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An LD pattern tells a story in terms of helping identify where the causal SNP is, or helping determine if a phenotype might contain the same causal SNP as another phenotype, but I don't think that's what AlphaGenome is doing. If we knew the specific causal variant in ME/CFS, and gave it that in...

Yeah, I'll need to try to understand this more. It looks interesting, but I'm not exactly sure what it's doing. I think there might be two modes? 1. Check the difference in predicted effect between a single ref and alt allele. 2. Just give a long sequence of DNA and see what the prediction is...

Maybe the plot should be zoomed out more? It's only showing one gene at the moment, but the variant could be affecting something else Edit: I think just a bigger number here: interval=variant_output.reference.rna_seq.interval.resize(2**15),

I haven't tried this yet. Been a bit confused about the docs so far. But maybe its better to test all the significant variants in a locus [edit: at the same time] instead of one? I'd be interested in each locus's variants' predicted effect on the brain.

This protocol seems odd. The control is alfacalcidol, some sort of vitamin D analogue, and the active group is alfacalcidol + vitamin D and guidance on ways to get vitamin D, like sun exposure and exercise: Why is the control a vitamin D analogue if they're testing vitamin D efficacy...

Thanks for the detailed analysis. Should we have a system where some scientists run a study and create data, then they hand it off to people they have no connection to, who analyze it and publish it, somehow with no incentive to embellish results? Though I think the "no incentive" is the tricky...

Gotcha. Can it just be metabolites related to two different systems? As in the metabolites in plasma that change due to exercise being involved in pathways that are unrelated to the pathways that make urine metabolites increase.

Some of the above about how normalization might affect this gets a bit out of my comfort zone, but overall, I think we're basically coming back around to the idea that there may be more variability in deltas in specific metabolites. Exemplified by this amazing illustration: Scenario #1 with...

I think I understand, but it seems to me that this is just what we expect to see all the time. I'll refer to this: If one group gets a true effect intervention, while the other gets the placebo, then the plot of change in steps would look pretty similar to the plots from the study. The code...

I'm a bit confused about what you're trying to show. HC ends up with a significant difference because they do have a difference, while ME/CFS doesn't because they don't. Your plot has equal SDs for one metabolite, and a true difference between groups, so the plot seems like what we'd expect...

Maybe that'd be fine in a paper, but in terms of general discussion of a disease, maybe it's good to be able to place it in a category. "What kind of disease are you studying?" "It's neurological. "Oh, interesting, vascular issues? "No, neuroimmune." People outside the field might not have any...

Would this very brief summary of your thoughts, @Jonathan Edwards, be accurate and maybe clear up some confusion? "If you think you have MCAS or hEDS, and you think telling your doctor might help improve your care, then feel free. If you want to convince others they may have MCAS or hEDS...

This part?: This seems to suggest that it's okay to do this: https://repub.github.io/DLC_statistical_guides/docs/R/repeated-measures-ANOVA.html Maybe emmeans accounts for the non-independence if it's a mixed effects model somehow. Whether it's actually good for this, I don't know. Some...

Oh ok. That's actually reassuring in terms of data privacy if the investigators literally have no way to identify a sample. I assumed the data was anonymized for analysis and for sending to other institutions, but that there would be some sort of master list identifying each sample in a secure...

If there are any sets of at least two siblings with ME/CFS in the DecodeME cohort, then they could potentially just request the DNA samples of healthy family of those people, since they already have the ME/CFS DNA.

Ah, I see. Maybe.

They may have considered that too:

My baseline interpretation is, we shouldn't interpret a lack of significance as evidence for a lack of effect. Though what makes me be a bit hesitant to discount on the basis of one group randomly not reaching significance is the stark difference between groups, with hundreds of compounds...

Yes, but that's what the delta column is showing. It's not variance of raw values of compounds, it's variance of how much a compound changed before to after exercise. If control compounds tend to trend upward a similar amount, while ME/CFS compounds tend to go up or down in a more spread out...

I think they considered whether it might be due to increased variance, and found no general difference in variance between groups. Specifically for changes due to exercise, this would be the Delta plot in S3A below. The plots you posted above might show increased variance in ME/CFS, but this...