Hacker News Reader

> I'm just saying that IMHO it's not a definitive study

It's not, and I'm disappointed in the submission's title. The paper's title is "No evidence that vitamin D is able to prevent or affect the severity of COVID-19 in individuals with European ancestry: a Mendelian randomisation study of open data" Which is correct; no evidence was found in the study that correlated Vitamin D levels with Covid severity. But yes, this is not an RCT and we cannot use the study's conclusion to definitively disqualify Vitamin D supplementation.

> it was not even based on data about actual vitamin D levels

Medelian Randomization is a pretty well-established study technique which _isn't_ an RCT, but often yields results close to them. It's a bit simplistic to say that "the data isn't about actual Vitamin D levels", when MR is specifically a study method used to step around direct measurements to analyze effect.

> "the data isn't about actual Vitamin D levels", when MR is specifically a study method used to step around direct measurements t

Yeah, this would make sense if you ignored all dietary and solar variations in Vitamin D productions. So yeah, this person has a bias towards high or low levels but you're not actually measuring it

I don't think it's an honest assessment

This would only make a difference if P(low dietary vitd) or P(low solar intake) is small (and assuming dietary values/solar values are independent of having a genetic disposition to lower vitd levels and independent of COVID prevalence), which I don't think is true. What I think may be true and may not be compensated for by the study is the fact that individuals with genetic disposition for lower vitd levels may be supplementing (through either greater sunlight exposure or dietary supplements) to bring up their vitd levels, even before COVID came onto the world stage.

> I don't think it's an honest assessment

Of what though? This is just a study trying to prove a correlation with VitD deficiency and COVID prevalence, of which they couldn't find any. Any stronger conclusion is out of the scope of the paper.

> Yeah, this would make sense if you ignored all dietary and solar variations in Vitamin D productions

No, actually, MR specifically accounts for these variations.

However, one idea (one that would need a lot of evidence in my opinion, but to give you a clearer picture) that is not captured by MR is horizontal pleiotropy. So, if the genetic variants used in this study e.g. actually cause someone to seek out dietary modifications/solar augmentation of vitamin D, that would not be accounted for here.

I don't think the biology in this case allows for that to any significant degree, but I'm not an expert in vitamin D metabolism/action or COVID.

> I don't think it's an honest assessment

The title here is maybe a bit simplified, but the paper is quite honest about its weaknesses if you read it in its entirety.

> MR specifically accounts for these variations.

How exactly? The only mention I see is using the British Biobank data which is 10-15 years old

Well, it's a fundamental technique in statistical genetics, so the paper doesn't explain it in depth. MR uses the technique of instrumental variables. [1] looks like a good explanation.

The basic idea is to identify a variable Z (genotype, in the case of MR) that causally impacts your outcome Y (COVID, in this case) only through your exposure X (vitamin D levels). If you can find and measure such a variable Z (which meets a few other conditions [2]), then you can robustly identify whether X has a causal impact on Y only from observational data.

[1] https://www.youtube.com/watch?v=NLgB2WGGKUw

[2] https://en.wikipedia.org/wiki/Instrumental_variables_estimat...

This is a fantastic call out of the caveats of the study and makes me realize that a more accurate title would have been to say that genetic predisposition for higher/lower levels of Vitamin D don't appear to be associated with Covid severity.

Your proposed title is so great that I have created an account after a decade of lurking! However, I must suggests what I consider to be a more correct formulation :

  Genetic variants associated with vitamin D deficiency appear to be uncorrelated with the severity of COVID-19

I'm flattered, and I concur with your formulation being more accurate. I'd edit the title if I could, but at this point it looks like I'm not allowed to anymore. Would love to see the title updated if the mods see this!

Mendelian randomization (MR; for the interested layman - the term for instrumental variables techniques when the instrument is genotype) is a well-founded research paradigm with several known potential flaws which I discussed in more depth in reply to another comment below. But, fundamentally I agree with your assessment that the study does not definitively answer the question. More generally, the articles I referenced in the other comment may be of interest to you as well - specifically around the reliability of MR studies in general.

[1] doi:10.1038/s41588-018-0099-7

[2] doi:10.1093/hmg/ddy163

Maybe I'm entirely misunderstanding the study but wouldn't we see the same results in a population that supplements vitamin d, or population that has vitamin d deficiency, or both?

> the individual does not change their vitamin D intake according to their genotype

I did. I looked at the vitamin D level on a blood test, saw it was on the low side, and started taking D supplements.

I would guess a large fraction of people in the developed world have looked, or had a doctor look at a blood test and make vitamin recommendations.

Going off of my friend circle here in Seattle, a city not exactly known for winning awards for exposure to sunlight, nobody I talked to has had bloodwork done that included vitamin deficiency panels in recent memory, so I don't know about "a large fraction of people in the developed world."

You don't even need to do bloodwork. You just need to be aware that vitamin D deficiency may potentially cause COVID, and then increase your vitamin D intake.

This must be the weirdest Vitamin D take yet. Whatever Vitamin D does, likely nothing, it does not cause COVID.

OP does say _deficiency_, so it doesn't sound like they're claiming Vitamin D causes COVID?

A Vitamin D deficiency can still not cause COVID, why would you think that?

Fair enough, yeah, when you put it like that, it's obviously false haha.

