11 ms·

Vitamin D uncorrelated with Covid severity in those of European descent

265 points by whoisburbansky 6y ago

WoodenChair 6y ago
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)
minikites 6y ago
First it was vitamin C that cured everything, now it's vitamin D. I'm predicting the next "miracle vitamin" will be vitamin E.
- mojuba 6y ago
  Or an artificial vitamin C++
  - trhway 6y ago
    the future here is iron oxide. Wrt. the original post there is also another correlation - vitamin D insufficiency is more prevalent in African American and Latin populations and those populations are more seriously affected by Covid. Also i think genetic predisposition to vitamin D that the original post uses doesn't matter much (until it hits pathological edges of course) because daily exposure to Sun would be more important factor than genetic predisposition.
    - Sunspark 6y ago
      Yes and no. If you live in a northern hemisphere country, it is possible to spend hours in the sunlight with pale skin during the colder months and not receive enough vitamin D if you don't have supplemental sources.
      - metalliqaz 6y ago
        I seem to remember this "sun" thing you are talking about. Don't think I've seen it since sometime in October.
- hammock 6y ago
  That already happened in the 90s
- GuB-42 6y ago
  Vitamin C certainly helps with scurvy. I think the big question is about the effect of vitamin D deficiency on COVID-19. It has been shown that vitamin D deficiency has a number of detrimental health effects, some of them related to the immune system. It is not that much of a stretch to think that if makes things worse for COVID-19 patients. As always with vitamins and other micro-nutrients, not being deficient is important, but if you are not deficient, you don't really need more. In the case of vitamin D, with winter and an indoors lifestyle, it is thought that many people are deficient. Being dark skinned and living in higher latitudes certainly doesn't help either.
nradov 6y ago
This site has an index of most of the studies on Vitamin D and COVID-19. Before commenting here I recommend at least reading those abstracts. https://vitamin-d-covid.shotwell.ca/ https://vitamin-d-covid.shotwell.ca/
- deleted 6y ago
  [deleted]
curiousgal 6y ago
Let X be a standard normal variable (mean 0, variance 1). Let Y be equal to X*X. What would the correlation between X and Y be? Edit: point being that non-correlation doesn't mean independence.
- whoisburbansky 6y ago
  The correlation here averages out to zero because X can be negative but Y can't, right, what are you trying to show here?
  - curiousgal 6y ago
    It's a standard example of why non-correlation doesn't mean independence.
  - klmadfejno 6y ago
    Not only that, but while there's no LINEAR correlation, there's a perfect non linear function that any half-credible scientist would identify.
    - whoisburbansky 6y ago
      Agreed, but I still don't see how that's relevant to the Vitamin D/Covid severity correlation question. Presumably you aren't modeling either of the associated parameters with random variables that can be negative, and so even if one were a non linear function of the other, the linear correlation wouldn't be zero?
      - klmadfejno 6y ago
        shrug. You could imagine, for example, that too little Vitamin D is bad, and too much is bad, and arrive at a similarly (flipped) nonlinear fit with negligible linear correlation
- legerdemain 6y ago
  Sure, and another way to get a zero correlation is if you arrange all the data points evenly around a circle. Are you seriously suggesting that authors who took the energy to get a manuscript reviewed and published in a BMJ publication wouldn't examine a scatter plot or check the estimate of a quadratic trend that their analysis software almost certainly outputs?
tgb 6y ago
Two thoughts: 1) Vitamin D levles is strongly correlated with physical activity levels, so a mere observational study can be strongly confounded - which may be part of why this study finds disagrees with some the merely correlational studies in the past. 2) This study is a Mendelian Randomization study, where since you haven't randomized individuals' Vitamin D levels, you instead assume that their genetics are random (you either get a variant from your parent or not, by chance) and that genetics may cause Vitamin D levels. So if those genetic variants are correlated with COVID outcomes, then we say it's because of Vitamin D. Notice the problem? You need to assume that the genetics do not affect anything else except via Vitamin D. Now I think that's where this is very tricky: they're identified variants that predispose someone to high/low Vitamin D via a genome-wide study, i.e. just check everything for correlation with Vitamin D. The obvious problem is that correlation isn't causation so some or most or all of those variants will influence other factors too, and it becomes harder to say that Vitamin D is the reason COVID was severe or not. Ideally you have instead hand-picked variants with obvious known mechanisms as to how they affect Vitamin D metabolism, say. In lieu of that, you have to do various tests that try to spot how problematic this problem is. (Look for "pleiotropy" in the paper. Back-causation is the other problem you need to consider generally, but it's not really a concern here.) Personally I don't trust those tests further than I can throw them as they make some questionable assumptions. The main method this paper uses is MR-Egger, which (IIRC) assumes that the non-Vitamin D ways the variants affect the outcome are inconsistent across different variants. Like, this variant might act on Vitamin D and immune system but this other one acts on Vitamin D and your cardiac system so we don't expect the non-Vitamin D portion to be consistent. That seems highly questionable, even I would expect the typical state to not be that, where variants that affect Vitamin D are likely in pathways that also affect specific, consistent other attributes. The authors are aware of these difficulties. I can't assess whether they've succeeded in addressing them or not, but I believe the problem is extremely difficult and they have an up-hill battle.
