I wanted to give some time to read and digest this. I’ve been through a fair bit of the paper and this thread but probably need a few more listens to digest it more, there’s a lot there! But here’s my initisl notes, thoughts, questions. Not to anybody in particular but maybe they’ll help discussion.
- First off this looks like the sort of good rigorous analysis we’ve come to expect from the group in Edinburgh. Thank you as ever.
- The preprint server does a great job of formatting the paper in a way screen readers can read it, so I was able to listen, nice!
- I don’t understand it all so have some more reading and learning to do!
- That there was replication seems significant.
- Even if it wasn’t possible with DecodeME, what this tells us could be really interesting and important. The problem is working out what this study is telling us, it feels a bit like 42 being the answer to the ultimate question but we need to understand what the question is.
- It seems to reinforces the neurological signal. But what do the loci tell us about the condition? What do the differences tell us about the cohorts?
- Can all the different genetic findings in different cohorts all be pointers to something still hidden? More x’s on the treasure map leading us to something still buried?
- I’m interested in the methodology here. Can we use these approaches and techniques on different datasets or subsets, on DecodeME data?
- We’re comparing different groups with different criteria and different methods at the moment. It is perhaps unsurprising we get different results. And maybe more surprising we got replication with separate cohorts.
- This brings us back to looking at groups by severity imho. This is s something we talked about before on DecodeME, can or should we subgroup by severity? I think the numbers were said to be too small to look at severe only but does this approach change that? Or if not what about excluding severe?
- Study/patient selection criteria seem more important than ever. Does this study give us any other insights into how to best to define groups to best understand the condition in other studies?
- Findings like the B12 one are interesting given how that’s a topic which has cropped up and been an area of interest for many over the years.
- The difference between a poorly performing and completely broken B12 gene/pathway reminds me of some of the sickle cell treatments where through CRISPR treatments a different functioning pathway can be activated. Maybe there’s a similar possibility for some patients here?
