7 ms·

Note that this study was not a placebo controlled trial, and it was not even based on data about actual vitamin D levels. Instead, it was retrospective analysis

Note that this study was not a placebo controlled trial, and it was not even based on data about actual vitamin D levels. Instead, it was retrospective analysis using instrumental variables. I'm not saying its conclusions are wrong, I'm just saying that IMHO it's not a definitive study. Quoting the study: "Although we will need well-powered and carefully executed randomised trials and a subsequent meta-analysis of the different studies to provide an accurate estimate of the effect of vitamin D on COVID-19 prevention and severity, we can anticipate the results of such studies by comparing individuals who are genetically predisposed to lower vitamin D levels with those who are not, based on the Mendelian randomisation (MR) paradigm. In a randomised controlled trial, we would minimise the effect of confounding factors by randomly assigning participants to a treatment group receiving vitamin D supplements or to a control group receiving a placebo and thus estimate the true effect of the intervention. In the natural experiment of MR, genetic variants predisposing the individual to higher levels of vitamin D are assigned randomly at conception, based on the genetic polymorphisms of their parents, in relation to other possible confounding traits. As genetic polymorphisms remain constant throughout life and the individual does not change their vitamin D intake according to their genotype, the use of this information can provide indirect evidence of causality.18 Here, using data from genome-wide association (GWA) studies for vitamin D levels, vitamin D deficiency and COVID-19 incidence and severity, we test whether genetically increased vitamin D levels are associated with SARS-CoV-2 infection risk and COVID-19 severity."

whoisburbansky 6y ago
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.
- nick__m 6y ago
  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
  - whoisburbansky 6y ago
    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!
wxnx 6y ago
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
- tacitusarc 6y ago
  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?
howmayiannoyyou 6y ago
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"
david_draco 6y ago
It still tells you that the effect cannot be huge, otherwise it would have shown up here too.
- deleted 6y ago
  [deleted]
- sdenton4 6y ago
  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).
Karrot_Kream 6y ago
> 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.
- deleted 6y ago
  [deleted]
- raverbashing 6y ago
  > "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
  - Karrot_Kream 6y ago
    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.
tlb 6y ago
> 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.
- whoisburbansky 6y ago
  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."
  - the__prestige 6y ago
    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.
    - stefan_ 6y ago
      This must be the weirdest Vitamin D take yet. Whatever Vitamin D does, likely nothing, it does not cause COVID.
      - whoisburbansky 6y ago
        OP does say _deficiency_, so it doesn't sound like they're claiming Vitamin D causes COVID?
        stefan_ 6y ago
        A Vitamin D deficiency can still not cause COVID, why would you think that?
addicted 6y ago
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.
alicorn 6y ago
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.
- zepearl 6y ago
  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-d#2.-Herring-and-sardines 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?
  - alicorn 6y ago
    Just Sweden does not eat an unreasonable amount of fish (see https://ourworldindata.org/grapher/fish-and-seafood-consumption-per-capita 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/arla-dubblar-maengden-d-vitamin-i-mjoelken-1254843/ 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/livsmedel-som-maste-berikas 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 https://www.livsmedelsverket.se/om-oss/psidata/apimatvanor (also in Swedish, but hey, Google Translate is your friend)

whoisburbansky 6y ago

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.

nick__m 6y ago
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
- whoisburbansky 6y ago
  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!

wxnx 6y ago

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

tacitusarc 6y ago
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?

howmayiannoyyou 6y ago

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"

david_draco 6y ago

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

deleted 6y ago
[deleted]
sdenton4 6y ago
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).

Karrot_Kream 6y ago

> 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.

deleted 6y ago
[deleted]
raverbashing 6y ago
> "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
- Karrot_Kream 6y ago
  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.

tlb 6y ago

> 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.

whoisburbansky 6y ago
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."
- the__prestige 6y ago
  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.
  - stefan_ 6y ago
    This must be the weirdest Vitamin D take yet. Whatever Vitamin D does, likely nothing, it does not cause COVID.
    - whoisburbansky 6y ago
      OP does say _deficiency_, so it doesn't sound like they're claiming Vitamin D causes COVID?
      - stefan_ 6y ago
        A Vitamin D deficiency can still not cause COVID, why would you think that?

addicted 6y ago

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.

alicorn 6y ago

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.

zepearl 6y ago
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-d#2.-Herring-and-sardines 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?
- alicorn 6y ago
  Just Sweden does not eat an unreasonable amount of fish (see https://ourworldindata.org/grapher/fish-and-seafood-consumption-per-capita 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/arla-dubblar-maengden-d-vitamin-i-mjoelken-1254843/ 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/livsmedel-som-maste-berikas 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 https://www.livsmedelsverket.se/om-oss/psidata/apimatvanor (also in Swedish, but hey, Google Translate is your friend)