Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome, 2024, Walitt et al

Arvo said:
Indeed, "calm down dear, it's only a commercial" when someone just ran into your car. Note the choice of the word "anxiety" instead of "concern", it categorizes criticism as emotionality fuelled by irrational fear, and thereby as something that can be dismissed.

I think Nath and Koroshetz's replies are ridiculous.





I find this jawdropping: a paper is THE communication medium for presenting your finds and articulating your views and arguments around them. It's THE place where you connect with others about what you have done, and you must do so in a way that is clear and without a shred of ambiguity. That's like paper writing 101.

When you have to respond to criticism on your paper with "yeah, but what we really meant was...", then you've messed up.

Are we supposed to believe or accept that this study cost 8 million dollars, took 8 years, and has small village of authors (75), but none of that produced a paper that says what they mean?
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I find the test with these things - and the authors who are becoming the stooges inadvertently for others might want to do this check on themselves - is to just substitute any other minority and related tropes into what you've just said and see if you think your job/partner/friends would ever look at you the same again.
 
Arvo said:
I do not get the impression that this part of the study is an honest, illness- and patientinput-driven look into ME; to me it looks an awful lot like an effort to (further) establish the acceptance of a desired "effort preference"/effort avoidance framework of ME. More tool than find.

Looking at some context, it also doesn't not reassure me that it's not. Walitt called ME a somatoform disorder (a psychiatric disorder where patient's symptoms have no physical basis, and where there is "often a degree of atention-seeking"; the replacement term for hysteria) and sees it through a behavioural lens.

As mentioned elsewhere, "[Walitt's] research protocols focus on deeply phenotyping persons with disorders characterized by aversive symptoms that develop after exposures, such as infection. Currently, he is working with patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI), and Post-Acute Sequelae of SARS-CoV-2 infection (PASC)."(Link)

Disability stemming from disease is not the same at all as "aversive symptoms that develop after exposures".
Like the psychiatrists before him, he is framing ME disability as a tendency to avoid activity, as something patients do instead of what happens to them.

Walitt is also the director of the Introceptive Disorders unit.
(I don't know since when, but gaining this new position might have happened during the ME/CFS study period, see the remark from Paddler, a participant: )


And since 2013 Walitt has (among other functions at the NIH) been the acting Clinical Director of NCCIH - National Center for Complementary and Integrative Health.
Here's the NIH's plan on interoception research: Interoception Research | NCCIH (nih.gov)

So far it's mostly a framework/model; this new presentation looks still quite novel and in its infancy substantiationwise, and the intention is to expand it. And this worries me, as this makes patients tools instead of the exit point. (Interoception will need to justify its existence, and they need to do that by proving that its framework is applicable and useful; firstly by showing how and that interoception plays a role in patients, and then secondly that this can be targeted with treatment -which they intend to pull from "complementary and integrative health approaches" like mindfullness, CBT and nutrition- in a way that is useful and cost-effective.)

Interoception is named as a "top scientific priority" of the NCCIH.


"Because of its potential importance, research on interoception in the context of complementary and integrative health approaches requires a deeper understanding of the connections between brain and body. In addition, tools and methods to probe interoceptive processes, especially in human subject research, are largely limited to self-reports and a handful of measures such as heart rate variability and skin conductance. An expansion of innovative and quantitative methods to study interoception may significantly enhance our understanding of how interoception works. These new tools and methods may also provide novel insights into how complementary and integrative health approaches may modulate the interoceptive processes and interoceptive clinical outcomes."

What Does Success Look Like?
  • Expanded understanding of the mechanisms underlying interoception.
  • Improved, innovative tools and methods to probe interoceptive processes, especially in human subjects.
  • Increased understanding of the impact of specific complementary and integrative health approaches on interoceptive processes.
  • Improved understanding of the efficacy and effectiveness of complementary and integrative health approaches on interoception-related clinical outcomes, especially those related to musculoskeletal and visceral pain.
Priorities
  • Build on basic interoceptive pathway studies to investigate mechanisms important for complementary and integrative approaches.
  • Expand mechanistic research on interoception involving pain, cardiovascular conditions, and digestive conditions.
  • Develop translational and clinical efficacy studies supporting development of new tools to probe interoception in humans and animal models.
  • Support natural product research related to interoception involving brain-gut interactions and brain-cardiovascular/immune and brain-endocrine pathways, including both neural and nonneural pathways.
  • Support mind and body research involving brain-respiratory (meditation), brain-musculoskeletal (acupuncture/manual therapy, movement-based therapies), brain-cardiovascular, brain-endocrine, and vagal/spinal pathways.