So I don't believe that Vitamin D prevents COVID but I still increased my intake of Vitamin D because it seems like Vitamin D deficiency increased the severity of COVID. I wear a mask and practice social distancing to prevent COVID.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385774/ is a UK study from July that doesn't come to any conclusions but they say "Our opinion is that if vitamin D does in fact reduce the severity of COVID-19 with regard to pneumonia/ARDS, inflammation, inflammatory cytokines, and thrombosis, then supplements would offer a relatively easy option to decrease the impact of the pandemic."

I think you may have misread the parent comment, which reads “vitamin D deficiency”.

Vitamin D deficiency also does not cause COVID.

Also in Seattle, every annual me or my wife has had includes a vitamin D check. Even at different hospitals.

Huh, I had to ask specifically for it during my annual. Still salty about that since my insurance supposedly covers annual physicals but asking for the test meant that I was going beyond a routine physical and so they coded it as an office visit and billed me a not insignificant amount for it (for the visit, not the test itself, which was extra). Talking to the billing department and the insurance company got me nowhere.

I donate blood. The American Red Cross sometimes gives away small gifts ($5 Amazon Gift Card, windbreaker with ARC logo, etc.) to promote donation. The are now testing blood for COVID so I've had one free negative test so far.

There are different tests that you can get from places like LabCorp or Quest Diagnostics - doctors working for these places prescribe the test. Anyway, since ARC is testing your blood anyway, it seemed like a reasonable incentive would be to test your blood for Vitamin D deficiency. Or testosterone or cholesterol levels or whatever you wanted from a menu of choices.

That would be nice but blood tests aren't free and blood banks would have to pass that cost on to their customers. The main reason they tested for SARS-CoV-2 antibodies was to identify potential convalescent serum donors.

I agree, but I think there are a ton of people who take various multivitamins, apparently a slight majority of Americans and 70% of Americans over 65, so I think that plays a large role here.

I have told everyone around me to make sure that they do not have a vitamin D deficiency because it "might" help prevent severe cases of COVID-19. I even bought some pills for my mother in law and another friend. So around me vitamin D levels are definitely higher than in previous years.

Also this: "Vitamin D levels were represented by measures of 25(OH)D which, despite being the most commonly assessed vitamin D metabolite in a clinical setting, does not directly measure the activated form of vitamin D and its measurement and relevance to health are under discussion.38"

It still tells you that the effect cannot be huge, otherwise it would have shown up here too.

Yeah, this seems like someone said: 'If it's a huge effect, we should be able to see it with a relatively weak study.' As it turns out, the weak study turned up nothing, indicating it's either a weaker effect or the study was pointed at the wrong people in one way or another (eg, northern europeans may have different response from people in india, or there's a smaller subpopulation that it makes a difference for, but they get lost in the bigger study).

I am lazy and did not read the study, sorry. But nowhere in the comments I see discussion related to whether it somehow accounts for dietary variance in vitamin D intake via fortified products. In Sweden, for example, because we are so far north, milk is routinely fortified with vitamin D. So even if a person has a genetic variance for low vitamin D, they will still be supplemented without actively doing anything, as long as they drink milk. On the other hand it stands to reason that if foodstuff fortification had a significant effect on vitD levels in population AND vitD had significant effect on immunity / severity of covid-19 then Sweden would have statistically significantly lower covid-19 infection and mortality rates than countries where food fortification with vitD is not practiced. Afaik that is not the case, otoh there is an insane amount of confounding variables so it might not be possible to assess such an effect in any scientifically valid manner.

Interesting post for me in general (didn't know that Sweden did that "enrichment" + destroys at the same time my idea of "milk" just being "milk").

In general I would think that if there are countries that are not poor in relation to vitamin D, then it would be Sweden & Norway, as I understand that fish does contain a lot of vitamin D (random hit here: https://www.healthline.com/nutrition/9-foods-high-in-vitamin... ) (at the same time I'm subjectively assuming that people in Sweden & Norway & other nordic countries eat a lot more fish that others) => I'm therefore conflicted: if that's correct, assuming as well that the population eats fish (relatively often), then why enrich milk with extra vitamin D?

Just Sweden does not eat an unreasonable amount of fish (see https://ourworldindata.org/grapher/fish-and-seafood-consumpt...). According to press release by Arla (the largest Swedish milk products company by far) some years ago (see https://www.arla.se/om-arla/nyheter-press/2015/pressrelease/..., in Swedish), there was a national study done by the government organization that controls foodstuffs which identified a large risk for vitamin D deficiency in general population, perhaps despite fish eating and law was passed making enrichment mandatory. So they are enriching.

Edit: removed sidenote about cooperation between government and private companies, since it seems that there is an actual law governing this stuff. Almost all milk, milk-like and fatty products (such as margarine), except cheese, must be enriched (see https://kontrollwiki.livsmedelsverket.se/artikel/448/livsmed..., in Swedish).

Edit++: Apparently data from the national study about food habits is available via an API which I think is super cute, see https://www.livsmedelsverket.se/om-oss/psidata/apimatvanor (also in Swedish, but hey, Google Translate is your friend)

Puah - ok, that's surprising, at least for me :)

Thanks!

Yet when it comes to articles that suggest links between Vitamin D and COVID severity, they may not even be studies, but rarely will the top comment be the one calling out the caveats.

It's an interesting reflection of how even HN's fairly simple mechanism of ranking comments promotes groupthink.

FWIW, I take daily Vitamin D tablets because when COVID was fairly new my doctor suggested there might be a link, and gave me a prescription that would help maintain my vitamin D levels.