Vitamin D uncorrelated with Covid severity in those of European descent
nutrition.bmj.com
nutrition.bmj.com
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."
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.
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
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.
How exactly? The only mention I see is using the British Biobank data which is 10-15 years old
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...
> 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.
Genetic variants associated with vitamin D deficiency appear to be uncorrelated with the severity of COVID-19[1] doi:10.1038/s41588-018-0099-7
[2] doi:10.1093/hmg/ddy163
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.
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.
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."
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?
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)
Thanks!
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.
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.
I generally question Mendelian randomization (MR) results by default as well, but I do think there is good MR research out there. Some positive things to look for (IMO): attempts to quantify (or at least discuss qualitatively) horizontal pleiotropy (e.g. by looking at known human protein-protein interactions), attempts to mitigate the effects of horizontal pleiotropy through methodology (rare, not sure if I've actually seen this in papers with more exciting results, but an active research area), and attempts to quantify causal loops / elucidate the broader causal structure.
There's also a fair bit of general research on the reliability of MR results [1, 2] which may be of interest to readers.
Additionally, there is a false intuition among people who regularly conduct association analyses but not MR studies that horizontal pleiotropy can only serve to increase the causal effect size. However, this is not true (mentioned in [2] but better elucidated mathematically in the instrumental variables literature): negative results (such as the one posted) can be induced by horizontal pleiotropy as well (of course, not saying that it was).
[1] doi:10.1038/s41588-018-0099-7
[2] doi:10.1093/hmg/ddy163
A popular motif (and perhaps the most illustrative example) is to restrict the instrument to be genotype variants within a specific gene, and use its protein product (for example, its serum concentration) as the exposure [1]. In this way, horizontal pleiotropy is significantly mitigated.
This is sort of a natural extension (on a statistical methodological level, really a simplification) of a popular technique where a drug which has a known protein target is used in a "factorial MR" scheme [2]. Unfortunately, I'm less familiar with the literature here because it's very domain-specific.
[1] doi:10.2337/dc18-2444
[2] doi:10.1016/j.jacc.2015.02.020
Edit: removed one of the references because it's a somewhat convoluted example, and on a deeper read, wasn't actually the paper I was thinking of.
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.
But generally being outdoors, on a grey winters day in the northern hemisphere, with just your face exposed, and having darker skin, for an hour, is not going to get you enough D.
30 min of sun exposure will give you the equivalent of 10,000 to 20,000 IU.
If you moderate your sun exposure and are responsible, there is no reason you can't use the sun to your advantage.
If you don't you're likely to become vitamin d deficient listening to that person.
For an acute infection I think it is a blunt instrument at best, as there is going to be a lot more noise in the inferred target variable.
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.
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+canad...
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.
Yes, it is. Europe is largely a country with free movement of people, goods, services and capital.
The difference between a country, an alliance, a confœderation, and a fœderation is as meaningless as the difference between a language family, and a language.
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?
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.
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?
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.
“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.
Genetic sample data is not truly randomised, and tends to greatly over-represent a particular subgroup of 10% of people who share common genetic markers (including recognisable phenotypic consequences such as: in general having white skin, and in general adults being tolerant to lactose) that are not globally common. For convenience, we'll say that groups of people with those markers are "of European descent".
The extent of the over-representation is so great that edge cases are likely to have no impact in changing the overall bias of the data.
As such, conclusions drawn globally should be treated at least with caution - and with suspicion when one of those genetic markers is highly relevant to the conclusion.
I'm still not sure as to what exactly the sampling is here and what “European descent” communicates? The way I see it it can mean any of the following:
- Participants were asked to self-report their “race”, any that did not report “white” were excluded.
- Participants were given a pencil test to determine their “whiteness”, those failing were excluded.
- Participation was drawn from U.K. residents
> The extent of the over-representation is so great that edge cases are likely to have no impact in changing the overall bias of the data.
You say so, but I feel this distinction is more a cultural meme than biologically meritful. I for instance rarely see, prominently in the title “in those of Boston descent” when all participants were selected from Boston, which could produce similar biases.
I feel it is likely that it is highlighted because they feel that “race” is more meaningful than it biologically is, and are attempting to draw inferences from it.
Try telling that to sufferers of sickle cell anaemia.
They’re not making a general statement about race, they’re relating it to a specific thing. “Race” may be an overloaded, and often misused term - certainly a misnomer - but it still can be used as a shorthand that is useful especially in medical contexts. Here, it’s probably to warn against generalising beyond whites, though the meaningfulness will be borne out by research with regards to this specific virus, not through your feelings or inferences about possible inferences.
And do you believe that the persons who in various cultures would be called “black” but are actually genetically 95+% “white” would be more likely to suffer from that? or conversely that the persons who are genetically 95% “black” but would in various cultures be called “white” are not?
Such risk factors do not of course care about arbitrary cultural racial classifications which are often noted to be asymmetrically contagious in various cultures.
