[HN Gopher] Vitamin D uncorrelated with Covid severity in those ...
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Vitamin D uncorrelated with Covid severity in those of European
descent
Author : whoisburbansky
Score : 162 points
Date : 2021-01-20 19:40 UTC (3 hours ago)
(HTM) web link (nutrition.bmj.com)
(TXT) w3m dump (nutrition.bmj.com)
| WoodenChair wrote:
| 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."
| wxnx wrote:
| 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
| tlb wrote:
| > 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 wrote:
| 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."
| howmayiannoyyou wrote:
| 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 wrote:
| It still tells you that the effect cannot be huge, otherwise it
| would have shown up here too.
| [deleted]
| Karrot_Kream wrote:
| > 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.
| raverbashing wrote:
| > "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 wrote:
| 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.
| wxnx wrote:
| > Yeah, this would make sense if you ignored all dietary
| and solar variations in Vitamin D productions
|
| No, actually, MR specifically accounts for these
| variations.
|
| However, one idea (one that would need a lot of evidence in
| my opinion, but to give you a clearer picture) that is not
| captured by MR is horizontal pleiotropy. So, if the genetic
| variants used in this study e.g. actually cause someone to
| seek out dietary modifications/solar augmentation of
| vitamin D, that would not be accounted for here.
|
| I don't think the biology in this case allows for that to
| any significant degree, but I'm not an expert in vitamin D
| metabolism/action or COVID.
|
| > I don't think it's an honest assessment
|
| The title here is maybe a bit simplified, but the paper is
| quite honest about its weaknesses if you read it in its
| entirety.
| [deleted]
| whoisburbansky wrote:
| 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.
| dukeofdoom wrote:
| 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
| robocat wrote:
| 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.
| minikites wrote:
| First it was vitamin C that cured everything, now it's vitamin D.
| I'm predicting the next "miracle vitamin" will be vitamin E.
| GuB-42 wrote:
| 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.
| gt565k wrote:
| If you have a healthy diet, get enough sun exposure, and are
| physically active, you don't necessary need supplements like
| vitamin d or c.
|
| The fact is, most people's diets are shit, especially in
| America where people avoid vegetables and fruits like the
| plague.
| metalliqaz wrote:
| Vitamin D is mostly not found in fruits and vegetables.
| hombre_fatal wrote:
| Their first sentence has the full prescription which
| includes sunlight. Sunlight gives you more than enough.
|
| One great part of working remotely is that I can take my
| shirt off and sit on my patio in the sun while thinking or
| just take my laptop outside.
| nytgop77 wrote:
| How much sun exposure is enough? Lot of sources say 10-40
| minutes. But nothing is said about how much skin should be
| exposed for that duration. (recommendations that are so vague
| are dismissed as useless)
|
| .. and since i'm venting, diet experts use formula "1 cal = 1
| kilo cal". why oh why?
| benibela wrote:
| https://fastrt.nilu.no/VitD_quartMEDandMED_v2.html
| nradov wrote:
| The amount of sun exposure necessary depends on latitude,
| time of day, weather, skin color, diet, etc. There's no
| simple answer. Probably the best approach for most people
| is to get a periodic blood test and then adjust sun
| exposure and supplementation up or down as needed.
| perardi wrote:
| Nah, we already had a brief Vitamin E fad, and that went
| nowhere.
|
| https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4578028/
|
| https://www.ahajournals.org/doi/10.1161/01.cir.99.4.591?url_...
| mojuba wrote:
| Or an artificial vitamin C++
| trhway wrote:
| 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 wrote:
| 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 wrote:
| I seem to remember this "sun" thing you are talking
| about. Don't think I've seen it since sometime in
| October.
| hammock wrote:
| That already happened in the 90s
| ggm wrote:
| Linear progression. Most biological sequences are Fibonacci so
| it should be vitamin K
| nradov wrote:
| 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/
| amelius wrote:
| Are they updating their Github repo with this new paper?
| curiousgal wrote:
| 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 wrote:
| 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 wrote:
| It's a standard example of why non-correlation doesn't mean
| independence.
| klmadfejno wrote:
| 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 wrote:
| 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 wrote:
| 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 wrote:
| 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?
| curiousgal wrote:
| My point pertains to the conclusion the public might draw
| from the study. Just because Vitamin D is uncorrelated with
| Covid severity does not necessarily mean that they are not
| related. Same way Y depends on X but is uncorrelated with it.
| legerdemain wrote:
| Yes, and my point is that for your point to be relevant,
| the authors would have to exhibit a negligence that borders
| on the fantastical.
|
| No one would look at a significant quadratic trend in the
| data and say, "Nope, not gonna publish that juicy nugget!"
| efxhoy wrote:
| 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?
| bravura wrote:
| Given that: a) preliminary research work is, by its nature,
| imperfect b) many of us don't have the background to grok how
| well situated and controlled this work is, not being experts in
| this field and its particular vagaries and puffery in a typical
| publication c) taking vitamin D is simple and does not involve
| serious compromise
|
| it does not seem like any action should be warranted for those of
| European descent. Keep taking Vitamin D. The bleeding-edge is for
| the experts, not you.
| lmilcin wrote:
| 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 wrote:
| _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+canad...
| hombre_fatal wrote:
| > 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.
| novaRom wrote:
| > Today I learned: Europe is a country
|
| Yes, it is. Europe is largely a country with free movement of
| people, goods, services and capital.
| annoyingnoob wrote:
| 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.
| zxcb1 wrote:
| The effects of excessive UV exposure are known; the effects of UV
| deficiency are ...
| axaxs wrote:
| 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 wrote:
| Perhaps not: 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 wrote:
| 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"
| tgb wrote:
| 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 wrote:
| 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.
| rxhernandez wrote:
| My physician told me that under no circumstances should I be
| getting my vitamin D from the sun as skin cancer was not
| worth it; she instead recommended I get it from my diet.
| gojomo wrote:
| Your physician is wrong, as _separate_ from just the
| Vitamin-D mechanism, greater lifetime sun exposure is
| correlated with many net-positive health outcomes,
| especially with regard to cancer & cardiovascular health,
| that outweigh the risks of skin cancer.
| abfan1127 wrote:
| I wondered the same thing. Not only are they sharing air with
| contagious people in poorly ventilated areas, but their own
| viral load isn't shed like it is outdoors. I also wonder
| about outdoor activity and mucus generation. Pollen, dirt,
| etc all trigger mucus generation and expectoration (coughing
| it out). External loads are caught up in this mucus and
| coughed out before you can get sufficiently infected and our
| own viral load can get caught up in the same mucus and
| coughed out as well. I have no experience in this field, just
| random thoughts. I'd love to hear from others with more
| experience in the field.
| mixmastamyk wrote:
| Not entirely. Diet, location, skin color, and age are
| significant factors.
| wxnx wrote:
| Horizontal pleiotropy is always a concern when analyzing MR
| studies, and I agree that this one does disappointingly little
| to preempt this criticism. I also agree with your point that
| causal loops aren't a concern here - vitamin D deficiency was
| measured pre-COVID, so there's no reason to think that COVID
| influenced that measure.
|
| 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
| whoisburbansky wrote:
| What are some example of papers you've seen that, in your
| opinion, do a good job of mitigating the effects of
| horizontal pleiotropy?
| wxnx wrote:
| Good question!
|
| 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.
| [deleted]
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(page generated 2021-01-20 23:00 UTC)