Preprint Replicated blood-based biomarkers for Myalgic Encephalomyelitis not explicable by inactivity, 2024, Beentjes, Ponting et al

I've just scanned through the moved posts and there is nothing in the content of those posts that indicates that they are specific critiques of this paper. I always find discussions about general topics within threads which are about particular papers to be unhelpful; having to read discussion which seems to have no link to the topic I am interested in to find out that I didn't want to read it is a waste of my time and energy.

 

With due respect Andy, the issue of the relation of investigations like this to diagnosis is absolutely central to discussion of the value of this paper.

I have not so far mentioned it, but I spent some of last week going through the paper in detail and provided Chris and colleagues with four pages of comments. Virtually all of that related to the problems of diagnosis and its relation to gathering data like these. It covered the difficulty in ascertainment of clinical diagnosis that makes the search for a high sensitivity and specificity spurious. It covered the problems of confounding factors that may mean that associated findings may not in fact have anything to do with the diagnosis as currently conceived. It covered the mistaken idea that doctors need 'diagnostic tests' rather than pointers to disturbed physiology that can be used as a basis for treatment. The whole concept of a diagnosis is a lay idea. If we want to further medical science we need to think clearly both in terms of mechanisms and decision making.

The discussion on the moved posts may not relate specifically to this paper, but that is simply because they are an exercise in analysing the underlying general misconceptions that may lead to the current study being undersold.

 

So as general discussion they are off topic to this thread and were correctly moved as per the forum rules.

 

I agree but overlaps with psychiatric illnesses would not in themselves point to psychosomatic processes, as illnesses with psychological symptoms have organic elements in causation - vicious circles which spin both ways where the skill is to break the chain or brake the process at the most opportune point. ME could be conceived similarly without the psychosomatic/behavioural/attitudinal dogma of the all too recent past.
Responsible psychiatrists treating mental illness do not dismiss the organic. If overlaps are found we will have to be on our guard against those who suggest "we told you it was all in their heads" in the dismissive sense. Responsible medicine does not belive that about mental illness.

 

Absolutely not if in order to understand the quality of the work we need to understand the underlying problems.

 

@Simon M makes a relevant point that the pre-print paper makes a comment about its relevance to diagnosis and treatment by making the statement their results show ‘it’s not a Psychological illness’.

Much of the discussion on this paper is/was about the evidential standard required to substantiate that claim as set out in the rest of the content of Simon’s post to which I am attempting to reply here.

The point I was trying to make (perhaps badly or simply not clearly enough) in my post yesterday (which has been moved from this discussion) was that I agree with the ‘high standard required in scientific research to prove causality’ and that same high standard should be applied to the ‘scientific’ evidence or lack of it put forward to support psychological causation as being a feature of ME.

The major point being that neither Physical science or Psychological science meets the required threshold for proving or identifying causation. Hence ME/CFS has no effective identified treatments with none on the horizon and much misinformed harmful diagnosis/treatment being made/prescribed by muddled Medical/Scientific analysis of what is known and what is not yet known.

The objective I believe must be to greater rigor in all scientific research and in the useful analysis of results with regard to ME/CFS.

I tend to agree with @Jonathan Edwards that it might be unhelpful to separate this part of the discussion from this thread as the pre print Paper itself actively includes this aspect.

I do however understand the difficulties, which I have myself, of following complex and interrelating strands in conversations and that Moderators have to make judgements. I apologise if I have wrongly posted this here.

 

I could do but if members don't have the capacity to read a lot four more pages may not be appropriate. What I have tried to do in the thread is to break the points up into bite sizes, one at a time. Most of the material has now been covered , but there are a few more points that I was intending to introduce as and when they seemed appropriate.

From my perspective the most important people to read these threads are scientists doing the work - either the paper in question or similar work. The issue of diagnosis and its relation to gathering physiologic data is absolutely central.

But without an understanding of why the paper has presented the data in what I think are inappropriate terms there is no hope of understanding the implications.

