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

[ME/CFS Science Blog]

I think the focus on the 2-day CPET and deconditioning in the Davenport et al. letter is a bit besides the point. It would have been better if the journal had also published the other letter that focused on the problems with the EEfRt. Now Walitt et al. largely ignore these. The only info they add is:

In the commentary, the Commentators “challenge [Walitt, et al.]’sconclusions by suggesting the key symptom, exertion intolerance,along with the patient’s strategy to avoid the debilitating PEM, are themost likely explanations for the patient’s reduced activity.” We agree and posit that the strategy described by the Commentators is an effort preference. As explained above this effort preference is not an overt‘voluntary’ strategy nor it is an intentional basis for exerting less energy. As stated in our paper, “Conscious and unconscious behavioral alterations to pace and avoid discomfort may underlie the differential performance observed”. It seems that, in essence, the commentators agree with us.

 

[bobbler]

I'd love to hear @Snow Leopard's thoughts on figure 1 in Walitt et al.'s response to Davenport et al. I don't see how this suggests activity avoidance. To me it just looks like people who struggle with CPET also struggle with everyday life. Doesn't tell us anything about why they struggle with either.



View attachment 28829

Indeed. The insinuations of the term 'effort preference' rather than referring to it as 'disability' in that paper were merely based on the incredibly problematic EfFrt test being used with a rather dodgy new metric invented to draw what seems a strange conclusion (compared to what the tool was designed to test) that could then be used to back-fill as some weird inference over all the rest of the tests that they are explained by 'effort choices' only.

I guess the litmus test is if the rest of the authors thought to read said paper through with said dodgy EFfrt completely removed (as it might due to its problems) then would they begin to feel cringey and uncomfortable at the chosen inferences and implications that have been sewn all the way through the paper next to all the rest of these tests?

Couldn't grip well enough = chose not to exert effort as the main claim was 'discovered' sounds like selling propaganda and almost feels like it might say something about those who choose to write such things without having any good reason for suggesting disabled people need to choose to try harder etc does it not?

and claiming the 'hysterical' calm down dear we aren't saying you do it consciously nonsense means that they aren't saying what they are saying makes it even more embarrassing - maybe at best they've deluded themselves they just mean 'I'm not saying you are aware you are doing it' - but given that makes an untruth sound as if it should stand and not even be replied on as being 'untrue' but pretending their incorrect interpretation isn't incorrect because those criticising it 'don't realise' is just trying to infer the other testimony and/or witness must be the ones who are 'confused'. Ie is a silencing tactic teamed with unjustified denigration of someone’s testimony and as a person on top. What a bad habit certain 'isms' can become to reach for those not even realising its an ism deeply within themselves it just vomits out as if it’s not pure ‘otry’ but just what they think of ‘certain types’ without any evidence but them not realising that distinction.

 

[bobbler]

I think the focus on the 2-day CPET and deconditioning in the Davenport et al. letter is a bit besides the point. It would have been better if the journal had also published the other letter that focused on the problems with the EEfRt. Now Walitt et al. largely ignore these. The only info they add is:

indeed the careful 'reframing' by chopping up specific bits and choosing which comments submitted will even be published over the space of 18months starts to look a little bit cynical. Someone made a choice not to publish a group of these replies together but drip-feed them an extremely long time after everything had died down.

Was there ever a norm whereby when someone published a paper and lots of proper, strong comments were submitted in good time then they were all actually published together - and you know the questions they posed actually answered directly as per moving forward the subject as an academic field rather than seeing it as a political debate?

If someone rushes to submit a comment in a week, then it is held onto for 18months and not replied to in a very straight up way then it surely starts to become an issue of things submitted in quick time being weaponised if there isn't a proper protocol

- you don't rush something in in a week so that there is a swift response in a journal in order for it to be cached or studied for over a year to see how and when it can be used 18months on, and not have a chance to see said replies and say 'I don't approve' given the time lag surely?

 

[ME/CFS Science Blog]

Davenport et al. write:

The increasing effect of PEM in participants with PI-ME/CFS during the test, because of the test itself, could impact the results and interpretation

This isn't entirely on point IMHO. The test only took a couple of minutes, so the increasing symptoms and debility that patients experienced during the test should probably not be viewed as PEM. The term PEM is normally used to describe delayed worsening after the effort.