> They’re not making a general statement about race, they’re relating it to a specific thing. “Race” may be an overloaded, and often misused term - certainly a misnomer - but it still can be used as a shorthand that is useful especially in medical contexts. Here, it’s probably to warn against generalising beyond whites, though the meaningfulness will be borne out by research with regards to this specific virus, not through your feelings or inferences about possible inferences.
If that be their intent, they firstly communicate it poorly and should have simply said so, and secondly it's useless.
Again, in various countries with a majority nonwhite population, a person who might genetically be 5% white, and 95% local population could conceivably be termed “white”: — is it their intention and your contention that the results of this research may then be applied to such a person that is effectively genetically close to local population?
Individuals and populations are different.
> Such risk factors do not of course care about arbitrary cultural racial classifications which are often noted to be asymmetrically contagious in various cultures.
Risk factors may not care but individuals in at-risk populations are likely care that knowledge of different risks to them, based on their race or not, is available.
> If that be their intent, they firstly communicate it poorly and should have simply said so, and secondly it's useless.
That's your contention, I'm yet to see a cogent argument or any evidence for this.
> Again, in various countries with a majority nonwhite population, a person who might genetically be 5% white, and 95% local population could conceivably be termed “white”: — is it their intention and your contention that the results of this research may then be applied to such a person that is effectively genetically close to local population?
Reading this, it is my belief that you have missed the point of the authors intent, the reasons for using race as a category in medicine, and all of the arguments put forth to you.
They do literally cite in words where they got their sample data in the first two sentences of the linked article.
This, and referencing an apartheid test for ethnicity, suggests you are no longer speaking in good faith. I have already explained why this is biologically highly relevant to this case.
There is no particular additional harm in claiming this research result applies in general to people with European descent, a known problem of bias in existing data sources that is known to have an impact on the quality of medical care, and whereby you can make your own decision as to whether this might apply globally.
There is potential additional harm in claiming this research result applies globally, since you are working with highly biased data, and applying solutions that appear to work for a distinct subset of the population might work ok but also might be harmful to the other 90% of people.
No, they do not. They say they used the U.K. biobank, but otherwise do not tell how they selected upon “European ancestry" in that bank.
> This, and referencing an apartheid test for ethnicity, suggests you are no longer speaking in good faith. I have already explained why this is biologically highly relevant to this case.
And I have argued why it isn't by the argument that an individual that is biologically “white” or almost fully white can culturally be considered “black”, depending on the culture, and obviously vitamin-D production cannot be assumed to care about such cultural divisions.
It has long been noted that many persons in the Anglo-Saxon world, particularly the U.S.A. that are referred to as “black” are genetically speaking effectively “white” and almost completely “of European ancestry”; — the article and those who replied to me are entirely unclear whether they are included or not in the sample.
> There is no harm in claiming this research result applies in general to people with European descent, a known problem of bias in existing data sources that is known to have an impact on the quality of medical care, and whereby you can make your own decision as to whether this might apply globally.
There is absolute harm in using vague terms of which no one exactly knows what it means.
What do you, for instance believe the actual selection of “with European ancestry" signifies here? What concrete, testable definition of “of European ancestry” was used?
> There is potential harm in claiming this research result applies globally, since you are working with highly biased data, and applying solutions that appear to work for a distinct subset of the population might work ok but also might be harmful to the other 90% of people.
Indeed there is, but there is no false dilemma here. — both can be as ridiculous as the other and in fact do not exclude each other, because the term “ancestry” is used, not “residence” which indeed implies that the result holds for persons of European descent, globally. One can be located anywhere in the world and still be “with European ancestry”.
The UK Biobank study is linked (and also has its own wikipedia page in any case).
This is simply how science research works. They are not repeating the information given in the source.
And I find that in practice if research include a vague criterion in it's very title, it tends to come with far clearer definitions of that criterion in it's body than this.
They asked people in the UK in a digitally supported questionnaire/interview, for their ethnicity.
(Wikipedia also mentions that UK Biobank is criticised for sampling bias towards wealthy white Brits)
As I said in another comment: I am entirely unsure how “of European descent” was selected upon and the research does not make it clear at all what it means by it, and it could mean any number of things.
For such a vague condition to be so prominently featured in the title, they could at least define how they selected upon it, if at all.
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.
It is not a study intended to say anything about the correlation/non-correlation for non-Europeans.
That's what the entire paper is based on.
I would assume that looking for UV deficiency related statistics would be trivial with dark skinned people living in a European country.
"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?
Fact: a strong immune system reduces the chance of contracting COVID-19.
End of story.
Fact: proper T-cell immunity is how you get a mild / asymptomatic covid form
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.
The fact is, most people's diets are shit, especially in America where people avoid vegetables and fruits like the plague.
It's a lot easier to get sunlight when you're not cooped up in a cubicle all day.
Or, forced to work from home and discouraged from going outside.
.. and since i'm venting, diet experts use formula "1 cal = 1 kilo cal". why oh why?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4578028/
https://www.ahajournals.org/doi/10.1161/01.cir.99.4.591?url_...
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.
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.
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?
No one would look at a significant quadratic trend in the data and say, "Nope, not gonna publish that juicy nugget!"