Protocol Serial Paediatrics Omics Tracking in [ME] (SPOT-ME): protocol paper for a multidisciplinary, observational study..., 2024, Armstrong+

Thank you Chris, @MelbME, and team. Great to see this.

I thought this study was well underway? The good day, bad day study in adolescents? Is this just the delay in getting the protocol through the publishing process?

I like the description of ME/CFS in this paper, better than what was used in the (mostly otherwise very good) UK Biobank paper. I noticed you mentioned the twin peak idea in that paper too, here it is in this paper:

I think the evidence for the twin peaks is very weak, and it's not as if there are not a significant number of onsets in people in their twenties, or even in people older than 39. You say that ME/CFS affects individuals in all age groups, so I really don't think mentioning the twin peaks idea (which probably amounts to a myth created by frequent repeating) adds anything.

 

I'm not sure what you mean by 'illness process'. I interpret that as meaning severity, symptoms and e.g. eventual outcome (recovery, worsening) rather than risk factors for onset. The paper has already noted the 'notable female preponderance'.

ref 2 is the Bakken Twin Peaks paper, I don't think it says anything about a sex difference in the illness process, just some differences that they found in the incidence ages.

ref 7 is a paper about the developing adolescent brain and doesn't talk about ME/CFS or CFS at all. Was this reference meant to be somewhere else? (probably the next sentence)

ref 8 is the 2019 UK ME/CFS Biobank study of risk factors. They found that younger age was associated with severity, but they did not report finding that sex was associated with severity or any particular symptomology. The only sex difference they mention is in prevalence, and they note that there are biases that may be inflating that.

ref 9 is
'The underlying sex differences in neuroendocrine adaptations relevant to Myalgic Encephalomyelitis Chronic Fatigue Syndrome'
by some of the authors of this protocol. I guess it's a valid reference for the claim, but I couldn't see anything much in the paper that wasn't speculation or a result from small or otherwise weak studies. Of course it's likely that the menstrual cycle affects symptomology somewhat, but I doubt that it amounts to a difference in illness process. Yes, pregnancy may affect ME/CFS, but I don't think we yet have a clear understanding even of what percentage of people improve, what percentage deteriorate, let alone what might be influencing that change. I haven't yet seen good evidence for any sex differences in ME/CFS (other than probably incidence) that aren't likely to be rather downstream of the core disease process.

There's also a great deal written about cortisol in that paper (as well as the latest UK Biobank paper). Please read the commentary here on the cortisol studies that are cited - the evidence for cortisol being a core part of ME/CFS pathology is, I think, unconvincing. Happy to discuss more if anyone is interested.

 

I've started jotting down my thoughts and summaries of forum analyses of papers relevant to the 'cortisol in ME/CFS' question here:
Cortisol levels in ME/CFS

 

You got it into the BMJ, congratulations. I assume it is then easier to get your subsequent papers into that journal?

Formulaic but accurate is fine by me. @Ravn had some good comments somewhere, arising from some discussion about a recent paper from Ponting's team. We concluded that short is good - there's no need to give readers a very detailed explanation of ME/CFS especially as anyone trying to give a lot of detail usually ends up speculating and saying things that are not well evidenced. I'll see if I can find the thread.


Just on the apparent peak in the 10 to 20 age period: it might well be true.

The effort of growing in those years is surely a major stressor. I harbour a suspicion that my daughter recovered from ME/CFS after a couple of years whereas my son (who became ill at the same time) did not because, by onset, she had past the time of her growth spurt. Whereas my son's onset was when he was 13. When he was 14 and growing rapidly, his illness worsened greatly and he ended up sleeping 20 hours a day for a month.

It's also a time when a lot of people get EBV, which of course seems to be a common trigger of ME/CFS.

Also, I expect that children who actually have an ME/CFS onset as a young child, less than 10 years old, probably take a long time to be diagnosed. It's harder when the child can't exactly say what is wrong, even with a well-defined illness. So, if a child developed ME/CFS at age 8, I reckon they might have to jump through all sorts of accusations of school phobia and parental facilitation and probably would not be diagnosed until that 10-20 age bracket.