I've nosed through the attached PDF of the NCCIH Strategic Plan FY 2021–2025 (which is from May 2021 and interestingly does not mention the word "interoception"once) and it indeed reads like European liaison psychiatry aims and bps ideology in a glossy wrapper. What I've seen looked very, very familiar to me.

It's wrapped in unctuous words and peppered with the familiar buzz words, at first scan the basics are the same. The BPS movement aims to inegrate psychiatry with conventional medicine in order to be able to treat medical issues from a psychiatric angle (CBT); they claim that this way they are treating the "whole person", and are very loudly claiming they are working "evidence-based", based on their own wobbly studies. The NCCIH "has worked to advance the position that evidence-based complementary therapies should be “integrated” with and not used as an “alternative” to conventional medicine." And the subtitle of their plan is: "Mapping a Pathway to Research on Whole Person Health" (and the phrase "whole person" is lavishly peppered throughout the plan).

About those "complementary therapies" it says:

"Complementary and integrative health approaches include a broad range of practices and interventions that may have originated outside of conventional medicine and are gradually being integrated into mainstream health care. These approaches can be classified by their primary therapeutic input, which may be nutritional, psychological, and/or physical. Psychological and/or physical approaches encompass what have been commonly considered mind and body approaches. Commonly used psychological approaches include meditation and cognitive behavioral therapy, while physical approaches include acupuncture, other manual therapies (soft tissue manipulation, massage, spinal and joint manipulation, and related devices), and physical exercise. Some approaches, such as yoga and tai chi, comprise both psychological and physical components."

Now, going back to the NIH ME/CFS study, this says:



and it aligns nicely with the NCCIH aim of "the integration of complementary and conventional care" and its inetroception info:
"Processes involved in interoception could often serve as therapeutic targets of many complementary and integrative health approaches, including psychological and physical approaches such as meditation, acupuncture, and other manual therapies, as well as nutritional approaches such as natural products."

The way it is presented in the NCCIH plan makes it sound benign and helpful, but for me it sounds like it has a great risk, even intention, of pulling meditation, mindfulness, CBT etc into the place where actual medical treatment should be.
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Agreed. And I think the appropriate term is it being an individual's manifesto.

With a few points to some whizz bangs to say 'look laypersons some science because it turned blue' being used to cover for what seems to be a term that doesn't originate from either laboratory or solid validation.
 
Amw66 said:
Given Naths mixed messaging perhaps he simply did as he was told .
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My guess is that after the pandemic Nath didn't really want to be working on this given the other projects he had/has going on. As a result, he got Walitt to write up the majority of the paper and then probably felt he couldn't push back as he hadn't done the work. Given how long it took, there was probably as rush to get it published and move on even if he knew it was a pretty crappy paper. Obviously he's still responsible for allowing it to go out in this state.
 
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Sean said:
The question is not can patients perform a single action, it is can they do it repeatedly, and without abnormally high cost?
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This is a late reply, but it seems to me that this important question (which seems so obvious!) is something that is not understood by most people, including doctors and researchers, when it comes to ME/CFS.

This same concept is often ignored when it comes to long term disability claims.

I don't know the best way to translate this idea into guidelines for a research study, but surely the mere concept is not too difficult to grasp, right?
 
Eddie said:
My guess is that after the pandemic Nath didn't really want to be working on this given the other projects he had/has going on. As a result, he got Walitt to write up the majority of the paper and then probably felt he couldn't push back as he hadn't done the work. Given how long it took, there was probably as rush to get it published and move on even if he knew it was a pretty crappy paper. Obviously he's still responsible for allowing it to go out in this state.
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This was a challenging paper to write - difficult topic and difficult circumstances. It needed an exceptional scientist to guide it. Nath was not that scientist. He let down the mission of science by permitting this to be published in its current form.

As the sample size receded they needed to rein in ambitions and make sure what got into the abstract was on an exceptionally strong footing.Instead they went grasping for marginal findings from experimental measures. I dont' care about the internal politics of NIH or Brian Wallitt's feelings, the senior author needs to make sure the paper makes sense.

I'm not actually sure yet if there's anything in there that pops out as an undeniably strong finding. These metabolomic findings are in cerebrospinal fluid and that hasn't been analysed as often as plasma or serum so there's not a lot of precedent.
 
