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Posted by supermatou 3 hours ago

Vitamin D3 During Pregnancy and Cognitive Performance at 10 Years(jamanetwork.com)
156 points | 74 comments
Aurornis 57 minutes ago|
> We found that high-dose supplementation was positively associated with 3 of 11 functions assessed: verbal memory, visual memory, and flexibility or set shift. However, the association with flexibility or set shift was not significant after correction for multiple testing.

They tested 11 different measures. Only 3 of those tests showed significance, but after they corrected for multiple testing the significance of 2 of those disappeared. Only 1 test remained below the significance threshold.

This is on a set size of about 500 children who completed the study, randomized to the two groups.

The only measure that remained statistically significant was visual memory. If you look at Figure 2 it's not even clear that there was a trend toward improvement because everything is so scattered, including a couple measures that were trending worse with higher Vitamin D levels.

This study isn't very convincing. It's a classic p-hacking trick to include many different smaller tests so if one of them pops up as an outlier you can claim that something was significant.

marcosdumay 33 minutes ago||
> It's a classic p-hacking trick

It's a hypothesis seeking study. It just invalidated 8 of them and picked 1 ok-ish candidate to run an actual study in.

The only thing wrong here is there's only one format for submitting a paper.

medymed 10 minutes ago||
And if the 1 ok-ish candidate study turns out to have significant results, publication bias has to be considered: that dozens or more other studies of vitamin D (or whatever) may have not found significant results of previously ok-ish hypothesis candidates and those negative studies are often not published.

I think this is quite the case for vitamin D which has multiple physiologic roles and is studied extensively for relation to many categories of health issues. One more reason why it can be stunningly impressive when something/anything health-related is eventually proven.

jampekka 29 minutes ago|||
Also it was an asthma prevention study, not cognitive functioning one, adding even more "researcher degrees of freedom".

Doing such side studies is fine in itself, but selling such shakey results as "This study suggests that high-dose vitamin D3 supplementation during pregnancy may be associated with improved cognitive functioning at age 10 years." is a stretch.

letmevoteplease 36 minutes ago|||
Where are you getting "after they corrected for multiple testing the significance of 2 of those disappeared"? The text you quoted says, of the three, one disappeared and two remained.
margalabargala 49 minutes ago||
Relevant xkcd

https://xkcd.com/882/

niteshpant 1 hour ago||
I have thoughts on this

1. Yes, vitamin D actually controls a lot of bodily functions it’s very easily set aside as not a “main” factor when in reality it actually controls a lot

2. This study was done on women in Denmark only which isn’t a great study subject considering Denmark doesn’t get a lot of sun to begin with so most of these women would already start at very low levels

3. This doesn’t directly correlate to women of color because WOC need higher dosage of vitamin D than white women do. The general range of “good” level of vitamin D that doctors tend to use is related to studies results gotten from white people when in reality brown and black people need way more for their range to be at a normal place.

xwowsersx 1 hour ago||
Study seem to have addressed point #2 in several ways.

1. They measured maternal vitamin D before supplementation began. They explicitly adjusted for these preintervention levels.

2. the two groups started at essentially the same vitamin D levels.

3. They specifically tested whether baseline vit D status changed the effect of supplementation

tdb7893 1 hour ago|||
For point 2: I don't think there's really good or bad places to study it, it might not generalize to sunnier places but the reverse is also true. Presumably the scientists working on this can understand these things (I know in my field I'm aware that studies in the tropics will find different things than studies in Canada).

For my own point: in this study they have like 22 test values but still use the 95% confidence interval. Even on random data there will be a significant result like a third of the time so I think it's easy to interpret these result as more definitive than they are. Not that it's a bad study though (no study will be everything, baby steps like this are important in science).

senkora 57 minutes ago||
I just skimmed the summary but in the results section it reports three significant results and two after “multiple-test correction”. I’m not sure how they did that correction; I would expect that measures of cognitive performance are correlated for each child and so the standard Bonferroni correction might be too harsh to apply here.