- CoolGuySteve 6y ago
  Vitamin D deficiency is caused by a lack of exposure to UV light. I wonder if the retrospective studies that correlate low vitamin D levels to worse COVID outcomes are actually finding that people who spend more time indoors are more likely to have a higher viral load due to sharing more air with contagious people in poorly ventilated areas.
robocat 6y ago
This study was “using participants of European descent.” It is not a study intended to say anything about the correlation/non-correlation for non-Europeans.
dukeofdoom 6y ago
Sine majority of those dying are very old, and often in nursing home or bed ridden. Wouldn't vitamin D levels just correlate with age, since they spend less time outdoors
- jansan 6y ago
  That is the question. Quite a few studies suggest a correlation of Vitamin D and COVID-19 severity, but we do not not if there is a causality or if vitamin D levels are just marker. But it is not wrong to avoid vitamin d deviciency in any case. It is also easy and cheap.
lmilcin 6y ago
My understanding is this. Europe is very far north compared to other countries. Half of people in Canada leave as close or closer to equator than Croatia, which in Europe is thought as hot climate. But that doesn't change the fact that for most of the Europe there is very little sunlight during winter and that europeans had to adapt to it by being more resistant to low amounts of sunlinght. See, we are already predisposed to sitting at home for extended periods of time.
- perardi 6y ago
  Europe is very far north compared to other countries. Today I learned: Europe is a country. Half of people in Canada leave as close or closer to equator than Croatia Well I be damned, Toronto is actually closer to the equator. Though Toronto is always way more south than I “feel” it is. https://www.wolframalpha.com/input/?i=latitude+toronto+canada+vs+latitude+zagreb+croatia+vs+latitude+montreal+canada https://www.wolframalpha.com/input/?i=latitude+toronto+canad...
  - hombre_fatal 6y ago
    > Today I learned: Europe is a country. Please leave the Reddit gotchas on Reddit. They don't think Europe is literally a country. It does us no good to have people like you looking for silly interpretations that you can point out. Anyone can shorten "most of the countries that make up Europe" to "Europe" on my watch because I'm interested in their point, not trying to catch them in a gotcha.
    - redis_mlc 6y ago
      I like the feigned dismay that somebody on HN would be pedantic. As one commenter said last year, "This is HN. Pedantry is our job."
    - 488pista 6y ago
      Many people think Asia is a country in North America and Europe tho.
  - 6y ago
zxcb1 6y ago
The effects of excessive UV exposure are known; the effects of UV deficiency are ...
- axaxs 6y ago
  Not a scientist...but strongly feel humans would not have diverged into different skin colors if UV deficiency weren't a fairly large issue.
  - nomel 6y ago
    Perhaps not: https://www.ucsf.edu/news/2016/06/403401/darker-skin-stronger-skin-says-new-view-human-skin-color https://www.ucsf.edu/news/2016/06/403401/darker-skin-stronge... I would assume that looking for UV deficiency related statistics would be trivial with dark skinned people living in a European country.
    - axaxs 6y ago
      Interesting, thanks. When I made that statement I thought to myself the only other reason that makes sense would be if pigmentation was somehow expensive, which is what the article concludes if I understand correctly - "a pigmented skin barrier, which is metabolically expensive to produce, became less important" As for the latter comment, I've read numerous times that black adults in the US have lower vitamin d levels. I guess back to the GP's point, is there proof that is a detrimental thing?
efxhoy 6y ago
I don’t know genetics but this smells like weak instrument to me? The genetic risk score instruments explained only 2% of variation in vitamin D deficiency. Relevance in the first stage of an instrumental variables analysis is crucial to get power. So the analysis is using only 2% of the variation in vitamin D deficiency to try to explain COVID severity, and unsurprisingly getting not significant results. Can anyone who’s up to speed on their stats figure out how big the causal effect of vitamin D deficiency on COVID severity would have to be to be detected by this data and method?
deleted 6y ago
[deleted]
deleted 6y ago
[deleted]
annoyingnoob 6y ago
I take Vitamin D because my levels are low without it. A study like this sure isn't changing anything I do. There are reasons beyond covid to have a proper Vitamin D level in your body.
rbrbr 6y ago
Fact: Vitamin D deficiency leads to a weakened immune system which is partially attributing to a higher level of infectious diseases during low sun winter seasons in affected countries. Fact: a strong immune system reduces the chance of contracting COVID-19. End of story.
- nafix 6y ago
  Nicely stated.
- jansan 6y ago
  Another fact: Preventing vitamin D deficiency is easy, cheap and almost risk free.
- lambdaba 6y ago