Shared this in another thread but also wanted to ask here (mods feel free to delete/move as you see fit)

Does anyone think we should try this route? Just was wondering.

'Research Misconduct: Research misconduct is defined as fabrication, falsification and plagiarism, and does not include honest error or differences of opinion."

https://grants.nih.gov/help/report-a-concern#research

'Who to Contact:'
'Requirements for Making a Finding of Research Misconduct'
  • There be a significant departure from accepted practices of the relevant research community;
  • The misconduct be committed intentionally, knowingly, or recklessly; and
  • The allegation be proven by a preponderance of the evidence.'
https://grants.nih.gov/policy/research_integrity/requirements.htm
 
Trish said:
Thank you Arvo for digging further into Walitt's past influence and current and future central role in ME/CFS research at NIH. I find it deeply disturbing. I hope US ME and Long Covid organisations will take action to get him and his influence removed.
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MEAction issued a response a week ago to the NIH study which included recognition of the effort and sacrifices of the patients who participated as well as a critique of its contents.l
"NIH’s recent paper on ME/CFS elicited strong reactions from the community. While we recognize the incredible sacrifice of the patient community who gave their health and time to make this study possible, ultimately, we caution against drawing any sweeping conclusions from this study. "

It continues to list perhaps its 3 major weaknesses
1) a narrowly drawn unrepresentative cohort of patients focussed on the mild/moderate
2) the incredibly small sample ( 17 ME/cfs patients)
3) the doubtful pattern of behaviour called "effort preference"
"The paper draws conclusions based on an atypical cohort that may not be representative of the ME/CFS community, and from a very small sample size, and there are also conclusions drawn in regards to “effort preference” that may not be supported by the evidence. "

Read more about #MEAction’s analysis below:

https://www.meaction.net/2024/02/29/meaction-nih-study-response/

edit: The paper is worth reading and is printed in large, well laid out type that is accessible to pwme
 
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Binkie4 said:
MEAction issued a response a week ago to the NIH study which included recognition of the effort and sacrifices of the patients who participated as well as a critique of its contents.l
"NIH’s recent paper on ME/CFS elicited strong reactions from the community. While we recognize the incredible sacrifice of the patient community who gave their health and time to make this study possible, ultimately, we caution against drawing any sweeping conclusions from this study. "

It continues to list perhaps its 3 major weaknesses
1) a narrowly drawn unrepresentative cohort of patients focussed on the mild/moderate
2) the incredibly small sample ( 17 ME/cfs patients)
3) the doubtful pattern of behaviour called "effort preference"
"The paper draws conclusions based on an atypical cohort that may not be representative of the ME/CFS community, and from a very small sample size, and there are also conclusions drawn in regards to “effort preference” that may not be supported by the evidence. "
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We've discussed the issue of patient selection before, but I think MEAction are not helping by suggesting the cohort of patients was unrepresentative. There were criteria such as time since onset, infectious onset and severity that could have been something different, but were perfectly reasonable choices. The participants were screened by ME/CFS clinicians. Perhaps some of the participants don't have ME/CFS - it's impossible to know - but participant selection is not a weakness worth targeting. I think the NIH could reasonably ask 'well, what more would you ask of us when it comes to patient selection?'. Unless there's evidence that Walitt somehow skewed the sample, I think the patient selection argument hurts rather than helps, detracting from the stronger arguments.

The small size of the sample, including the even smaller size in some of the studies, definitely is a strong argument.
 
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Hutan said:
The participants were screened by ME/CFS clinicians. Perhaps some of the participants don't have ME/CFS - it's impossible to know - but participant selection is not a weakness worth targeting.
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I believe their point is that the selected participants did not reflect the spectrum of severity of ME.
If I remember correctly, the average steps per day for pwME was about 3500 steps. So that is a weakness of the study even if it's understandable why more severe patients were not involved.
 
Medfeb said:
I believe their point is that the selected participants did not reflect the spectrum of severity of ME.
If I remember correctly, the average steps per day for pwME was about 3500 steps. So that is a weakness of the study even if it's understandable why more severe patients were not involved.
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I don't think it's necessarily a weakness given their stated desire to reduce the possibility that deconditioning and other consequences of years of a sedentary lifestyle might obscure results. The selection leaves a lot of room for followup studies of course, but I'd call it a limitation rather than a weakness.

