Depression-Gene Studies Were Built on Shaky Foundations

https://www.theatlantic.com/science/archive/2019/05/waste-1000-studies/589684/

by wyclif • 7 years ago

138 88 7 years ago

hairytrog• 7 years ago

This happens when you have a boatload of "educated" people with degrees in psychology/neuroscience who have to do "research." There's something like 100,000 new psych grads each year - and there's only so many coffee shops.

dang• 7 years ago

Please don't post shallow dismissals to HN, and please don't snark. These are two of the site guidelines. If you'd read them, and follow them when commenting here, we'd be grateful.

https://news.ycombinator.com/newsguidelines.html

scribu• 7 years ago

The Slatestar Codex blog post linked in the article is a much more entertaining read, I think:

https://slatestarcodex.com/2019/05/07/5-httlpr-a-pointed-rev...

matt4077• 7 years ago

Scott is always a good read, and rarely not entertaining. The Atlantic’s piece is a bit less snarky, but has other redeeming factors.

It is quite obvious when comparing the two that a journalist’s first instinct is always to call a bunch of experts and incorporate their views. It’s also laudable that the author rejects the easy cynicism of accusing these scientists of individual intentional deception, and instead redirects our scorn onto the publish-or-perish dynamic.

AstralStorm4• 7 years ago

Statistics. Garbage in, garbage out.

This shows why you have to explicitly quantify statistical power and error model for your study design. Tools are good, but not good enough to do it for you.

Then, do calculate effect size instead of a binary answer. You will get answer with a digit in fifth place with a proper size unbiased sample. Note that for proper genome study, the sample size for observational studies is in tend of thousands barring inbred model studies. (Mice or men, with easily detectable disease process.)

wallace_f3• 7 years ago

It's amazing how convincing statistics are--even for supposed experts--and not just for the reason you elaborate on.

In 2019, they really are the best way to lie.

lm284692• 7 years ago

Science became a new religion. Instead of saying "shut up god made it that way" you say "shut up science says it's that way".

You can find hundred of studies to support your arguments, no matter what they are, it's even easier if you don't actually read the studies and stop at the summaries made by popular medias.

thanatropism4• 7 years ago

We did go WAY overboard with the data-driven rhetoric. Data was supposed to replace theory going forward.

What a generational clusterfuck.

searine4• 7 years ago

Statistics. Garbage in, garbage out.

The problem isn't the statistics, and it isn't the solution either. Its the diagnosis data.

How do you quantify if someone is depressed? How depressed are they? How do you compare two people depression? It is an incredibly nebulous disease.

AstralStorm4• 7 years ago

That's part of "garbage in". Just because you can put a number on it does not mean the number is well scaled, validated or in any way meaningful.

raverbashing• 7 years ago

It's just naive to pin something as complex as depression on a single variable (but that's Popperian scientificism for you)

Now it might be that the 1st study identified an effect on a (very specific) subpopulation and in the bigger study case that subpopulation is not present or not identifiable. But who knows

Now of course it's not wrong to study a certain gene, but to go "all in on" a very narrow study path is stupid. Now, if on the course of the depression studies they found this gene had everything to do with a different disease that would be "p-hacking" or something, right? RIGHT?

More statistical power and "rigour" won't lead research anywhere because it's not the studies that were necessarily flawed, it's that the effects might be small, or dependent on a chain of other factors, so unless the effect of a single factor is predominant it might not even matter (as an isolated factor).

raxxorrax• 7 years ago

that's Popperian scientificism

I believe his criticisms would be very close to yours. For me, this is on the border between medicine, anthropology and in general social sciences. I wouldn't list hubris as a strength for anyone in these fields to underline popular prejudices.

But aside from that, even if statistics are vigorously checked for correctness, it still leaves a lot of room to get different interpretations.

fromthestart• 7 years ago

It's just naive to pin something as complex as depression on a single variable

Why? There are other complex diseases with purely genetic causes, e.g. Huntington's Disease; depression isn't necessarily different. Hindsight is 20/20.

thanatropism4• 7 years ago

Yes, but Huntington's is an explicit cluster of symptoms at diagnosis + a specific prognosis. Uppercase D "Depression" is a diagnosis built around a single symptom, lowercase d "depression". But many people experience depression, both in "core mental illnesses" like bipolar and outside. (Note how bipolar is much better constructed -- indeed the method of differential diagnosis was invented by Kraepelin to differentiate bipolar from schizophrenia)

If it was up to me, big D Depression would be redefined as "responds to Prozac" or something.

mrosett• 7 years ago

Huntington’s is a very precisely defined disease. Depression has a much wider range of manifestations.

Nasrudith2• 7 years ago

Thinking that a single gene could cause depression isn't fallacious - pinning all depression on it would be.