  Anecdote: supplementing high dose vitamin d in winter did wonders for my energy levels, despite having been outside all summer
- lambdaba 6y ago
  Fact: vitamin d is crucial for T-cell immunity - "Another reason vitamin D is important: It gets T cells going - Scientific American Blog Network" https://blogs.scientificamerican.com/observations/another-reason-vitamin-d-is-important-it-gets-t-cells-going/ https://blogs.scientificamerican.com/observations/another-re... Fact: proper T-cell immunity is how you get a mild / asymptomatic covid form
- catlifeonmars 6y ago
  I think this is generally good advice, especially for individuals, but it’s hardly the end of the story. It’s critical to establish causal links as well as effect size of various factors in order to properly allocate resources to fight a pandemic.
coding123 6y ago
> to generate the genetic risk score for vitamin D deficiency That's what the entire paper is based on.
INTPenis 6y ago
If you're taking skin color into account (european descent in other words) then you should also take geography into account. A lighter skin in southern latitude vs. darker skin in northern latitudes. It's not a simple thing but I do believe vitamin D had a big role to play to boost immune systems. We've been using it for years here in Sweden, every winter. I even found a video online from a local TV channel that was recorded in 2019, reviewing different brands of Vitamin D and suggesting how many IUs you need every day.
tinus_hn 6y ago
The title of the report 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 The title of this submission is editorialized.
Blikkentrekker 6y ago
What exactly am I supposed to read into “European descent”. For something so prominently featured in the title, implying some significance to it, I cannot find any further explanation of it: > We predominately used previously published and freely available data for this study. The study by Jiang et al 19 is a meta-analysis of GWAs of vitamin D levels carried out using participants of European descent. The COVID-19 Host Genetics Initiative20 uses data from multiple cohort studies,21–26 including the UK Biobank (UKB). Does it mean “U.K. residents”, “European residents”, or “persons whose ancestors had European residence, wherever they be located now.” and to how many generations back is this?
- throwaway2245 6y ago
  It is a genetics term of art that means "white people". This is particularly important for Vitamin D, since the colour of your skin has a meaningful influence on Vitamin D production. The research article says "Our results also cannot be used to comment on the relationship between vitamin D and COVID-19 in non-Europeans." - they take no stance for non-Europeans. This reflects the common point that most medical/genetic data is sourced from Europe and North America: there often isn't enough data for People of Colour to accurately comment on points of racial difference, whether white people have been sourced deliberately or inadvertently.
  - Blikkentrekker 6y ago
    Methinks that would be letting scientific thought be influenced by cultural memes. “race” is not really a distinction that has any actual biological merit and is purely a cultural creation, There is really no expectation that different “races” would be statistically differently affected any more than something other completely arbitrary and cultural such as “office workers" or “virgins”. > This is particularly important for Vitamin D, since the colour of your skin has a meaningful influence on Vitamin D production. Yes, but the lines between races is arbitrary and culturally drafted. The same man who would be considered “black” in the U.K. would be considered “white” in Kenya. What test is even used as discriminant of “white people”? self-report, a pencil test? In particular, I've seen many persons who are apparently considered “not white” in the U.S.A. whose skin complexion woud surely not have such a meaningful influence. Consider also the story with Rachel Dolezal, which showed well that race is a cultural meme, not a phænotypically defined set of traits, nor something upon which a biological significance can be built.
ummonk 6y ago
In other words their sample wasn't large enough to pick up the small changes in Covid risk/severity you would see based on genetic predisposition to produce slightly different levels of vitamin D.
anon321321323 6y ago
This study doesn't mean much to me. I started taking Vitamin D as soon as I heard about it being of benefit ... early last year. My reading of the literature showed that Vitamin D is useful for so many health effects due to its many interactions. Being low in general isn't a good idea. I'm in direct sunshine for around 2 hours a day. White skin with a tan. So I chose a dosage that shouldn't cause imminent death and then a few weeks after I got a full blood test. Mainly to confirm that side effects of too much vitamin D weren't taking hold. Surprisingly even with taking the capsule once a day I found I was still low. So the doctor upped my amateur considered dose to his recommendation. Get your own blood tested and confirm for yourself. Leave the anti-vitamin people to themselves. I got repeatedly criticized for supplementing. People quickly shut up when you show your blood results. I realise anecdata is fun to mock, but in my sample size if I'd seen a study like this and fully believed it then maybe I wouldn't have done the blood test. I wonder how many other people are low in vitamin D and have no clue.
tpoacher 6y ago
I always find it a bit weird when papers say "we found no evidence" and then slap a p=0.10 next to it ... surely a compatibility with the null hypothesis of only 10% is some evidence ...