 

The thread I mentioned:
How to write a good introduction for an ME/CFS paper?

 

@MelbME, did you have any comments on the lack of evidence for cortisol being a problem in ME/CFS?

I think the plain language summary rather glosses over the significant use of surveys to gather information about the psychological status of the young people in this project. We've said it before, psychological information seems so often to be the tax that has to be paid in order to get decent biological studies. This study is no exception.

These are some of the the surveys that the protocol says will be applied.

Re HADS and it having been recommended as a mood screening tool in ME/CFS: Reference 42 is
Deale A, Husain K, Chalder T, et al. 2001, Long-term outcome of cognitive behavior therapy versus relaxation therapy for chronic fatigue syndrome: a 5-year follow-up study.
That's hardly a reliable recommendation. It's easy to think that these surveys are a lot more scientific than they actually are. MelbME, if you haven't already, please do the surveys yourself, imagining that you are a young person with ME/CFS.

Have a look at this thread on HADS
The Hospital Anxiety and Depression Scale (HADS) - a discussion
Towards the end of that thread, there are links to a number of papers that found that HADS is not suitable in chronic disease and specifically not in ME/CFS.

I don't think we have discussion threads on the other two surveys yet.

The results from flawed surveys have the potential to do a lot of harm. They have been used to cause harm. I really hope that your patient advisory panel are monitoring issues related to the use of these surveys closely and that they will be given the chance to scrutinise anything planned to be published about the results.

 

@MelbME, I wonder if your team has really thought carefully about why they need to do those surveys I listed above in a project that is tracking omics? If you want to track mood or cognitive ability against levels of various molecules, why not just ask the young person and their parent that directly? You can ask a few questions on an app such as 'do you feel happy today?', 'does you child seem happy today?'; 'are you thinking well today?' or even assess reaction times frequently, so that you can correlate mood and function with your omics results.

You can't expect parents to fill out a 173 item questionnaire with questions about whether the child is internalising or externalising problems, followed by a 63 item questionnaire covering questions about whether the child appears inhibited every day. So, what is the point of these surveys?

I understand that funding was gained with the protocol as it is, and you have Sarah Knight and her team waiting for the data from the surveys. But I think it is worth considering if it is really ethical and even scientifically valid to be collecting this information about young people.

The parents and young people who are taking part in your study are not likely to be representative of young people with ME/CFS and their parents generally in terms of behaviour. So, what will these surveys really tell you about young people with ME/CFS?

If you want to assess things like working memory, aren't direct measure less biased than a report from a parent?

 

I've made a thread to look more closely at the second survey there:
Behaviour Assessment System for Children, BASC - a discussion
It has questions that assess, among other things, somatisation and withdrawal.

Chris, @MelbME, can you tell us what is your team doing to ensure that this survey is safe for the families participating in your study and for the ME/CFS community who will be affected by any resulting papers drawing conclusions about the personalities and behaviours of young people with ME/CFS?

Why is it appropriate to assess somatisation and withdrawal in an 'omics project? Have the questions or scoring system been modified to take into account the constraints and real symptoms young people with ME/CFS endure?

Have participants (both parents and young people) been fully informed that somatisation and other psychological pathologies are being assessed in this project? Were your patient advisory panel members involved in the development of the protocol? Were they and are they aware that an assessment of somatisation is part of the project? Were they, are they, comfortable with that?

 

@MelbME.
I share Hutan's serious concerns about using psychobehavioural questionnaires on children with ME/CFS and their families. If my child had been intending to take part in an omics ME/CFS study and we'd been confronted with these questionnaires I would have withdrawn them from participation.

I think it's unethical, and impossible to give informed consent in advance of participation because the participants can't be fully informed in advance what (likely false and damaging) conclusions may be drawn from them.