Walitt et al. also accounted for increasing fatigue during the test, but not for differences in symptoms or ability in finger-tapping before the test started. That was the main flaw, but it seems that this didn't really come through in this correspondence.

 

[rvallee]

Davenport et al have a published commentary in Nature Comms' Matters Arising today:

Altered effort and deconditioning are not valid explanations of myalgic encephalomyelitis/chronic fatigue syndrome [ | PDF link ]

Walitt et al have responded:

Link | PDF

A major objection of the Commentary authors is that we did not include a group of “deconditioned controls” for comparisons, for which there is no standard

And yet, somehow, it has long been declared that we are deconditioned. Even though there is no standard assessment for such a thing. That would make a curious person think. That should make a scientist think hard. Ah, well.

I must say that academic discussions like this do not inspire confidence. Instead of working through issues with methods, it's always about defending what was done. I never seen any actual discussion in response, it's about as useful as a political debate at changing opinions.

Given the stigma faced by patients with ME/CFS we agree that further explanation of the term “Effort Preference” is necessary since the use of this term can be easily misinterpreted and perpetuate stigma. Realizing these issues, we addressed these concerns immediately following the publication of our manuscript, including a frequently asked questions website and a public seminar (https://videocast.nih.gov/watch=54675).

If you have to explain your explanation, then your explanation is bad. Especially when the original explanation is splashed on page A1 for days, and the correction is found in the lesser-printed edition, on the last page, between some classified ads and commercial ads.

Altered effort preference was also observed using the Effort-Expenditure for Rewards Task.

But it wasn't. It's a made-up concept and no such thing was observed, it's what was interpreted, in a very biased manner.

This task uses the chance of small monetary awards as encouragement, in contradistinction to the strong verbal encouragement during CPET and the minimal encouragement during the grip strength experiments.

I find this deeply insulting and underwhelming. It's almost as if encouragement does not matter here. The idea that people should be motivated by pennies is frankly ridiculous, and it makes no difference when motivation is not actually a factor. They did this wrong, it's not complicated, but they won't back down because this is about them and their career, not about us.

We agree and posit that the strategy described by the Commentators is an effort preference. As explained above this effort preference is not an overt ‘voluntary’ strategy nor it is an intentional basis for exerting less energy. As stated in our paper, “Conscious and unconscious behavioral alterations to pace and avoid discomfort may underlie the differential performance observed”. It seems that, in essence, the Commentators agree with us.

Can't tell if trolling here. It's a strategy, but also it's not a strategy. Obviously they don't agree with you, good grief read the actual words and their intended meaning. What a bunch of nonsense.

As stated in our paper, “Conscious and unconscious behavioral alterations to pace and avoid discomfort may underlie the differential performance observed”. It seems that, in essence, the Commentators agree with us.

It seems they either understand none of those words, or are just saying whatever excuse gets them to ignore this. They have no idea what they're talking about here, but I'm leaning more on the side that they do know better, but are blocked by their ideological biases.

A better understanding of the biology of effort preference, rather than the biology of fatigue, may be the science that best serves those with PI-ME/CFS.

Yes, we get it. This is all about you and what you want. What a total disaster.

 

[Evergreen]

It would have been better if the journal had also published the other letter that focused on the problems with the EEfRt. Now Walitt et al. largely ignore these.

Something advocates and researchers can do is always cite both responses (and any others that are published in the future) rather than just one. Kirvin-Quamme et al. 2025 and Davenport et al. 2025.

I think the most powerful part of Davenport et al.'s piece is the authors - these are clinicians, researchers and advocates from across the globe and a number of different fields who came together to say, this reinforces stigma and perpetuates misunderstanding of PEM. This is not a "vocal minority" of patients who just don't understand neurobiological terms. If Fluge and Nacul were miffed after reading the Deep Phenotyping study, it's miffing.

At the risk of being a patient who just doesn't understand neurobiological terms, can someone explain to me how a conscious behavioural alteration to pace and avoid discomfort would not be considered voluntary?