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)

minikites 6y ago

First it was vitamin C that cured everything, now it's vitamin D. I'm predicting the next "miracle vitamin" will be vitamin E.

mojuba 6y ago
Or an artificial vitamin C++
- trhway 6y ago
  the future here is iron oxide. Wrt. the original post there is also another correlation - vitamin D insufficiency is more prevalent in African American and Latin populations and those populations are more seriously affected by Covid. Also i think genetic predisposition to vitamin D that the original post uses doesn't matter much (until it hits pathological edges of course) because daily exposure to Sun would be more important factor than genetic predisposition.
  - Sunspark 6y ago
    Yes and no. If you live in a northern hemisphere country, it is possible to spend hours in the sunlight with pale skin during the colder months and not receive enough vitamin D if you don't have supplemental sources.
    - metalliqaz 6y ago
      I seem to remember this "sun" thing you are talking about. Don't think I've seen it since sometime in October.
hammock 6y ago
That already happened in the 90s
GuB-42 6y ago
Vitamin C certainly helps with scurvy. I think the big question is about the effect of vitamin D deficiency on COVID-19. It has been shown that vitamin D deficiency has a number of detrimental health effects, some of them related to the immune system. It is not that much of a stretch to think that if makes things worse for COVID-19 patients. As always with vitamins and other micro-nutrients, not being deficient is important, but if you are not deficient, you don't really need more. In the case of vitamin D, with winter and an indoors lifestyle, it is thought that many people are deficient. Being dark skinned and living in higher latitudes certainly doesn't help either.

nradov 6y ago

This site has an index of most of the studies on Vitamin D and COVID-19. Before commenting here I recommend at least reading those abstracts. https://vitamin-d-covid.shotwell.ca/ https://vitamin-d-covid.shotwell.ca/

deleted 6y ago
[deleted]

curiousgal 6y ago

Let X be a standard normal variable (mean 0, variance 1). Let Y be equal to X*X. What would the correlation between X and Y be? Edit: point being that non-correlation doesn't mean independence.