But a single gene as a possible cause isn't surprising given other more extreme single gene effects with other cognitive and developmental effects - angelman syndrome is marked for its cheerfulness and niceness.

If you were seeking such a gene you would search for anomalous histories of suicides in a family tree.

searine4• 7 years ago

It's just naive to pin something as complex as depression

No it's not. Twin-based heritability studies show depression risk has about 10% heritability across all cases and 50% heritability among severe cases. There is a genetic component to the disease.

That complexity is mediated by dozens of genes, but each one gene contributes a percentage to that heritability. Single genes can and will be found which link genotype to phenotype. It is just a matter of time and money.

logjammin• 7 years ago

You don't think you're mixing up "heritable" with "genetic" here? In my family, liking the Yankees is highly heritable across generations, but my grandfather would've laughed in your face if you claimed it was genetic.

unityByFreedom6• 7 years ago

Odd that this article cites Scott Alexander as if that is the name of a real psychiatrist,

“What bothers me isn’t just that people said [the gene] mattered and it didn’t,” wrote the psychiatrist Scott Alexander in a widely shared blog post.

Scott Alexander is the pen name of a person running a blog who claims to be a psychiatrist, and AFAIK, his authenticity is not proven due to his anonymity.

Lazare2• 7 years ago

His identity is hardly a deep secret; anyone who really cares can find it out, and verify his credentials.

(Not that those credentials are really relevant here, no?)

atomical2• 7 years ago

I care about reading something written by a professional instead of a Tim Ferriss type. I've found several suspect items in his blog articles. I would like to know his credentials.

unityByFreedom6• 7 years ago

The blog actively misleads readers into thinking Scott Alexander is his real name,

SSC is the project of Scott Alexander, a psychiatrist on the US West Coast. You can email him at scott[at]slatestarcodex[dot]com. Note that emailing bloggers who say they are psychiatrists is a bad way to deal with your psychiatric emergencies, and you might wish to consider talking to your doctor or going to a hospital instead. [1]

Journalists citing that blog should note it is an alias, and deeply question whether or not he really is a psychiatrist.

And no, I don't find it easy to verify his identity, and yes, it is completely relevant here as he's being cited as a real psychiatrist. That's not verifiable without knowing a real name.

[1] https://slatestarcodex.com/about/

YeGoblynQueenne• 7 years ago

> His identity is hardly a deep secret

Well, who is he then?

gnoppa2• 7 years ago

Now please let the same epiphany come about cancer research or personalized medicine based on genes.

icegreentea22• 7 years ago

Let's not throw the baby out with the bath water. No doubt there's a lot of sketchy stuff going on, but also the fields are very wide with lots of "verticals" going on. Just cause one vertical might be built on a shakey foundation, doesn't mean all of them are (and the converse is also true).

gnoppa2• 7 years ago

You might be right that not everything in those fields is bad, but most is. Nevertheless, what is so terrible is that all the money is put into research (gene mutation causing cancer) even though it has been proven wrong many years ago. That becomes very clear after reading Thomas Seyfried's work (cell fermentation causing cancer).

Sadly, academics have the incentives to publish papers in prestigious journals that make them sound smart and not to find a simple cure. Likewise, the free market does not have the incentive to easily and cheaply cure people but to maximze profits. Hence, so much research is absolutely abysmal, wrong, misleading and harmful. Sadly the human mind is constructed in such a way that we self-deceive to gain advantages. That is why there is no need for a conspiracy but just the wrong kind of incentive structure.

hmd_imputer• 7 years ago

imagine how many times a valid counter argument was silenced because of the "are you denying science?" bull* argument

thanatropism4• 7 years ago

I think pop sci rags going wild over papers that claim radical breaks are a part of the problem, even if a small one.

There's simply no reason that people who are not technical enough to read scientific papers would be up to date on the latest cancer research. People have a right to knowledge? Then open up the journals.

mattkrause2• 7 years ago

It’s on a slightly different level.

There are strong incentives to find ‘sexy’ results, but this is mostly aimed at getting a paper into Nature, Science, or Cell. Publishing in these journals can have an outsized effect on one’s career, even if the results don’t actually hold up.

In contrast, there’s not a huge pay off for getting something into Popular Science or the New York Times science section. Publicity is good and can help show the relevance of your research. It’s also fun to show your mom (who still wants you to go to med school), but people tend not to chase it nearly as hard as a “glam” paper.

thanatropism4• 7 years ago

That's probably a bigger effect.

People have a huge trouble accepting that their wonderful science is a social process.

searine4• 7 years ago

As someone who works on depression GWAS, this isn't the end of finding causal genes for depression, it's the beginning.