> Covariate-adjusted analyses of standardized scores (mean [SD], 0 [1]; higher values indicating better performance) showed positive associations of high-dose vitamin D3 with verbal memory (β = 0.17 SD; 95% CI, 0.03-0.32 SD; P = .02), visual memory (β = 0.24 SD; 95% CI, 0.06-0.42 SD; P = .01), and flexibility or set shift (β = 0.19 SD; 95% CI, 0.01-0.37 SD; P = .04); however, high-dose vitamin D3 was no longer associated with flexibility or set shift after multiple test correction.

tdb7893 17 minutes ago||
My statistics isn't great but reading the study more it looks like they control the rate of false positives via the q values so my initial concern may be unwarranted. I'm surprised that it keeps so many barely significant results with so many hypotheses. I'll have to look it up when I get time.
tchalla 1 hour ago|||
> This study was done on women in Denmark only which isn’t a great study subject considering Denmark doesn’t get a lot of sun to begin with so most of these women would already start at very low levels

Generally, when a study is done in the US - no one will ever question the location. The moment the study is outside the US, "not US so not generalisable" questions always arise.

filoleg 1 hour ago|||
The grandparent explained exactly why it is an issue though. It isn't because US is somehow just magically more legitimate than Denmark.

As they stated, it is because the population of Denmark is very homogenous, as opposed to the US. If you are trying to make a generalization that applies to a range beyond just white people, having Denmark as your sole sample is clearly flawed.

Along the same lines, picking Japan for the purpose of generalizing to wider racial/ethnic groups would also be a bad idea. Not because their research is untrusted/considered non-reputable (it is quite the exact opposite), but because their population is too homogenous.

wrsh07 57 minutes ago|||
> considering Denmark doesn’t get a lot of sun

> As they stated, it is because the population of Denmark is very homogenous

If you know about vitamin D, you'll note that sun exposure is one of the primary reasons location matters for this study. It would be similarly relevant if they only studied students in Miami or southern California.

Essentially: sun exposure helps you create vitamin D, and so you shouldn't naively generalize this study to other lines of latitude

dheera 1 hour ago|||
I don't think it invalidates a study as long as you do things on relative terms and have a control group. Another study can see if the same delta effect is reproducible in an e.g. homogeneous Asian population and report on it.

It is probably a logistical nightmare to do a study of this sort in multiple countries and regulatory systems simultaneously.

wrsh07 55 minutes ago||
It doesn't invalidate the study at all! On the contrary, if you're measuring vitamin d levels from blood tests, it is easy to adjust the dosage to match.

It's just an important factor - if you live much further south or spend a lot of time outdoors, your target dosage will be different than someone in _Denmark_.

darth_avocado 1 hour ago||||
> when a study is done in the US - no one will ever question the location

Studies everywhere are now being scrutinized for the participant cohorts because it is now widely recognized that biological differences exist between different groups. Some medications for example aren’t sufficiently studied for effects on women vs men and are being reviewed.

Plus, studies in US are less scrutinized because researchers are aware of the need for a diverse cohort and you are more likely to get one in the US vs elsewhere.

fridder 1 hour ago|||
to be fair, the US has a lot more variability in climate and population than most countries
cientifico 1 hour ago|||
Correction in 2. Contrary to popular believe, sunnier countries in Europe have higher deficiency in vitamin d.

Spain have lower levels of vitamin d than Denmark.

doikor 1 hour ago||
The countries in the northern parts of Europe know this is an issue and thus fortify some commonly consumed food items (milk) with vitamin d.

In places like Spain only some “premium” milk gets this treatment.

kloop 1 hour ago|||
Do they need more vitamin D? I thought they just needed more sun to get the same vitamin D
nine_k 1 hour ago|||
Apparently the pale, semi-translucent skin is a mutation that allowed hominids to live at high latitudes, where darker-skinned hominids would whither due to the lack of vitamins of the D group [1].

That same mutation made them vulnerable to the levels of sunlight at lower latitudes, susceptible to sunburns, etc.

[1]: https://pmc.ncbi.nlm.nih.gov/articles/PMC8359960/

cenamus 1 hour ago|||
At these latitudes they just get almost none naturally, that's why you need to supplement more
HexPhantom 46 minutes ago|||
Women in the study weren't all starting from very low vitamin D levels
dheera 56 minutes ago|||
> Denmark doesn’t get a lot of sun to begin

First, that's only true for about 4 months of the year. Second, people cooped up in offices in China, India, and the US don't get a lot of light either. In fact I'd bet the better work-life balance in Denmark means people actually do get more light there because they spend more of their evenings and weekends outside instead of in the office. Office buildings in Denmark also tend to have much better sunlight by design.