whoisburbansky 6y ago
The correlation here averages out to zero because X can be negative but Y can't, right, what are you trying to show here?
- curiousgal 6y ago
  It's a standard example of why non-correlation doesn't mean independence.
- klmadfejno 6y ago
  Not only that, but while there's no LINEAR correlation, there's a perfect non linear function that any half-credible scientist would identify.
  - whoisburbansky 6y ago
    Agreed, but I still don't see how that's relevant to the Vitamin D/Covid severity correlation question. Presumably you aren't modeling either of the associated parameters with random variables that can be negative, and so even if one were a non linear function of the other, the linear correlation wouldn't be zero?
    - klmadfejno 6y ago
      shrug. You could imagine, for example, that too little Vitamin D is bad, and too much is bad, and arrive at a similarly (flipped) nonlinear fit with negligible linear correlation
legerdemain 6y ago
Sure, and another way to get a zero correlation is if you arrange all the data points evenly around a circle. Are you seriously suggesting that authors who took the energy to get a manuscript reviewed and published in a BMJ publication wouldn't examine a scatter plot or check the estimate of a quadratic trend that their analysis software almost certainly outputs?

tgb 6y ago

Two thoughts: 1) Vitamin D levles is strongly correlated with physical activity levels, so a mere observational study can be strongly confounded - which may be part of why this study finds disagrees with some the merely correlational studies in the past. 2) This study is a Mendelian Randomization study, where since you haven't randomized individuals' Vitamin D levels, you instead assume that their genetics are random (you either get a variant from your parent or not, by chance) and that genetics may cause Vitamin D levels. So if those genetic variants are correlated with COVID outcomes, then we say it's because of Vitamin D. Notice the problem? You need to assume that the genetics do not affect anything else except via Vitamin D. Now I think that's where this is very tricky: they're identified variants that predispose someone to high/low Vitamin D via a genome-wide study, i.e. just check everything for correlation with Vitamin D. The obvious problem is that correlation isn't causation so some or most or all of those variants will influence other factors too, and it becomes harder to say that Vitamin D is the reason COVID was severe or not. Ideally you have instead hand-picked variants with obvious known mechanisms as to how they affect Vitamin D metabolism, say. In lieu of that, you have to do various tests that try to spot how problematic this problem is. (Look for "pleiotropy" in the paper. Back-causation is the other problem you need to consider generally, but it's not really a concern here.) Personally I don't trust those tests further than I can throw them as they make some questionable assumptions. The main method this paper uses is MR-Egger, which (IIRC) assumes that the non-Vitamin D ways the variants affect the outcome are inconsistent across different variants. Like, this variant might act on Vitamin D and immune system but this other one acts on Vitamin D and your cardiac system so we don't expect the non-Vitamin D portion to be consistent. That seems highly questionable, even I would expect the typical state to not be that, where variants that affect Vitamin D are likely in pathways that also affect specific, consistent other attributes. The authors are aware of these difficulties. I can't assess whether they've succeeded in addressing them or not, but I believe the problem is extremely difficult and they have an up-hill battle.

CoolGuySteve 6y ago
Vitamin D deficiency is caused by a lack of exposure to UV light. I wonder if the retrospective studies that correlate low vitamin D levels to worse COVID outcomes are actually finding that people who spend more time indoors are more likely to have a higher viral load due to sharing more air with contagious people in poorly ventilated areas.

robocat 6y ago

This study was “using participants of European descent.” It is not a study intended to say anything about the correlation/non-correlation for non-Europeans.

dukeofdoom 6y ago

Sine majority of those dying are very old, and often in nursing home or bed ridden. Wouldn't vitamin D levels just correlate with age, since they spend less time outdoors

jansan 6y ago
That is the question. Quite a few studies suggest a correlation of Vitamin D and COVID-19 severity, but we do not not if there is a causality or if vitamin D levels are just marker. But it is not wrong to avoid vitamin d deviciency in any case. It is also easy and cheap.

