laymen will assume predictive power for them is similar.

I think to the layman, it is very useful to make a clear distinction between "near 100% predictive power" and "significantly less than 100% predictive power". There are some genes that I do think we could call "causal" in the sense that ~100% of the people with gene X will suffer from disease Y and people without gene X have ~0% chance of getting disease Y. In this scenario, saying "gene X causes Y" correctly informs the layman on how to think about gene X and disease Y.

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I'm not sure that 'predict' a good word here? Mostly for the usual correlation vs causation reasons.

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Except that it doesn't predict it. If you have the genes you are still very unlikely to have the disease. Cause seems better in this sense as a nonexistent phenomenon does not need a cause (cause is generally only assumed in the presence of the symptom).

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This isn't how probability and prediction works.

No one's making the claim "If you have the genes we predict you will get it" it's "if you have the genes we predict you will get it X% of the time" and this necessarily incorporates the fact that shizophrenia is ulta-multifactorial and has a wide distribution.

But this is still useful because we would NOT say "if you are 6ft tall we predict you'll get it X% of the time", wed say "your height has no .meaningful impact on our prediction of whether you get it".

If you wanted to know your risk of schizophrenia, learning about your genes would be the piece of information that caused by far the largest update in your estimate.

I think this is all splitting semantic hairs of course - to me it seems perfectly fair and defensible to say predicts OR or causes, and just be ready to clarify. The universe is not simple and for all that we want to, things generally can't be described both accurately and in 4 words.

The crux of the matter is that, if you want to do something about schizophrenia, either for society at large or personally for yourself or your future children, things that impact the genes will have the greatest effect on the prevalence of schizophrenia

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Feb 1·edited Feb 1

If schizophrenia requires a certain genetic makeup to manifest, then "schizophrenia is conditional on genetics". If it just increases the risk, then just say that. I'd prefer it if scientists used more clear and precise language, and this isn't really a situation where dumbing it down for laymen is necessary. It's not like you can change your genes (unless we develop the technology for that, in which case we should just leave it to their doctor to explain it for them).

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Two thoughts:

1. Finding an intermediate link in the causal chain doesn't discount calling the upstream stuff "causes". Unless time is quantized at the Planck scale, there's *always* an intermediate cause.

2. We can already prevent (half of) the cases of schizophrenia, if the embryo selection people are right. (I'll say they are for the sake of argument.) Presumably, if embryonic gene editing were possible at large scale, we could just give a child all the schizophrenia genes we know of, and I predict they'd be almost certain to get it. Wildtype (non-mutant) schizophrenics aren't that far into the tail of the genetic distribution.

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I agree on (1).

> I predict they'd be almost certain to get it

This is a reasonable hypothesis, and as soon as someone does some experimentation that supports it I would be much more keen on saying that genes X,Y,Z cause schizophrenia. I don't think it is appropriate to assign causation based on a hypothesis that doesn't have strong supporting evidence when we cannot predict outcome with near 100% accuracy.

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First of all, some schizophrenia is probably caused by antibodies - an immune reaction. (https://www.psych.ox.ac.uk/news/new-study-finds-antibodies-that-may-be-the-cause-of-schizophrenia-in-some-patients)

Leaving that aside, the whole concept of disease and causality is complicated, and the very idea of something "causing" a disease is context-dependent.

For example, every child born in the U.S. gets tested for a condition called PKU. If you look at a diet Coke can, you will see a warning that it “contains phenylalanine.” PKU is a genetic disease, and the people who have it have a mutation in the gene for the enzyme that allows them to digest phenylalanine.

But take a step back. If instead being a tiny percent of the population, if the mutation were prevalent – for example, like the mutation that allows us to digest milk – then it wouldn’t even be considered a disease. It would be considered normal, and phenylalanine would simply be considered to be a toxin.

Similarly, if instead of 1% of the population, 99% of the population had the CCR5 mutation that made you immune to HIV, then HIV would not be an infectious disease but a genetic disease instead.

Diseases are intellectual constructs. They’re like boundaries of countries. Sometimes they’re based on the contours of natural geography, much like borders that wind along rivers or stop at mountains. Other times, they’re arbitrary, like vertical lines dividing some of the American Midwestern states. What’s the dividing line between pneumonia vs. bronchitis? What’s the difference between a heart attack and angina? Where we divide the diseases into categories and how many divisions we draw, as physicians, are not God-given. They’re man-made.

