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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 agr

by 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.

by wxnx 6y ago

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.