Scroll_Swe 55 minutes ago|||
2. Good for me as I live in Sweden. Started only in my 30s to take Vitamin D and multivitamin. My 20s where wasted really. I studied and worked but felt even more shit. Less shit now I guess.
Scroll_Swe 1 hour ago||
2. Good for us who live in Northern Europe! Or does everything have to be tested in California or MENA or India?

You can probably have the same results in the New England area of the USA, no? Even NY with 10mil people?

3. Okay, and?

jbellis 1 hour ago||
> the association with flexibility or set shift did not remain significant after false discovery rate correction

this is right there in the abstract, isn't that the entire game?

tarkin2 1 hour ago||
I'm perhaps missing something but if there were a significant connection, wouldn't this mean those in sunnier climates would have better verbal and visual memory?

If there were a connection then I would wager that there are more significant factors, since I have seen or heard of no evidence to assume those in sunnier climates have better verbal and visual memory.

The results of this study seem to show no significant correlation, anyhow.

HexPhantom 43 minutes ago||
The paper isn't saying vitamin D determines cognition in general, just that there was a modest signal in a couple of memory measures
appplication 1 hour ago||
Not necessarily, if the effect was due to exposure to levels beyond what you’d even get in sunnier climates. It also could be possible those in sunnier climates do experience this effect and it was unnoticed, due to political and socioeconomic issues associated with typical equatorial countries
cortic 53 minutes ago||
Vitamin D excess can lower blood levels of vitamin K2, reducing bone development. Not sure if the levels would be high enough for this (difficult to find safe numbers for in utero), but the side effects, joint pains, stiffness, could have motivated the kids to stay indoors and focus on more intellectual pursuits, leading to better cognitive performance.

I point this out because there are so many known factors both positive and negative that contribute to increased 'cognitive performance' it is impossible to account for all of them, even within a randomized trail such as this. People are weak to assumptions when it comes to correlation.

pkoird 2 hours ago||
I'm not sure if there are any research showcasing the effects humanity has had in general due to low sun exposure. From all the benefits of Vitamin D and the recent human behavorial shift leading to low sun exposure (car travel, air conditioning, sunscreens even), there are bound to be new biological or psychological changes humanity is experiencing for the first time.
HexPhantom 41 minutes ago||
What I find more plausible is that low sun exposure is one small contributor among many
logicchains 1 hour ago|||
One study found a difference in mortality between the max-sun-exposure and min-sun-exposure cohorts: the second was twofold higher, which is comparable to the effect of cigarette smoking. https://pubmed.ncbi.nlm.nih.gov/24697969/ . I.e. avoiding sun exposure completely is as harmful as smoking cigarettes.
api 1 hour ago|||
I've wondered for a while if the apparently higher cognitive performance and resulting societal wealth at higher latitudes might be some kind of second order side effect from long-term selection for lower sun exposure. We already know this vitamin D is almost certainly why Northern peoples evolved lighter skin.

(I realize this is a frought topic, so please hold the race science bullcrap replies or the over-reactions in the other direction. I am not a believer in hard biological determinism or "race science," but I also don't dismiss the existence of variations. As with everything else in population genetics and biology, any variations that do exist probably have more than one cause.)

If there's any truth to this, it might be further compounded as people with darker skin spend more time indoors in the modern world. If you have darker skin you need, as far as I know, more sun to make vitamin D, which normally is not a problem if you're outdoors near the equator. Maybe darker skinned people need to be taking more D supplements.

HexPhantom 39 minutes ago|||
The vitamin D angle seems much more plausible to me as a public-health issue than as an explanation for broad population-level cognitive differences
georgeburdell 1 hour ago|||
Does not explain India where there is high genetic diversity and generally the South is more educated and wealthy
bethekidyouwant 1 hour ago||
The reason that southern India is generally richer is very complicated.
close04 58 minutes ago||
GP was wondering if sun exposure triggers the education>wealth cycle. I’m not sure it does. Norway wasn’t particularly educated or wealthy in the ‘50s. Then they discovered they have oil and now they are both.