Schizophrenia is particularly germane example because it is a mix of what are probably very different processes. Catatonic schizophrenia is very different from classic forms. Doctors tend to lump very different diseases into one category if (as was true for a long time for schizophrenia) there isn't much you can do about it. Generally, diseases are categorized by what therapy they respond to, because pragmatically, if you're going to treat the patients the same, you lump them together. And if not, you separate them. (In some instances, especially in psychiatry, diagnosis can be driven by reimbursement considerations too.)

Here is an example of a disease that some pharma companies invented: high blood pressure. Until the 1970s, there was a great deal of debate over whether hypertension was a disease that needed to be treated, especially in the elderly. Some physicians thought that as we aged, and as our blood vessels became stiffer, hypertension was a natural effort by the body to maintain blood flow to all the important parts of the body. It wasn’t until a strenuous effort by Merck and other companies to change people’s minds that it became accepted that hypertension had to be treated.

I should note that it is not clear still how, when, and with what we should treat hypertension. As more data comes out, it is becoming clear that some drugs work better than others (and some are actually harmful). Not too long ago, the guidelines were changed to make treatment of elderly patients less aggressive. The complexity of the consensus guidelines suggests that there are still many unanswered questions. The very fact that there are guidelines means the answer is no obvious - only when there is uncertainty is a guideline needed.

I have a post expanding on this at: https://clinicaltrialist.com/2017/11/13/whats-in-a-name/

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I agree this is true but I also think it's what I mean by isolated demands for rigor. In a world where we didn't say that viruses caused the flu, smoking caused cancer, or that genetic mutations in phenylalanine hydroxylase caused PKU, I would be okay with not saying that genes caused schizophrenia. The point of this post is that by ordinary standards, they do. I'm not really invested in completely reworking our use of causal language from the ground up, partly because that wouldn't work.

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Not sure it matters much to the bottom line, but I’d be cautious about using the terminology associated with smoking risks as the sort of default baseline. Seems to me like this is an atypical situation, where there were enormous policy influences on the language and terminology associated with smoking; there was a huge (justified and good) campaign to discourage smoking, and the public health community was heavily involved in the messaging in ways that shouldn’t necessarily be assumed to be normative for every other terminological situation. I’m not saying that the scientific community wouldn’t have reached the same “smoking causes cancer” formulation even in the absence of the unusual public health campaign surrounding the issue; just that it would probably be safer to use a different and less policy-laden example as a semantic baseline for this sort of thing.

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Sure, smoking was an atypical situation, but anything having to do with genetics is atypical in similar ways. There's a huge ongoing campaign to discourage admitting that genes matter for anything. Whether that's justified and good is controversial though.

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This right here is the reason why Scott's arguments won't convince anyone. No one making those arguments actually gives a shit about the truth.

They have an agenda: "People cannot believe things are genetic". Then apply a mountain of motivated reasoning and sophistry to confuse people and make it seem like it's a complicated thing.

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You might be interested in some posts from Robin Hanson when he investigated smoking-cancer revisionism back in the '00s:

https://web.archive.org/web/20091231023359/http://www.overcomingbias.com/2009/12/animal-smoking-studies.html

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Feb 1·edited Feb 1

I'm far more hereditarian about psychological and behavioral traits than most liberals, so it's funny for me to take the non-hereditarian side of this one, but I'll at least offer some thoughts.

The reason we readily say that smoke has a causal, not merely a correlative, relation to cancer is not because of the statistics (although they are important). It's because we have a mechanistic explanation of the causal pathway. Tobacco has over 70 carcinogens that directly cause DNA damage, in addition to oxidative stress and chronic inflammation.

Now, of course, whatever genes do is also ultimately mechanistic, but here's where the similarity ends. We have no mechanistic account of how genes might cause schizophrenia. Of course, one might protest that that's just a statement about our knowledge. But it's worse than that. It just doesn't seem likely that whatever is going on neurologically has a causal pathway anything as straightforward as the effects of carcinogens. The interactions with the environment seem like they're far more intricately involved. It's as if smoking caused cancer, but only at certain altitudes, within certain temperature zones, when you ate certain foods, etc., etc. If the latter were the case, we'd be much more hesitant to just say "smoking causes cancer."

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Thank you, this was the exact genre of example I was going to reply with: "smoking causes cancer but only if paired extensively with some other stuff". This argument applies pretty similarly to a significant proportion of mental illnesses in the DSM.