As explained above this effort preference is not an overt ‘voluntary’ strategy nor it is an intentional basis for exerting less energy. As stated in our paper, “Conscious and unconscious behavioral alterations to pace and avoid discomfort may underlie the differential performance observed”.

 

[Eleanor]

Still can't find the quote I'm looking for but did spot this one with Walitt saying "effort preference" plays "an important role in other disorders such as MS and Parkinsons". How's that idea working out, I wonder.

Post in thread 'USA Centers for Disease Control (CDC) news (including ME/CFS Stakeholder Engagement and Communication Calls) - next call 4 Dec 2024'

May 6, 2024

Questions:
Effort preference playing an important role in other disorders such as MS and Parkinsons- Walitt. Yes, it does. Further studies will bring more understanding

How can NINDS get more funding for treatment trials. Nath. He doesn't manage funding so he can't really answer. Federal agencies don't really have the funding; pharmaceutical companies are the ones who can do this.

Muscle findings - Nath. Innate immunity may be affecting muscles. Nath is most focused on trials. Hwang is looking at muscles.

• Hutan

• 

 

[Evergreen]

I must say that academic discussions like this do not inspire confidence. Instead of working through issues with methods, it's always about defending what was done. I never seen any actual discussion in response, it's about as useful as a political debate at changing opinions.

Agree.

 

[ME/CFS Science Blog]

I think the most powerful part of Davenport et al.'s piece is the authors - these are clinicians, researchers and advocates from across the globe and a number of different fields who came together to say, this reinforces stigma and perpetuates misunderstanding of PEM. This is not a "vocal minority" of patients who just don't understand neurobiological terms.

Yes, it's helpful in this regard.

But also a bit disappointing that it then becomes a clash of eminence, and that the more detailed issues with methodology disappear in the background. Got the same impression with the Cochrane review and the Zeraatkar review on Long Covid.

 

[Evergreen]

Still can't find the quote I'm looking for but did spot this one with Walitt saying "effort preference" plays "an important role in other disorders such as MS and Parkinsons". How's that idea working out, I wonder.

Post in thread 'USA Centers for Disease Control (CDC) news (including ME/CFS Stakeholder Engagement and Communication Calls) - next call 4 Dec 2024'

May 6, 2024

Questions:
Effort preference playing an important role in other disorders such as MS and Parkinsons- Walitt. Yes, it does. Further studies will bring more understanding

How can NINDS get more funding for treatment trials. Nath. He doesn't manage funding so he can't really answer. Federal agencies don't really have the funding; pharmaceutical companies are the ones who can do this.

Muscle findings - Nath. Innate immunity may be affecting muscles. Nath is most focused on trials. Hwang is looking at muscles.

• Hutan

• 

Yeah, in the symposium they brought up PD but it wasn't remotely similar. In Chong 2015, people with PD had reduced reward motivation, which was resolved with dopamine-increasing medication. We didn't have issues with reward motivation. In my view it was trying to convince us that they were taking us seriously by bringing up neurological illnesses that everyone takes seriously. Except in PD they had an actual motivation deficit, which is what the EEfRT is designed for.

Edited to add link to study.

 

[Utsikt]

Walitt:

As explained above this effort preference is not an overt ‘voluntary’ strategy nor it is an intentional basis for exerting less energy. As stated in our paper, “Conscious and unconscious behavioral alterations to pace and avoid discomfort may underlie the differential performance observed”.

At the risk of being a patient who just doesn't understand neurobiological terms, can someone explain to me how a conscious behavioural alteration to pace and avoid discomfort would not be considered voluntary?

Good observation!

Although the implication of pacing being unconscious is that pwME/CFS are less prone to doing things by nature. I.e. we’re lazy.

So the statement doesn’t look good either way.

 

[bobbler]

I'm surprised they didn't publish it on Xmas eve

or as per the Cochrane pulling the overdue review of ME/CFS with a proper IAG etc .. the last day of parliament.

are there shut-downs of government of some kind over there happenning and do they affect likelihood of anything important getting 'lost' in the mayhem of what would affected by that?