lmilcin 6y ago

My understanding is this. Europe is very far north compared to other countries. Half of people in Canada leave as close or closer to equator than Croatia, which in Europe is thought as hot climate. But that doesn't change the fact that for most of the Europe there is very little sunlight during winter and that europeans had to adapt to it by being more resistant to low amounts of sunlinght. See, we are already predisposed to sitting at home for extended periods of time.

perardi 6y ago
Europe is very far north compared to other countries. Today I learned: Europe is a country. Half of people in Canada leave as close or closer to equator than Croatia Well I be damned, Toronto is actually closer to the equator. Though Toronto is always way more south than I “feel” it is. https://www.wolframalpha.com/input/?i=latitude+toronto+canada+vs+latitude+zagreb+croatia+vs+latitude+montreal+canada https://www.wolframalpha.com/input/?i=latitude+toronto+canad...
- hombre_fatal 6y ago
  > Today I learned: Europe is a country. Please leave the Reddit gotchas on Reddit. They don't think Europe is literally a country. It does us no good to have people like you looking for silly interpretations that you can point out. Anyone can shorten "most of the countries that make up Europe" to "Europe" on my watch because I'm interested in their point, not trying to catch them in a gotcha.
  - redis_mlc 6y ago
    I like the feigned dismay that somebody on HN would be pedantic. As one commenter said last year, "This is HN. Pedantry is our job."
  - 488pista 6y ago
    Many people think Asia is a country in North America and Europe tho.
- 6y ago

zxcb1 6y ago

The effects of excessive UV exposure are known; the effects of UV deficiency are ...

axaxs 6y ago
Not a scientist...but strongly feel humans would not have diverged into different skin colors if UV deficiency weren't a fairly large issue.
- nomel 6y ago
  Perhaps not: https://www.ucsf.edu/news/2016/06/403401/darker-skin-stronger-skin-says-new-view-human-skin-color https://www.ucsf.edu/news/2016/06/403401/darker-skin-stronge... I would assume that looking for UV deficiency related statistics would be trivial with dark skinned people living in a European country.
  - axaxs 6y ago
    Interesting, thanks. When I made that statement I thought to myself the only other reason that makes sense would be if pigmentation was somehow expensive, which is what the article concludes if I understand correctly - "a pigmented skin barrier, which is metabolically expensive to produce, became less important" As for the latter comment, I've read numerous times that black adults in the US have lower vitamin d levels. I guess back to the GP's point, is there proof that is a detrimental thing?

efxhoy 6y ago

I don’t know genetics but this smells like weak instrument to me? The genetic risk score instruments explained only 2% of variation in vitamin D deficiency. Relevance in the first stage of an instrumental variables analysis is crucial to get power. So the analysis is using only 2% of the variation in vitamin D deficiency to try to explain COVID severity, and unsurprisingly getting not significant results. Can anyone who’s up to speed on their stats figure out how big the causal effect of vitamin D deficiency on COVID severity would have to be to be detected by this data and method?

deleted 6y ago

[deleted]

deleted 6y ago

[deleted]

annoyingnoob 6y ago

I take Vitamin D because my levels are low without it. A study like this sure isn't changing anything I do. There are reasons beyond covid to have a proper Vitamin D level in your body.

rbrbr 6y ago

Fact: Vitamin D deficiency leads to a weakened immune system which is partially attributing to a higher level of infectious diseases during low sun winter seasons in affected countries. Fact: a strong immune system reduces the chance of contracting COVID-19. End of story.

nafix 6y ago
Nicely stated.
jansan 6y ago
Another fact: Preventing vitamin D deficiency is easy, cheap and almost risk free.
lambdaba 6y ago
Anecdote: supplementing high dose vitamin d in winter did wonders for my energy levels, despite having been outside all summer
lambdaba 6y ago
Fact: vitamin d is crucial for T-cell immunity - "Another reason vitamin D is important: It gets T cells going - Scientific American Blog Network" https://blogs.scientificamerican.com/observations/another-reason-vitamin-d-is-important-it-gets-t-cells-going/ https://blogs.scientificamerican.com/observations/another-re... Fact: proper T-cell immunity is how you get a mild / asymptomatic covid form
catlifeonmars 6y ago
I think this is generally good advice, especially for individuals, but it’s hardly the end of the story. It’s critical to establish causal links as well as effect size of various factors in order to properly allocate resources to fight a pandemic.

coding123 6y ago

> to generate the genetic risk score for vitamin D deficiency That's what the entire paper is based on.