The issues I have raised suggest that none of the factors the authors suggest are related to the process behind ME/CFS have anything to do with ME/CFS. As others have pointed out, they are probably due to confounders that arise because of diagnostic ascertainment problems. You only get to understand those problems if you understand how fragile a concept 'diagnosis' is in scientific terms.

 

I may be wrong about various things but, as I have said often before, I am well motivated to take papers like this seriously and try and find the important content. If I find that hard going the great majority of scientists we would hope to take an interest will switch off at the abstract. The sort of scientists we want to take ME/CFS seriously are the sort of scientists who will immediately pick up the irrelevance of discussion of diagnostic tests and the Catch22 of looking for tests that will provide that when there are likely to be serious ascertainment problems in the cohort selection.

 

So what about other discussion threads about papers where the study authors suggest that their results are, or could be, a biomarker? In order to understand the quality of that other work should we not copy all posts discussing biomarkers in general to all those other threads? If not, why not?

 

Basically I agree with you.

They are responsible when treating the mentally ill in that they do not "psychologise" the conditions away or invent the organic component. This has not translated in the cases of certain prominent psychiatrists into a responsible approach to ME/CFS -even though it is they who have proclaimed us mentally ill and therefore it might be reasonable to expect that they would deal with us us as responsibly as they do their definitivlely mentally ill patients (unless of course they dismiss the organic in them too or reduce it to lack of a good walk).

Some psychiatrists to be fair do differ from the BPS school of "thought" on ME/CFS.

My point is to turn their traditional approach and assertions back on themselves If there is an overlap in the findings (pertinent to this thread) with mental patients and some declare "all in the head, We told you so" we answer "So, you have found some overlap with mental illness. Do you make up solutions in mental illness, do you deny the organic, do you reduce the organic to lack of a good a walk etc. ?If not, don't do it to us, please, and least of all in the name of "mental health care".

I am sorry of this was unclear.

You are right imo re. lack of "good faith" but good faith is excluded by their "understanding". CBT/GET was ruse medicine to get a response by changing an unhelpful mindset causing nocebo symptoms. Placebo vs nocebo. Dogmatism was assumed to be the best way, hence shut down on other views. Belief and conformity essential to cure. Objective good faith in discussion of truth not helpful to project. I agree. The approach in itself entails shut down of other approaches as roots of "false attributions". No objective discussion of a largely "non objective" illness. Same with several other psych approaches. Good if they work and the rest of us be........Their approach excludes good faith ab initio and how can we assumethat has changed (given the above logic).

I agree with your last paragraph and have shared some similar experiences.

Has the post to which this was a reply disappeared?

 

Yes i apologise I realised my post was pulling the thread off topic after mods had already moved posts.

 

Fair enough. Thanks.

 

Would there be any interest in a discussion, given the extracellular SOD (SOD3) result in this paper, of a discussion of the potential role of superoxide dismutase? Much of my background reading over the last few days has been on that subject; I'd be happy to post some papers on this or a new thread if there is any serious interest in the biochemistry. My current reading list includes papers on the potential role of SOD3 specifically in inflammatory disorders & hypertension, and, more generally, a number of papers in which quantification of SOD has been performed in forced-exercise animal models (shedding light on the relationship between activity/exercise and the activity of the different forms of this enzyme) as well as papers discussing the effect of sex hormones on circulating SOD levels.

 

A very precise reason.
In this particular case a group has reported some fascinating findings based on hard work and very timely and initiative-driven data gathering. But the data have been presented in the context of what look to me to be spurious arguments. And, importantly, that is linked to the presentation of the data being very difficult to follow and missing some key aspects. SOD3 and complement proteins look very interesting but we have almost no information about where the values lie in relation to normal scatter or whether they occur in the same people, and so on. There is very lengthy mathematical modelling in terms of 'mediation analysis' but if the diagnostic ascertainment problem is as big as we have been led to believe you cannot even begin to build a mediation model. Additionally the causal diagram looks to be back to front, again relating to a concept of a diagnostic 'disease' unity.