 

[poetinsf]

In the commentary, the Commentators “challenge [Walitt, et al.]’s conclusions by suggesting the key symptom, exertion intolerance, along with the patient’s strategy to avoid the debilitating PEM, are the most likely explanations for the patient’s reduced activity.” We agree and posit that the strategy described by the Commentators is an effort preference.

This thread finally got me to re-review the paper that I have been meaning to do for a long time. Besides small sample size and various problems with data collection/analysis that have been pointed out by many, I also see a problem with their interpretation of the results. And this reply further muddles it by conflating pacing with what they call "altered effort preference"

As explained above this effort preference is not an overt ‘voluntary’ strategy nor it is an intentional basis for exerting less energy. As stated in our paper, “Conscious and unconscious behavioral alterations to pace and avoid discomfort may underlie the differential performance observed”.

Even if they call it involuntary or unconscious, this reply still makes their "altered effort preference" a psychosomatic conditioning to avoid PEM. This is just not true, and patient experiences bear that out. (How is the inability to lift your arm to hold phone to your ear or to dry your hair an attempt to avoid PEM?). Instead, another possibility, assuming their data gets validated in larger trial, is that the patients are indeed fatigued through whatever the mechanism, but the group difference on fatigue sensitivity were wiped out by motivation in PI-ME/CFS for higher rewards of hard tasks. That would also explain Fig 6e and 6f that showed PI-ME/CFS positively correlating to NE/DA level while HC didn't.

In any case, this paper is the exhibit A of the pitfalls of focusing too much on fatigue instead of PEM. They don't deny PEM is real, but they are still minimizing it as "discomfort". (This is why I call Wallitt et. al. PEM-minimizers.) I still think, as most patients do, the key to ME/CFS is in unraveling PEM, not the fatigue.

edit: somatic -> psychosomatic

 

[Sean]

Yes I think Nath has essentially been played by Wallitt and the interroception crew into legitimising their bullshit.

Yep. That is exactly what has happened.

And yet, somehow, it has long been declared that we are deconditioned. Even though there is no standard assessment for such a thing. That would make a curious person think. That should make a scientist think hard.

Good catch.

They don't deny PEM is real, but they are still minimizing it as "discomfort".

Any argument that characterises PEM as 'discomfort' is invalid from the start, and for somebody in a very senior position, like Walitt is, it cannot be excused as ignorance or inexperience. It is deliberate obfuscation and misdirection.

Once again the psychosomatic cult has managed to hijack and pervert the whole show to their benefit.

The only good I see coming out of this farce is that it is slowly, reluctantly, but unavoidably opening the eyes of the rest of the medical science community to the real problem, how incredibly serious & deeply rooted & urgent it is, and what has to be done to fix it. And not even that much is certain, to be honest, given the glacial pace of the process.

 

[Chandelier]

Thread by C.H. Romatowski on BlueSky.
Here’s the TLDR:

“At this point, NIH is completely botching the study of PEM, and therefore the study of ME, since PEM is its cardinal symptom and dominates the lives of sufferers. The Roadmap will be a failure if this is not completely turned around.” Eighteen months later, I’m only even more concerned.

Page by C.H. Romatowski | @chromatowski.bsky.social

#NEISvoid inside baseball— The NIH team’s response to this (the Davenport et al comment) is awful. It’s here: www.nature.com 1/

skywriter.blue

 

[MSEsperanza]

Davenport et al. write:

This isn't entirely on point IMHO. The test only took a couple of minutes, so the increasing symptoms and debility that patients experienced during the test should probably not be viewed as PEM. The term PEM is normally used to describe delayed worsening after the effort.

Walitt et al. also accounted for increasing fatigue during the test, but not for differences in symptoms or ability in finger-tapping before the test started. That was the main flaw, but it seems that this didn't really come through in this correspondence.

So did the study authors just not account for symptoms immediately before the test or did they also not assess them at all at that time point (immediately before the test) ?

If they did actually not assess symptoms both in pwME and control group before the test, that seems 'problematic' . [*]

Study authors say the sample consisted mostly of moderate and severely affected pwME/CFS. So the participants must have been feeling ill most of the time every day -- not only after increasing their exertion with participating in 'extra' cognitive and physical/ motor tasks for the study?