Raising that as one of the top three problems with the study makes it really easy for the NIH to argue back, and sound entirely reasonable when doing so. They can use up plenty of words on explaining why they only selected post-infection mild/moderate participants with onset less than 5 years, and then gloss over the issues with the effort preference study with a quick comment about how patients are misunderstanding things.
 
rvallee said:
It was a bit weird that Nath chose to speak to a biopsychosocial conference (last year?) on Long Covid featuring nothing but psychosomatic ideologues. It seemed out of place and possibly a way for him to speak to them about how science can actually solve this.

But looking back from this, it appears that he simply agrees with them, and was speaking to a crowd of like-minded people.
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I think he does agree with them. Most neurologists I've met that were sympathetic towards ME, did not discount the "BPS" views as false or damaging.

They see the illness as having two layers:

Layer 1: an array of subjective symptoms mostly related to perceptions and way of thinking
Layer 2: the underlying biological process causing the layer 1 symptoms.

This is why their preferred hypotheses are usually something related to neuroinflammation or neurotransmitters.
And why they completely ignore PEM and never think of how they can find new ways to measure the impairment objectively. And why they are not bothered that the patients they recruited don't have POTS.

Because they have already decided (given themselves a huge bias) this illness is a problem of perception rather than a true disability.

I've already said this but patients (not in this forum but the broader community) need to learn that just because a researcher is doing biological measurements, it does not mean they are not misguided.
 
Might be slightly off topic but I think a lot of doctors are simply not bothered by inconsistency.

Let's say for example that you see a naturopath and he thinks your symptoms are caused by inflammation - prescribes you some herbs for it.

You tell him that you've tried many immune drugs, even powerful ones like high dose steroids and IVIG, to no avail.

He ignores your remark and seemingly doesn't care about the inconsistency - how could some herbs help you with inflammation (assuming that's the problem which it probably isn't) when the most powerful drugs we know had no effect?

The naturopath does think your problem is inflammation, he is just not bothered by the inconsistency.

Likewise, I think Nath does think of ME as a "BPS" type illness, but the fact that CBT and GET (the obvious treatments) don't work does not seem to bother him, and he wants to try stuff like IVIG. It is a weird and inconsistent view, a BPS type illness that would respond to immunomodulators and not CBT but that's what he wrote in his paper.

The mistake many patients are making is that just because Nath wants to do an IVIG trial (or whatever other drug), that he is "our guy" and he was forced to write BPS stuff by Walitt. I think this is silly, especially considering how weak this paper was even without the BPS stuff.

The simplest explanation is that we are dealing with very mediocre researchers who are not smart enough to come up with a coherent hypothesis that's backed by data.
 
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Hutan said:
I don't think it's necessarily a weakness given their stated desire to reduce the possibility that deconditioning and other consequences of years of a sedentary lifestyle might obscure results. The selection leaves a lot of room for followup studies of course, but I'd call it a limitation rather than a weakness.
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I actually think the recruitment may have been a huge problem. Things are complicated but in a sense their argument that the problem is 'effort preference' is based on proving that PWME could do everything, they just preferred not to. And that could very well have simply reflected the fact that to be able volunteer you needed to be able to do things at that level, at least to begin with. If the study is used to prove people can actually do stuff it is a highly problematic cohort.
 
chillier said:
View attachment 21351

Spermidine is the second most significant hit in the NIH intramural study's metabolomic data, as well as other polyamine related metabolites nearby (N-acetylputrescine).

Lots of other interesting things in there too in particular pyrroline-5-carboxylate/ arginine - these weren't seen in jason's data but have been seen in a few other places.

EDIT: I've just noticed that many of those p values are higher than the adjusted p values. This is... odd. How is spermidine not significant at p=0.056 but significant after it has been corrected for multiple testing correction at p=0.0036? Am I getting confused here?
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I noticed that in the NIH paper some of the p values they report for their metabolites are higher than their adjusted p values. This doesn't make sense because the p value should increase after multiple test correction not decrease. I asked the authors about this:

My email to Avindra Nath said:
I had a quick question about the CSF metabolites in your ME/CFS intramural study.

The p values are reported in supplementary data 14. I noticed the p values are often higher than their adjusted p values. For example in the picture attached, spermidine has a p value of 0.056 (not significant), but its adjusted p value is 0.0035 (significant).


I was wondering why this is and how to interpret this? If it is not significant initially, how can it be significant after multiple test correction?
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They were quick to respond which is good of them. I'll paraphrase as I didn't get explicit permission to pass it on:

The 'p-values' and 'adjusted p-values' are from the results of two different analyses and the latter is not a multiple test corrected version of the former.