Neuroscience functions as a massive aporia in the chain of material reason required to come up with a properly mechanistic causal explanation. It's so massive that we might as well consider neuroscience to be a hard disjunction epistemically, in the sense that we literally cannot make causal arguments if they must rely on a "well X causes brains to do Y which causes Z behavioral patterns". This is why Freud and others both 2000 years before and 100 years after him still rely on a set of derivative psychological primitives that are functionally dependent on observation and permit meaningful intervention (lest we forget that the goal is ultimately helping people), but have "no scientific (= properly material, very nice sleight of hand Popper) basis".

So from a purely interventionist standpoint, polygenetic filtering is basically the only thing you can *do* with a notion of genetic causality. Thorny ethical issues aside, it would still be great to have a real mechanistic model of mental illness (Freud wanted this way back in the 1800s! And was sad we couldn't figure it out!), but we should be aware that it may also require a total reorientation of our categories of illness: maybe you have a sore throat and a cough from a cold virus, but it could also be bacterial, and these require different interventions even if the DSM would still label both as "sore throat and cough disorder".

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Mind you, I have no doubt that genes are very, very important here. I'm just not sure their importance is well summarized by the English statement that schizophrenia is "mostly genetic."

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Indeed, genes are very, very important in all aspects of human life. Unfortunately we can't usually figure out the exact workings of how.

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I think this is what I'm trying to address in Argument 6B. I think we'll find that for each of the ~5000 genetic variants involved in schizophrenia, there's some long and convoluted story for how it contributes to causing it. I think there won't be anything beyond this. I don't think we should wait until we have all 5000 stories (which, to be clear, will be incredibly boring and involve pathways of a billion different proteins we don't understand) to start using the causal language.

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By this logic, can we not effectively describe anything the human body does as a collection of 5000 convoluted stories involving billions of proteins? My understanding is that typically genetic causality is reserved for situations where we can actually identify the exact story involved, or at least a set of major correlations...

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"My understanding is that typically genetic causality is reserved for situations where we can actually identify the exact story involved, or at least a set of major correlations..."

It was back in the dark ages when we thought of genetics in a mendelian way and could only identify the genetic causes of things that had only a few genes causing. Modern methods like twin and adoption studies and even more modern methods like GWASs can move past that past and allow us to identify genetic causes that are highly polygenic.

Polygenetic causes have been unrightfully slandered for to long and it's time it stopped.

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The purpose of the distinction, to me at least, is the utility of it not the 'truthiness' of it. I don't need the complete story I just need the conventional wisdom of what I need to avoid/actively do. If it's conventional wisdom that embryonic screening eliminates these risk factors, so trivially true that you or I and anyone in the thread would bet money on it, then I'm going to seek out that solution.

Call it genetic or not, I don't care. I as a market actor just want a result for my time and/or investment.

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If you or someone you know are schizophrenic then embryonic selection isn't going to help at all.

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We're talking about embryos.

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I thought we were talking about causality.

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My point is not that the causal pathways are many and complex. It's that they involve joint contribution from the environment in ways that just aren't true of smoking.

If smoking only caused cancer when you ate kumquats, we probably wouldn't summarize that just as "smoking causes cancer."

I don't disagree with you about what the 5000 neurological stories are likely to look like. I disagree with you about whether they are well summarized as "schizophrenia is mostly genetic."

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Does "social defeat" mean, like... getting bullied at school? (Or at work, I guess?)

Getting bullied is a (small) risk factor for schizophrenia?

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That's the claim! See https://en.wikipedia.org/wiki/Social_defeat

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So if someone interprets an election result as social defeat, it could literally raise their risk of schizophrenia?

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Seems like the defeats have to be early in life. People usually have their first psychotic break in their teens or 20's.

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Ah, so if we get kids invested in politics early in life, and then they experience failure, that might affect part of a generation?

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Well... that would explain a lot.

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More or less, but the specificity of this is significantly overstated, especially for women. The telephone game of "SZ onset range stretches across the lifespan, but men have a distinct peak around 18-30 and a thinner right tail than women" becomes "if you haven't developed schizophrenia by 25 you're fine" in the cultural consciousness, which is...not...quite...right. (Some studies manage to ignore all age of onset curves and work under this assumption themselves, which I'm sure gets us a lot of terrible results.)

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The key issue at the heart of the debate: whether as describing it as mostly genetic, we can then use genetic scores to motivate clinical action. See Kendler et al., 2023: Relationship of Family Genetic Risk Score With Diagnostic Trajectory in a Swedish National Sample of Incident Cases of Major Depression, Bipolar Disorder, Other Nonaffective Psychosis, and Schizophrenia

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Scott, obesity is also 80% genetic. Can I hear you say "fine, obesity is also genetic"? Do you bite this bullet?

