4 ms·

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

by 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.
- abfan1127 6y ago
  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 6y ago
  Not entirely. Diet, location, skin color, and age are significant factors.
- rxhernandez 6y ago
  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 6y ago
    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.
    - IndySun 6y ago
      Not necessarily. It's going to depend on your age, skin color and skin condition as to whether a pill beats sun. 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.
  - nradov 6y ago
    There is no evidence that moderate daily sun exposure increases mortality risk. Sunlight exposure also has other health benefits beyond vitamin D, such as stimulating nitric oxide production.
wxnx 6y ago
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 6y ago
  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 6y ago
    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.
Gatsky 6y ago
Beyond these methodological questions, I think that the Mendelian Randomisation approach works best for situations where the effect of some exposure is chronic eg LDL and atherosclerosis, particularly where the disease process may begin in childhood or adolescence. 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.
- tgb 6y ago
  This is an interesting perspective I haven't considered. Isn't the exposure here the Vitamin deficiency? And so that could have chronic effects even though the infection is acute.

by tgb 6y ago

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.

abfan1127 6y ago
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 6y ago
Not entirely. Diet, location, skin color, and age are significant factors.
rxhernandez 6y ago
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 6y ago
  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.
  - IndySun 6y ago
    Not necessarily. It's going to depend on your age, skin color and skin condition as to whether a pill beats sun. 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.
- nradov 6y ago
  There is no evidence that moderate daily sun exposure increases mortality risk. Sunlight exposure also has other health benefits beyond vitamin D, such as stimulating nitric oxide production.

wxnx 6y ago

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 6y ago
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 6y ago
  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.

Gatsky 6y ago

Beyond these methodological questions, I think that the Mendelian Randomisation approach works best for situations where the effect of some exposure is chronic eg LDL and atherosclerosis, particularly where the disease process may begin in childhood or adolescence. 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.

tgb 6y ago
This is an interesting perspective I haven't considered. Isn't the exposure here the Vitamin deficiency? And so that could have chronic effects even though the infection is acute.