A Unique Circular RNA Expression Pattern in the Peripheral Blood of ME/CFS Patients, 2023, Cheng et al

Participants all did 2 day CPET as part of the study.

 

How interesting. I'm excited to read the study.
If you, like me, don't know anything about circRNA other than it exists, you might find this paper helpful to read before tackling the ME/CFS study:
Circular RNA: metabolism, functions and interactions with proteins, 2020

 

This is background from the 2020 review paper I linked to:

So these circRNAs can be inside cells, in the cytoplasm, in the nucleus and even in mitochondria. They can be transported between cells in extracellular vesicles, and are in the blood and in urine. Therefore, there are many places to look for the circRNAs. This 2023 ME/CFS study looks at the circRNAs in blood. That raises the question of whether a circRNA found in the blood is being excreted from a cell as a waste product, or if it is being transported for a purpose. It sounds as though there is a lot to find out.

circRNAs are relatively stable. It seems that a viral infection of a cell causes an up regulation of RNAase, which destroys the circRNAs. It's reported that reduced circRNAs can lead to 'aberrant PKR activation and autoimmunity'.

 

The 2023 ME/CFS study has been done by a University of New South Wales team (Sydney, Australia). The supervising author (Michael Janitz) has a German connection also.

Sadly, this paper isn't open access. The snippets suggest that the team may be new to ME/CFS and have some ideas about it that are slightly odd. For example,

That's a surprising reference to use for PEM, and the definition isn't really right. And, it's the first I've heard of the Three Pillars idea - I don't think we've seen much evidence to support the HPA axis idea or the endocrine system being central in the pathogenesis of ME/CFS. And they are out of date with the criteria they cite. I don't think it's accurate to say that there are autoantibody and oxidative stress biomarkers. These things are not a big problem if the authors are experts in circRNA. It just suggests that they aren't very well informed about ME/CFS, maybe they just put in what came up when they googled, and so they might possibly put an unusual interpretation on any circRNA findings.

They do dismiss the idea of ME/CFS being psychogenic, so it looks as though they mean well.

 

Fortunately the people who did the original research and provided the data this was based on do, I assume, understand ME/CFS and how to diagnose it, since several of the Workwell team including Staci Stevens and Mark VanNess are co authors of the original data, so I assume they diagnosed the patients and did the 2 day CPET.

The patients in the original study were all female, so this data comes from an all female sample. Given differences being found in other studies between male and female biomedical results following CPET, it would be good if any replication studies used both male and female patients and included separate analyses of results.

 

Method

I haven't got to the end of the paper yet.

I think the idea of this paper is really good. We now need it to be replicated in much larger samples, and tied to detailed data on activity levels and symptoms. I think we need samples to be taken periodically from each person and correlated with activity levels etc. CircRNAs are found in saliva too - looking in saliva might make multiple sampling easier.

I expect the next few years are going to see major leaps in the understanding of what the circRNAs do, and that will help us.

Crossposted with Grigor - Martijn sounds like a handy friend to have.

 

A problem is that it isn't that straightforward. People with ME/CFS have highly variable results on CPETs - that seems to be almost a diagnostic feature. When I did two CPETS, the first one showed that I had normal fitness, the second one showed that my fitness was well below normal.

So, which CPET would you choose to match controls on? If it's the first one, can you be sure that any activity in advance of the CPET, perhaps even just preparing to get to the clinic, hasn't affected the person with ME/CFS? For example, in the two days prior to my first CPET, I had prepared the house so that my son could cope for a few days on his own, shopping, filling the fridge with prepared food, I packed, stood in airport queues, flew to another city, chatted to the taxi driver, and settled into my accommodation. On the day of my first test, I stood by the roadside in the cold for 15 minutes waiting to be picked up. If things aren't explicitly controlled, there will be confounders.

Probably the best matching for fitness would be on something like step counts over a sufficiently long period and with clear directions about pre-test activity and diet. Probably you need to have people wear activity monitors in the days before, during and after the test to ensure compliance.

I agree there could be more use of standard control data, it would reduce costs and make research quicker. But protocols would have to be very specific and standardised. And I think there's probably always a need for some controls samples to be processed along with the patient data, to make sure the researchers haven't inadvertently introduced some factor that changes the results. I think ideally you'd have a matched control sample of 30 or so that is processed along side the patient sample, but you would also report against results for larger samples of healthy controls and disease controls. I don't think that's very different to what researchers try to do now; probably there is just a lack of comprehensive comparison data collected with standard sampling protocols right now.

I agree though that research funders should give more funding for producing benchmark metabolomic and proteomic data for healthy controls covering different ethnicities, ages, fitness levels and sex, including keeping anonymised data in public databases so that subsamples can be selected for tighter comparisons with disease groups.