Of course, it does not match what we colloquially mean by "genetic" at all, since obesity is 100% environmentally malleable. Can we *please* adopt a more sophisticated frame than "is genetic" vs "is not genetic"?

You are modelling the world as if everything is a sum of small contributing factors. But it's not; sometimes there are AND gates. Sometimes you need to have the genes AND to eat the right food. It is not possible, conceptually, to assign a "percent heritability" in such a situation.

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Why would anyone have any trouble with saying that obesity is mostly genetic?

Of course, as Scott points out, what's appropriate to say depends on context.

So genetics explains a lot of the variability in obesity today. And a lot of the variability 50 years ago.

But the difference between today and 50 years ago is not genetic.

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I was under the impression that most people think fat people are fat because they're bad, lazy people... whatever that means.

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They think this because there's a grain of truth in it. Sticking to a good diet requires non-trivial amounts of planning/willpower, so on average lazy people will be fatter. Of course, publicly saying this in polite society marks anybody as Worse Than Hitler, but people do still think unspeakable thoughts.

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Feb 1·edited Feb 1

Do they need to moralize it though? People are ultimately products of circumstance, and it seems unproductive to demean people based on factors beyond their control. Especially when, again, obesity is 80% genetic. I'm the laziest person I know, and I still maintain a pretty average weight. I can't really pretend that I'm not obese because I'm a "better person".

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>Do they need to moralize it though?

They do whatever the culture tells them to. These days in the West the conventional wisdom seems to tilt in the "moralizing bad" direction.

>I can't really pretend that I'm not obese because I'm a "better person".

That's why I said "on average", some people are of course more genetically lucky than others.

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If it's beyond his control to keep his diet and exercise in check, it's equally beyond my control to keep my moralising in check. After all, moralising is also an evolved function, and we moralisers are ultimately products of circumstance.

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Perhaps one day someone will develop a pill against moralizing.

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And that's perfectly reasonable, and it's also why I hope humanity goes extinct!

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When I was a kid, obesity was rare. You never saw the kind of massively obese people that are common now.

So have genes changed since then?

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Genetics explains a lot of the difference in obesity in one country at one point in time.

Eg who was and who wasn't obese when you were a kid. And who is and who isn't obese now.

You are right the genetics does no explain the difference in obesity then vs now.

That point is already belaboured in Scott's text as number 5.

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Another commentator further up usd the example of lactose vs phenylalanine. Polygenic screening might help with PKU, but not with lactose intolerance. Thus also obesity: if "obesity is genetic" means that most people lack the special combination of genetic factors necessary to avoid the worst metabolic damage caused by modern 'food', the genetics really aren't the problem.

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Polygenic screening can help the next generation that isn't conceived, yet.

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Allow me to clarify: lactose 'intolerance' is the baseline human condition unless altered by a couple thousand years of animal husbandry. Good luck telling a couple from e.g. southeast asia they'll need to discard 95% of their embryos.

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What's the problem with discarding many embryos? Assuming you can produce many fertilised eggs without too much hassle, of course. I think there's a limit to how many eggs a woman's body can produce for this purpose?

I think the bigger issue with something minor like lactose tolerance is that it's just not very important.

Conceptually, you make up some kind of score, say intelligence at weight 100, health at 200, height at 80, lactose tolerance at 10, etc, and out of all the embryos, you pick the one with the highest score.

Even if South East Asians cared about lactose tolerance as much as Europeans (ie same relative weight), you are right that the same selection process over their embryos are much less likely to result in a lactose tolerant embryo 'winning' the competition for the highest score.

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Were you unaware of the worldwide prevalence of lactose intolerance and are now moving the goalposts? Or did you, from the beginning, think that polygenic screening 'helping' with lactose intolerance really would involve this kind of massive additional cost, labor, and suffering?

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I'm not quite sure what your point is?

Almost all humans can digest lactose when young. Genetics can influence how long (possibly forever) one can keep that ability.

I'm not sure why you care so much about lactose tolerance?

I also don't really know what you are trying to argue for or against and what you think you have tried to caught me in?

What even were those original goalposts you accuse me of moving?

Btw, the whole point of polygenic screening is to pick every baby you raise to be the 'best' (by some score) out of a group of dozens of potential siblings.

So discarding eg 95% of embryos is sort of the point. (However, you only have so much selection power to spend, and I would imagine most people would want to spend it on health and good looks and intelligence etc, not on lactose tolerance.)