I think a combination of good policies and ideally some preexisting wealth will trigger this upwards cycle.

therein 1 hour ago||
>car travel, air conditioning, sunscreens even

And even clothing.

throwup238 1 hour ago||
Tailored clothing is at least 80,000–170,000 years old based on genetic clock research in body lice [1] but archaic humans have probably been wearing hides for at least a million years (there’s currently a big debate about how they managed to migrate to colder climates like Spain 800k-1.2m years ago).

I don’t think clothing is that big a factor because all humans in hot environments adapt and very little survives in the archaeological record. Many populations lived in heavily forested jungles where they was little sun exposure and those in deserts used stuff like Otjize for sun protection. Given all the ethnographic reporting from the age of exploration, tons of that clothing was probably made of feathers, cordage, bark, and other materials we wouldn’t even think of using for clothing.

[1] https://academic.oup.com/mbe/article/28/1/29/984822

ezekiel68 32 minutes ago||
Still, 170,000 - 1.2M years is a fairly short amount of time if we go back only to the common ancestor who begat progeny that would become Pan and Autralopithecus (around 12 million years ago). It could be that early hide wearers started a trend that, to this day, continues to interfere with natural vitamin D metabolism (while also providing many benefits).
Aboutplants 2 hours ago||
Tangentially, with ai tools available, post hoc secondary analysis of studies (like this) has to be insanely easier to run through. Are there are companies/individuals focused on this specifically? Obviously most labs are doing some of this but I’m curious if there are broader analysis being done
Groxx 2 hours ago|
tbh I'd expect the opposite - inherent bias / regression to the current norm comes through quite consistently when they're used to summarize stuff, and that'll badly taint science using it.
HexPhantom 49 minutes ago||
I'd read this less as "high-dose vitamin D makes kids smarter" and more as "prenatal vitamin D might matter for some neurodevelopmental outcomes, and it’s worth testing more directly"
shiandow 1 hour ago||
Based on how many tests they did and the confidence intervals they got it's associated with fuck all. Doing lots of tests and then pointing to the few where the lower bound of the effect size was marginally above 0 proves very little.

At any rate their main marker for intelligence showed an impressive p=90%, so whatever cognitive effects were present they've not made them any smarter (at 10).

jtrn 1 hour ago|
Can you say p-hacking? It was designed and powered to test whether prenatal vitamin D reduces childhood asthma/wheeze, and found no effect on that primary outcome. The rest is just shuffling numbers and statistical methods around until something with p > .05 pops out.

They flags their own post hoc status, reports modest effect sizes, and applies some multiple-comparison correction. That makes the rhetorical sleight of hand harder to spot, because it's buried inside otherwise careful looking work.

The statistics are shit. They applied Benjamini-Hochberg FDR correction within cognitive domains, not across the family of 11 functions. That choice is what produced the headline "memory survived correction."

Watch what happens with the actual numbers. The two "winning" functions, verbal memory (p = .02) and visual memory (p = .01), both sit inside the memory domain — which contains exactly those two functions. BH within a 2-member family barely adjusts anything: the most lenient threshold is just 0.05, and both p-values are already under it, so the q-values come back at .02 and .02. The correction was toothless by construction, because the two hits happened to fall in the same tiny domain. A reviewer should have made them show the whole-family result side by side. The fact that they didn't is the tell. And there is much more that could be criticized in the same manner across the whole thing.

And then the observational data fail to corroborate the supplementation finding. The authors explain the mismatch via trimester timing of exposure, which is plausible, but the equally plausible reading is that the RCT hits are fragile, or that, more probably, it's not a real effect.

And even if there was an effect, it's so small and weak and NOT proven by even this data, that the recommendation for supplementation is not warranted at all. At best, this single study with their focus on recreating this effect is the only defensible conclusion. And yet they recommend supplementation.This is pure bias and D-vitamin cult babble once again.

The conclusion, based on the actual data, is: in a vitamin-D-sufficient cohort, high-dose prenatal D3 was not associated with offspring cognition on any whole-battery-corrected measure.

I hate this so much because it's stupidity like this that shows that science is not worth paying attention to, because the scientists basically lie through their teeth, at least from my perspective, where truth is something that is verifiable and relates to something real.

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