INTPenis 6y ago

If you're taking skin color into account (european descent in other words) then you should also take geography into account. A lighter skin in southern latitude vs. darker skin in northern latitudes. It's not a simple thing but I do believe vitamin D had a big role to play to boost immune systems. We've been using it for years here in Sweden, every winter. I even found a video online from a local TV channel that was recorded in 2019, reviewing different brands of Vitamin D and suggesting how many IUs you need every day.

tinus_hn 6y ago

The title of the report 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 The title of this submission is editorialized.

Blikkentrekker 6y ago

What exactly am I supposed to read into “European descent”. For something so prominently featured in the title, implying some significance to it, I cannot find any further explanation of it: > We predominately used previously published and freely available data for this study. The study by Jiang et al 19 is a meta-analysis of GWAs of vitamin D levels carried out using participants of European descent. The COVID-19 Host Genetics Initiative20 uses data from multiple cohort studies,21–26 including the UK Biobank (UKB). Does it mean “U.K. residents”, “European residents”, or “persons whose ancestors had European residence, wherever they be located now.” and to how many generations back is this?

throwaway2245 6y ago
It is a genetics term of art that means "white people". This is particularly important for Vitamin D, since the colour of your skin has a meaningful influence on Vitamin D production. The research article says "Our results also cannot be used to comment on the relationship between vitamin D and COVID-19 in non-Europeans." - they take no stance for non-Europeans. This reflects the common point that most medical/genetic data is sourced from Europe and North America: there often isn't enough data for People of Colour to accurately comment on points of racial difference, whether white people have been sourced deliberately or inadvertently.
- Blikkentrekker 6y ago
  Methinks that would be letting scientific thought be influenced by cultural memes. “race” is not really a distinction that has any actual biological merit and is purely a cultural creation, There is really no expectation that different “races” would be statistically differently affected any more than something other completely arbitrary and cultural such as “office workers" or “virgins”. > This is particularly important for Vitamin D, since the colour of your skin has a meaningful influence on Vitamin D production. Yes, but the lines between races is arbitrary and culturally drafted. The same man who would be considered “black” in the U.K. would be considered “white” in Kenya. What test is even used as discriminant of “white people”? self-report, a pencil test? In particular, I've seen many persons who are apparently considered “not white” in the U.S.A. whose skin complexion woud surely not have such a meaningful influence. Consider also the story with Rachel Dolezal, which showed well that race is a cultural meme, not a phænotypically defined set of traits, nor something upon which a biological significance can be built.

ummonk 6y ago

In other words their sample wasn't large enough to pick up the small changes in Covid risk/severity you would see based on genetic predisposition to produce slightly different levels of vitamin D.

anon321321323 6y ago

This study doesn't mean much to me. I started taking Vitamin D as soon as I heard about it being of benefit ... early last year. My reading of the literature showed that Vitamin D is useful for so many health effects due to its many interactions. Being low in general isn't a good idea. I'm in direct sunshine for around 2 hours a day. White skin with a tan. So I chose a dosage that shouldn't cause imminent death and then a few weeks after I got a full blood test. Mainly to confirm that side effects of too much vitamin D weren't taking hold. Surprisingly even with taking the capsule once a day I found I was still low. So the doctor upped my amateur considered dose to his recommendation. Get your own blood tested and confirm for yourself. Leave the anti-vitamin people to themselves. I got repeatedly criticized for supplementing. People quickly shut up when you show your blood results. I realise anecdata is fun to mock, but in my sample size if I'd seen a study like this and fully believed it then maybe I wouldn't have done the blood test. I wonder how many other people are low in vitamin D and have no clue.

tpoacher 6y ago

I always find it a bit weird when papers say "we found no evidence" and then slap a p=0.10 next to it ... surely a compatibility with the null hypothesis of only 10% is some evidence ...