The 'p-values' are from the result of wilcoxon tests of normalised data (they probably divided mass spec counts by total counts per sample or something like that) and are not multiple test corrected. The 'adjusted p-values' are from the results of an analysis pipeline called limma - which is much more complicated.

Wilcoxon is a non-parametric test that ignores the distribution of the data and looks at how much the data points overlap. Limma is a tool that I haven't used but have heard of; It makes use of a generalized linear model, which allows it to get a better model of the distribution of the data (it might log transform for example if the data is exponentially distributed), and to model other effects such as batch and probably stuff like sex. In principle this could be a more powerful and discerning way to analyze the data.
 
Murph said:
I did a quick dig to see if their measurement of metabolites in cerebrospinal fluid lined up with a previous study on the same topic. I bring bad news. The folllowing plot is just a rough draft of the final analysis but it shows big disagreement. Many things Baraniuk 2021 found high, NIH found low (in fact NIH found we were lower than healthy controls in all the metabolites that were also measured in Baraniuk). Perfect agreement would have the dots on an upward sloping line that ran through (1,1) (i've marked that in pink).
View attachment 21370

Instead most are below that and to the right, indicating NIH found them lower in patients while Baraniuk found them high.

It's hard to know what to think about this without a bit more context. Is the state of metabolomics just rubbish? Is one of these studies clearly wrong? Is this normal? I hope to do some other comparisons that will reveal a bit more!
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Thanks for this analysis Murph! Are these metabolites here significantly different in Baraniuk 2021? I had a quick skim but in the body of the paper they only report glutamate as changing and that's after exercise (in GWI). If not then the standard error on these fold change estimates could be large and there could be a lot of uncertainty about whether the effect actually goes the other way - or that there isn't one at all.

From other ME metabolomics papers (not of CSF) I think it's a possibility that these nitrogen related metabolites (urea cycle, glutamate, arginine, proline) could maybe be an exercise/exertion related effect. Maureen Hanson's two day CPET plasma metabolomics paper report changes in these metabolites only following exercise in ME/CFS patients (I think it was proline decreases, pyrroline-5-carboxylate increases, arginine increases but I might be misremembering). Armstrong I believe reported PEM associated differences at some point.

In the NIH study depending on the timings of when they were sampled they might have just been through a grueling exhausting week of tests/CPET, whereas I don't know the sampling conditions in Baraniuk 2021. I'm not saying this is the reason for the differences here but the point I'm making is that I think the metabolome is much more dynamic than the other 'omes' and changes in course metabolic state (fed, fasting, exercise) as well as many other things (diet, drugs, BMI) could lead to a systematic bias.
 
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chillier said:
In the NIH study depending on the timings of when they were sampled they might have just been through a grueling exhausting week of tests/CPET, whereas I don't know the sampling conditions in Baraniuk 2021. I'm not saying this is the reason for the differences here but the point I'm making is that I think the metabolome is much more dynamic than the other 'omes' and changes in course metabolic state (fed, fasting, exercise) as well as many other things (diet, drugs, BMI) could lead to a systematic bias.
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I agree with this take. The metabolome is very dynamic and highly individualised. Which means I think that a lot of metabolomic snapshots are less than useful. If there's no consistency in something then measuring it once is of dubious value.

The that chart above is not the first time I've compared two metabolomic studies. Stong agreement is rare. The interesting things are usually not consistent and the consistent things are usually not interesting. e.g. the hypoxanthine finding stands out in Armstong but doesn't stand up in Fluge and Mella's work.

metabolomics armstrong hoel.png


I got into reading research after Naviaux 2017's metabolomic paper ("dauer, hypometabolism" etc). It really sent me off in a new direction. I was full of hope and I've looked at a lot of metabolomic stuff since. I was especially impressed by Hanson's study with metabolomic measurements at 4 timepoints, before and after exercise. It is a great study design. But what's really come of it in terms of understandin the mechanisms of the disease?

To zoom out conceptually, you could even question if the rash of quantitative metabolomic deepdives recently might partially explain the lack of progress. It's easy to imagine that 40 subjects * 1500 datapoints MUST be useful because its such rich data. But ... what if it isn't?! Perhaps it is still just dominated by noise?

Just thinking out loud. I love to look at big data and I remain hopeful. But I'm open to the idea metabolomics needs to improve to actually reveal the mechanisms of disease.

Just to tie this back to the actual topic of this thread, I'm keen to compare all the nih findings to other metabolomic and lipidomic studies and make some more charts like the ones above to see if any findings are consistent
 
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