For what it's worth, I live in South East Asia. (Since you brought it up in your example.)

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> Sometimes you need to have the genes AND to eat the right food.

Sometimes the genes make it easier or more difficult to eat the right type or the right amount of food.

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I agree with this. "is genetic" (with its more insidious relative "is mostly genetic") and "is not genetic" and its relative "is mostly not genetic" are just terrifically terrible framings of virtually any problem, semantically equivalent to "bridge collapse is design." It either smuggles in a lot of unexamined and nuanced argument about causation, or taken on its face it's word salad.

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1. Out of curiosity. Kidney disease heritability. "We report heritability estimates of the CKD-defining traits eGFR (44%), UAE (20%), and UACR (19%), for the kidney biomarkers serum urea (31%), Scr (37%), and uric acid (48%), and for the serum electrolytes potassium (28%), calcium (27%), and sodium (22%) " They checked and basically every kind of family member with the disease elevates your risk, even "genetically unrelated" ones like spouses (assortative mating or maybe shared environment). https://www.sciencedirect.com/science/article/pii/S0272638620311628 It doesn't seem to be impressively heritable, but there's obviously some genetic causes of this, whatever they might be exactly.

2. There are some single mutations that cause schizophrenia alone, or schizophrenia like traits at least. https://www.pnas.org/doi/abs/10.1073/pnas.2112560118 "A total of 48.2% of individuals with severe, extremely treatment-resistant schizophrenia carried at least one rare, damaging missense or loss-of-function variant in intolerant genes compared to 29.8% of typical schizophrenia individuals".

3. Family studies yielding estimate of heritability, shared environment etc. tell you where to look for causes. They give you the overall importance of some group of causes, but doesn't tell you what they are except in a broad sense. In other words, they tell you where to dig for more. They also give you a decent idea about what kinds of interventions are going to be effective. When heritability is very high, it means that genetic selection will be effective. It scales linearly with the square root of the variance. If "family environment" doesn't show up or is very minor, then trying to modify risk factors in that area will not be effective unless you somehow introduce a new kind of thing that doesn't already vary between families. https://www.emilkirkegaard.com/p/high-heritability-does-mean-that

4. Assortative mating and measurement error are usually quite large downwards biases in family studies. This is particularly the case for self-report symptoms of mental health vs. more objective data (e.g. clinician ratings). I wrote a summary of such research. https://www.emilkirkegaard.com/p/heritabilities-are-usually-underestimated

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Feb 1·edited Feb 1

> When heritability is very high, it means that genetic selection will be effective. It scales linearly with the square root of the variance.

Something that this post and thread have caused me to wonder about is what we're abbreviating when we say "heritability of schizophrenia". Heritability is a measurement of percentage of variance explained. But variance is a numeric quantity, one that is sensitive to the absolute values of the random variable being investigated, and schizophrenia is a categorical variable. I tend to imagine that genetics is something of a categorical variable too. Does the concept of variance apply?

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You say it yourself, schizophrenia is quite hard to neatly define. So much so that perhaps it doesn't exist / isn't one unified thing.

I think most of these writers who are arguing that schizophrenia isn't genetic, and some of those arguing that schizophrenia shouldn't be prevented (only treated), they mean to instead argue "schizophrenia isn't real".

They don't make that argument, and instead get wrapped up in denying the practical facets you lay out, because they are the sorts of people who are not comfortable rejecting the existence of schizophrenia, for social-norm reasons. The people who feel "woke" social norms to treat-not-prevent are also the ones who have a cognitive bias towards saying it's intervention-able (not genetic).

But strip away their social and cognitive biases, and they probably would wish to unpack "what is schizophrenia actually? It's not well defined enough, there's more to learn. "

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E. Fuller Torrey is not a random name. He's the name synonymous with the reinstitutionalization cabal in mental health policy discussion, the guy who (per his glowing NYT piece) wakes up every morning and combs all the newspapers for anything he can interpret as "violence caused by mental illness" so he can crow about it to lawmakers. Torrey knows exactly what he thinks schizophrenia is.

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Huh, NYT is pro-institutionalization? I thought that violence caused by mental illness was a "far-right" talking point these days.

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No publication with two or more writers has a single party line. Torrey got his glowing NYT piece, and someone with his opposite views could too. They wouldn't have the same writer, most likely.

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Feb 1·edited Feb 1

Way to bring "woke" into the conversation. It is, after all, (much like Biden) responsible for all of the evils in the world. [edit: \S in case that wasn't obvious]

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