Not able to re-read the study report, now only read the comment by Davenport et al and the study authors' reply -- there were some other arguments that seem to me pointing to muddled concepts of general / daily ME/CFS symptoms and fatigability on the one hand, and PEM on the other hand -- both in the commentary and the reply.

But would be helpful to have a short summary how and how often they assessed general ME/CFS symptoms and PEM on a daily basis and immediately before and after doing tests (including the CPET and hand grip tests) -- both in pwME/CFS and in healthy controls) , and also how those symptoms relate to daily activity (that if I remember correctly were monitored by activity trackers?).

Of course the sample is still too small to firmly conclude anything but I think taking account of these considerations would be the minimum for a pilot or feasability study. (I like Davenport et al's idea to re-approach the study data / frame the study rather as a pilot study)


[*] (Sorry not finding a better word now despite having tried hard for a couple of minutes -- pushing through very 'unpleasant' symptoms and through heavy 'dicomfort' present already before starting to write).

 

[MSEsperanza]

Another point I think others already have made is the question whether the testing and data allow to tie effort preference to motivation.

Wallit et al seem to argue that in the different tests (finger tipping/ reward test, CPET, repeated hand grip) study participants have been motivated externally by the study personal to different degrees and that this somehow also played a role in the differences in the outcomes?

If they think that's a relevant factor did they specify it in the protocol and analysis?

If yes, how did they account for potential discrepancies or competition between motivation and rational (= conscious) decisions about how to spend effort?

I think that's also a point Davenport et al tried to make: Even if symptoms present already before the test did not limit the ability to perform a task, 'reward', 'effort' and 'motivation would mean very different things to an individual having a reduced activity 'reservoir' compared to another individual.

But if you don't assess symptoms before the test how are you able to distinguish between...

1) a conscious decision to spend effort
a) due to present symptoms making performing a task harder than without having these symtoms
b) due to reserving effort for things you have or want to do later that you would not be able to do if you spent more effort now
c) due to wanting to prevent worsening of symptoms and further limitations in ability that people have observed will follow the next days and can last for a long time (PEM) if they overdo it now.


2) limited ability to spend effort without having the choice to do more
a) due to reduced capacity already without being in a state of PEM
b) due to PEM?

Either way, if there actually were measurable differences in 'effort preference' for specific tasks, wouldn't you expect that this is an effect of the illness rather than a contributing factor? Are the methods and tests used in the study adequate to establish a causal relationship in either direction?


Edited to add more points.

 

[Trish]

I think one of the major problems hampering this study is their misunderstanding of PEM. I went back to their PEM paper done before the study and my letter of criticism about it. Basically, they did a focus groups study by phone, facilitated by a social scientist with no understanding of PEM. The questions conflated daily effects of exertion with delayed episodes of PEM. They grouped symptoms of both daily symptoms and PEM in such a way as to come out with a description of the core symptoms of PEM as exhaustion, and muscle and cognitive problems. They then conflated this with PEF experienced in other conditions.

They completely left out the core PEM features of delay, duration, episodic, loss of function and feeling very ill (malaise). The also seemed to think they had discovered something new when they described the effect of CPET, not realising apparently that CPET is simply used to trigger PEM for study, and is not a different phenomenon from delayed PEM from any exertion that exceeds our threshold.
See these threads:
Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (2020) Stussman, Nath et al.

A personal letter to the NIH team researching ME/CFS about their PEM study, 2020

I think this is relevant to this discussion because their interpretation of results is built on their understanding that PEM is the same as PEF, and is, as has been commented, just 'discomfort'. It also meant they didn't even realise there was such a thing as fatiguability and how it affects us all the time, not just during crashes.

I also disagree that the inablity of pwME to sustain grip in the hand grip strength tests and to complete the harder button pressing tasks has anything to do with pacing to avoid discomfort, conscious or unconscious. I think there is something physiological going on that means when we do an exertion, our ability to sustain it is much less than when well, even when we are not deconditioned.