And, most important of all, we know that the people involved are headed up by first rate minds at least one of whom we know personally and I can only assume that the analysis reflects lack of familiarity with the practical complexities around diagnostic categories and the way we interpret biological measures in terms of process models. The introduction jumps off with stuff about physical activity, and then settles back into an account of ME/CFS, which presumably should come first, since the issue of physical activity's relevance to ME/CFS is very specific to the history of the disease and its models and management. It looks to me like an enthusiastic draft rather than a paper.

In many other cases there doesn't seem much point in going in to deep discussion because the science looks pretty scrappy in the first place. Nevertheless, I do tend to raise these issues whenever studies claim to be looking for diagnostic markers, and raising them repeatedly in the context of specific studies does seem necessary because people are still making the same mistakes.

Science for ME needs to be at the level of science for MS or lupus or RA, and preferably a darn site better than most. Knowing what it is we are trying to do is essential.

 

Absolutely. I haven't had time to look into SOD3 but we need that background.

 

Thee is a link to the moved posts though, for anyone who wants to see the more detailed discussion? It just gives choices.

 

* A review of the role of SOD3, the extracellular isoform of SOD. (The International Journal of Biochemistry & Cell Biology, 2005). Although old I thought it useful background.

This post is going to become extremely long if I post snippets from different papers, so I'll just post my current list from Mendeley to begin with:

* This 2019 paper attempts to document SOD3's potential role in various inflammatory disorders & discussing its potential immunological role ("Anti-oxidative effects of superoxide dismutase 3 on inflammatory diseases", J Mol Medicine, 2019).
* This 2011 paper documents SOD3's potential role in hypertension ("Role of Vascular Extracellular Superoxide Dismutase in Hypertension", Hypertension, 2011) (also open-access PDF).
* "Extracellular superoxide dismutase, a molecular transducer of health benefits of exercise" - link (Redox Biology, 2020, open access).
* "Extracellular Superoxide Dismutase and Risk of COPD" - link (also open-access PDF).
* "Extracellular superoxide dismutase and cardiovascular disease" - link (Cardiovascular Research, 2002, open-access PDF).
* "Extracellular superoxide dismutase in biology and medicine" - link (Free Radical Biology and Medicine, 2003)

As it may be useful to look at superoxide dismutase more generally, especially in relation to physical activity:

* "Sex hormones modulate circulating antioxidant enzymes: impact of estrogen therapy" (Redox Biology, 2013, open-access PDF).
* Lower levels of SOD were found in idiopathic chronic fatigue patients (Nature Scientific Reports, 2018).
* This 2011 paper examines the role of SODs in redox signalling, vascular function & disease;
* This 2015 paper regarding the effects of an antioxidant supplement found that chronic forced exercise in mice depleted levels of various antioxidant levels including SOD. In another forced-exercise mouse model (this one a claimed model of CFS, sigh) decreased levels of SOD were found following the exercise.
* This 2020 paper - another forced running wheel one - examining numerous "oxidative stress" biomarkers reported that "exercise on an FRW significantly increased several serum biochemical parameters, malondialdehyde level and superoxide dismutase activity in all tissues of exercise rats compared with control rats".

I also came across three ME/CFS papers implicating another isoform, mitochondrial SOD (SOD2):

* "The most interesting observation was the downregulation in expression of the mitochondrial proteins pyruvate dehydrogenase phosphatase catalytic subunit 1 (PDP1) and manganese-dependent superoxide dismutase 2 (SOD2)" - a Prusty et al ME/CFS paper (link)
* In this preprint (Davis/Stanford) Long COVID patients' (but not the ME/CFS patients') CD4 & CD8 T lymphocytes had lower mitochondrial SOD (SOD2) levels. Also: "sex hormones such as estradiol can regulate the serum levels of antioxidant enzymes, including catalase, glutathione peroxidase, and SOD2".
* This 2009 muscle-biopsy transcription profile analysis found a downregulation of three mitochondrial genes encoding proteins the authors thought relevant to oxidative stress, including SOD2, in both male & female CFS patients.

 

It's an important process for members with no science background too. I've learnt so much from these discussions, but cognitive impairment and lack of education means it takes time and repetition for concepts to get embedded. If the community gradually moves forward in its collective understanding as well as the researchers, it can only help us help them.