Has there ever been a meaningful study of the male to female ratio under the different criteria?
What makes me ask is that I was recently reading a paper by Pelosi and Lawrie of epidemiological findings around Glasgow . I think it was 1994. it suggested equal numbers of males and females affected (which seems out of line with the modern view). Does a lot depend on the criteria, or are there other reasons for the different findings?
I always take a look at the male/female split in a study and I can't remember one with decent diagnosis that wasn't c75% female. Having said that, many with flaky diagnosis aren't so different (eg PACE using Oxford criteria).
It might, in part, be due to doctor's looking for it more in female patients as
@Jonathan Edwards suggested. But the same 75% emerges in unbiased prevalence studies (that screen widely), though the numbers are small in that. Same too for patients in the US private clinics, who self-refer, I think - so not dependent on doctor bias.
IF this change increases the chance of the species carrying it to develop ME, then that is a disadvantage to the species, and is therefore likely to be lost through natural selection, surely?
As the blog says, it's a very rare SNP in the human population (just less rare in mecfs patients). The idea is that this might just be random variation.
So the assumption that it is heritable is because it's a DNA sequence, and therefore passed down from our parents.
Not sure that's an assumption, as such! But the key point was that for most data, such as metabolomics, it's always hard to distinguish causes of the disease from effects of it (hence the need for sick as well as healthy controls). However, with the exception of cancer, diseases can't cause change is DNA.
That doesn't mean the DNA changes "cause" the disease, as such, more that they can contribute to pathology. E.g. if several DNA changes cluster on a particular metabolic pathway that would indicate a causal role for the pathway - though disease might only result if someone also had a particular infection and possibly other environmental factors too.
Absolutely possible. Rather than doing a huge study next I would pick the ten most correlated mutations, regardless of whether or not they reach significance in this study, and go to the DNA we have from the ME Biobank and see if they are confirmed. If you only test 10 mutations rather than thousands the chances of getting a significant finding are vastly greater.
That's the basic principle of GWAS: a discovery phase followed by a validation phase that focuses on the most promising findings from the discovery phase. But only of significant findings. The problem with GWAS is they include vast numbers of SNPs and so there is a huge problem with false positives. Or put another way, you would expect a lot of "nearly significant" findings by chance alone. So the current individual findings are likely to be less reliable (I think the overall findings of heritability is more reliable) - so attempts at replication might be futile.
What's really needed is a much bigger and better GWAS to identify the right candidates to take forward to the validation phase.
There seem to be 4 possible routes to approaching genetic studies in ME/CFS.
[my summary]
1. Piggyback on non-mecfs biobank
2. Large GWAS
3. Worldwide collab of existing mecfs gene studies
4. See findings from existing genetic studies replicate
For patients' sake, surely options 3 and 4 are the most productive and time efficient. I'm not against large scale GWAS as a long term aim, but in the meantime, I'd hate to see every other ME/CFS study in the UK not able to get funding because whatever funding is achieved is poured into such an expensive long term project.
The problem here is that 3 is nowhere near big enough to deliver robust results (though might contribute to a bigger GWAS). 4 is largely pointless because of the previous point: it's likely to be chasing noise and a negative result wouldn't mean much.
Also, it doesn't have to be a zero sum game. It's not as if there has been any biomedical funding at scale in the UK. And even if a GWAS were to happen, it doesn't mean other studies would lose out. Though I don't think that this thread is not the place to have a MEGA-style debate: nothing has been proposed yet.
Am I correct in thinking that a SNP is not necessarily a disease-causing mutation and could equally be silent, but could also indicate the possibility of further variation in that section of the genome (linkage disequilibrium)?
In general, yes, the SNP is not precise but highlights a stretch of DNA in linkage disequilibrium. However, I think Chris said (to me) that the collagen hit wasn't near to other coding regions in linkage disequilibrium.
And now I need to take a break!