It has nothing to do with pacing (or decondioning) that I can't walk more than a limited distance before my legs collapse and I urgently need to lie down, it has nothing to do with pacing that my handwriting that I used to be able to sustain solidly without a break doing a 3 hour exam, now barely lets me write a cheque, or when my ME/CFS was mild and I wasn't deconditioned, I had to type my reports at work rather than handwriting as we were supposed to do, as my hand couldn't sustain gripping the pen for dozens of reports on my students, especially when I needed to press hard for the words to come through the triple copies. It's not just exhaustion, it's a hard stop that means I can't go on doing the activity.

That has absolutely nothing to do with effort preference or pacing, it's something physiological. I have no idea whether it's in my central or peripheral nerves or muscles, but it's not a choice or a preference.

 

[rvallee]

I think this is relevant to this discussion because their interpretation of results is built on their understanding that PEM is the same as PEF, and is, as has been commented, just 'discomfort'.

Which often frankly disturbs me because post-exercise fatigue is pleasant. It's not just one of the reasons why a lot of people regularly exercise, it's also encouraged based on this: you feel better after it, when you have a healthy body. Yes, for the long-term overall benefits, but to most people the fact that it's pleasant, satisfying, is good enough in itself. That feeling of good weariness, the endorphin comedown, it all feels great.

To conflate PEM with post-exercise fatigue is frankly as ridiculous as comparing a slap to the face to a kiss. I have a really hard time taking people who make those claims seriously about anything. Do they not have bodily experience of their own? Why are they arguing that something that feels good and healthy to most people must be the same thing as something horrible that is clearly pathological? They would make just as much sense arguing that being sick feels great: what the hell are you even talking about here with this nonsense?

Post-exercise fatigue is not unpleasant, there is nothing unpleasant to avoid for most people here. To take this excuse and extend it to a few minutes of pressing buttons is straight up insulting our intelligence. We can keep insisting to them that we know, we can tell the difference, that this is something else entirely, but they don't have to listen. Sure, not everyone agrees to this, lots of people hate exercise, but it's a normal physiological reaction that most people do enjoy and they are warping it completely to suit their ideology. They keep having to invent fake mental illnesses to make up for their own incompetence. What a rotten system they have built for people like us.

 

[StellariaGraminea]

Another point I think others already have made is the question whether the testing and data allow to tie effort preference to motivation.

Wallit et al seem to argue that in the different tests (finger tipping/ reward test, CPET, repeated hand grip) study participants have been motivated externally by the study personal to different degrees and that this somehow also played a role in the differences in the outcomes?

If they think that's a relevant factor did they specify it in the protocol and analysis?

If yes, how did they account for potential discrepancies or competition between motivation and rational (= conscious) decisions about how to spend effort?

I think that's also a point Davenport et al tried to make: Even if symptoms present already before the test did not limit the ability to perform a task, 'reward', 'effort' and 'motivation would mean very different things to an individual having a reduced activity 'reservoir' compared to another individual.

But if you don't assess symptoms before the test how are you able to distinguish between...

1) a conscious decision to spend effort
a) due to present symptoms making performing a task harder than without having these symtoms
b) due to reserving effort for things you have or want to do later that you would not be able to do if you spent more effort now
c) due to wanting to prevent worsening of symptoms and further limitations in ability that people have observed will follow the next days and can last for a long time (PEM) if they overdo it now.


2) limited ability to spend effort without having the choice to do more
a) due to reduced capacity already without being in a state of PEM
b) due to PEM?

Either way, if there actually were measurable differences in 'effort preference' for specific tasks, wouldn't you expect that this is an effect of the illness rather than a contributing factor? Are the methods and tests used in the study adequate to establish a causal relationship in either direction?


Edited to add more points.

Really good summary of the conceptual mess that is the thesis of effort preference in this paper.

I'm thinking specifically of the prior research on "Effort Preference" (E.P.) which Wallit distorted** in a poor attempt to create a veneer of plausibility for his pet idea. I think the original E.P. researchers would have an opinion on it... and would also be ideally placed to call it out for the rubbish it is.

Wondering would it be worthwhile to try and sound out one of those E.P. researchers to get an opinion... perhaps even a formal reply*? Not sure how interested they would be, but if it's _their_ pet idea they might feel quite strongly about it too.


[*And wait another 18 months before it's published, of course ]

EDIT: [** The word "distorted" is overly generous here]