In the next few years we're going to see a waterfall of new rare variants linked to disease, all which have a much higher chance of causing functional change.

As WGS comes online for association studies it will both validate and more deeply explore the genetic nature of every disease. It is going to be mindblowing.

eggie• 7 years ago

As WGS comes online for association studies it will both validate and more deeply explore the genetic nature of every disease. It is going to be mindblowing.

But there is another layer of confusion, because WGS implies resequencing, and resequencing is only as good as your reference genome, and will distort results when the genome you're inferring is to far from the reference (reference bias).

The real mind bend will come when we have thousands or millions of whole genome de novo assemblies and we compare these to each other to do our GWAS. Only then are we going to have a hope of knowing what is actually causal in a genomic sense. Until then we remain in the land of association.

In nature, most adaptive variation appears to be large and structural. All the recent studies that have used whole genome assemblies to look at this have found the same thing. I would be surprised if this isn't the case for humans too. If it is, then much of current perspective on GWAS (both based on chips and WGS) will need to be rewritten.

asdff2• 7 years ago

GWAS is nothing more than correlations and by themselves aren't very remarkable. What is remarkable is when someone does a functional analysis on the variant they found in their GWAS and is able to describe the mechanism that it uses to affect the disease or phenotype. The way you do that isn't more sequencing, but with model systems that you can easily manipulate in the lab.

GWAS also doesn't compare to an arbitrary reference sequence. Some good numbers for a GWAS are >1000 cases and >2000 controls from the same population. You have to match populations, or else all your association study is going to find is the differences between east asians and europeans, for example. You need a lot of samples to get enough stats power to even see these rare variants.

mindgam32• 7 years ago

“Nor... should his work be taken to mean that genes don’t affect depression. They do, and with newer, bigger studies, researchers are finally working out which ones do.”

This part really needs some context/sources. Anyone know which studies he’s talking about?

bobcostas55• 7 years ago

Here's one: https://www.nature.com/articles/s41593-018-0326-7

mindgam32• 7 years ago

Thanks

DuskStar• 7 years ago

I love the quote from the Slate Star Codex article:

...what bothers me isn’t just that people said 5-HTTLPR mattered and it didn’t. It’s that we built whole imaginary edifices, whole castles in the air on top of this idea of 5-HTTLPR mattering. We “figured out” how 5-HTTLPR exerted its effects, what parts of the brain it was active in, what sorts of things it interacted with, how its effects were enhanced or suppressed by the effects of other imaginary depression genes. This isn’t just an explorer coming back from the Orient and claiming there are unicorns there. It’s the explorer describing the life cycle of unicorns, what unicorns eat, all the different subspecies of unicorn, which cuts of unicorn meat are tastiest, and a blow-by-blow account of a wrestling match between unicorns and Bigfoot.

https://slatestarcodex.com/2019/05/07/5-httlpr-a-pointed-rev...

lisper• 7 years ago

Between them, these 18 genes have been the subject of more than 1,000 research papers, on depression alone. And for what? If the new study is right, these genes have nothing to do with depression.

The article doesn't actually say anything about what these 1000 research papers actually claimed to show. It's entirely possible that most of them were negative results, there's no way to tell from the text of the article. It strongly implies that this is the case, but it doesn't actually say so. This is a significant omission for an article whose thesis is that these 1000 papers constituted a "house of cards."

[UPDATE]

"Sometimes the gene was linked to depression; sometimes it wasn’t. And crucially, the better the methods, the less likely he was to see such a link."

Seems to me like this is science working exactly as it is supposed to (except for the possible suppression of earlier negative results, but that's a known broad problem that has nothing to do with this particular gene study).

rossdavidh2• 7 years ago

It worked as it was supposed to...eventually. Instead of double-checking the initial results, hundreds of research papers by many research teams looked into questions that would be very important, if the genes in question were connected to depression.

Sure, it is great that it's not (quite) religious dogma, and it eventually gets revisited. But, a couple decades worth of work and ~1000 research papers, many of which took place AFTER the earlier 2005 paper that called into question the link to depression, is by no means what we should shoot for.

More fundamentally, there was nothing in the system that motivated anyone to do replication of the original link. The problem is not that the original link turned out to be spurious, and it's not that anyone did anything unethical. More worrisomely, nobody appears to have done anything unethical, but because of the systemic incentives for research grants, tenure, etc., replication of the foundational result wasn't attempted in a serious enough way until many times that much work had been done on something spurious.

pfdietz• 7 years ago

What's needed is for the Ignoble Prize people to focus on the people who start this sort of crap, not on humorous low value targets. Really call out the people who contributed negatively to the progress of science.

Depression-Gene Studies Were Built on Shaky Foundations

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