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

Surely this was evident to all the scientists involved in this study. The ME participants made a huge sacrifice to take part in this study. They knew that there was a high risk that it would have a detrimental effect on their health – certainly in the short and medium term – and yet they were willing to make that sacrifice in order to advance scientific understanding for the benefit of the community.

The notion that these people have an unfavourable effort preferences is obtuse to say the least. How on earth could all the co-authors signed this off? Presumably many of them got know the participants and were fully aware of the effort and sacrifices they made to participate. How could they then agreed to put their names to the wording in the abstract and discussion?

Sincere thanks @Paddler for taking part and for sharing your experience on here. And the same to all the participants.

 

Yes, they are reassuring - I felt it would be helpful to get clarity as there was speculation about the severity of patient participants.

No, according to the user agreement, I can only share data with others who have registered with mapMECFS.

I did that by clicking on the link under Data Availability on the paper - this link https://www.mapmecfs.org/group/post-infectious-mecfs-at-the-nih

The registration process was straightforward and I was approved within 24 hours. I identified myself as a Speech & Language Therapist with ME/CFS without an institutional affiliation, very briefly (2 or 3 sentences) described my interest in the SF36PF data amongst others, my research interests in ME/CFS including a paper I'm working on, gave my Orcid ID (which lists my one article and two letters that have been published). I do not know what the criteria are for approving access, only that I was approved quickly.

 

“Old wine in new bottles,” as an eminent scientist once said.

Having written this, it occurred to me that in this regard the participants may not be representative of ME patients in general. The nature of the study is that there is likely to be a bias with regard to the psychology of those who volunteered. Ironically, the fact that they chose to volunteer for such a gruelling study suggests that they may be more likely to make more effort for a potentially negative personal reward than an average patient or healthy volunteer. At a population level, such altruistic behaviour might be considered a favourable effort preference. For the individual it might be considered “unfavourable” – although that seems to be the opposite of what Wallit et al were meaning.

[edit – typos etc for clarity]

 

Not caught up yet, but just wanted to apologise to @Paddler, @B_V & Sanna, for thinking participants were mildly affected or even that some didn't have ME, as seemed to be indicated by the results. You knowingly subjected yourself to great risks for the greater good, and suffered significant and prolonged harm. How dare anyone say you "preferred" not to exert effort.

Just so angry with Wallit for the massive scale of gaslighting. Being so nice with participants, while intending to stitch them and all of us up in the conclusions. Participants who were so ill and massively declining due to the arduousness of taking part.

 

It's a head of department job is it? I note because there are different processes/criteria for the more standard academic type jobs and then you get into things like new departments being set up or management jobs etc.

 

Lots of excellent ongoing analysis in this thread.

I’m wondering how it might best be used. Are individuals planning to submit individual letters to the journal? If so, it might be sensible to coordinate and/or collaborate so that different people aren’t all making the same points, and other valid criticisms are not omitted.

Alternatively, I wonder if a more comprehensive analysis/criticism could be published as a collaborative paper.

I’m not well enough to contribute much atm but I think the above should be considered.

 

I've searched through the muscle data in the file "Supplementary Data 19" (a subset of this data also appears in Figures 18 a) and b) as well as the files for these figures in the appropriate source data files). I don't know anything about things that could be in relationship to WASF3, so I looked for those things that were looked at in the WASF3 paper and/or have appeared elsewhere in research.

The WASF3 paper has 10 HV and 14 ME/CFS patients (no mention of genders or anything else). In the WASF3 paper they found the following:

WASF3 higher in ME/CFS
PERK higher in ME/CFS
BiP (GRP78) lower in ME/CFS
CIV subunits (MTCO1 and COX17) lower in ME/CFS, respectively showed a significant negative correlation with that of both WASF3 and PERK

(When human myoblasts were put under ER stress they did also notice increased expression of WASF3 protein, without an increase in its mRNA and noticed a decreased CIV subunit MTCO1, which led them to conclude that there is also posttranslational regulation of WASF3 under ER stress)

In the intramural study we have 12 HV (M/F:7/5) and 13 ME/CFS (M/F:6/7) patients (so there’s obviously a mismatch between the healthy controls and ME/CFS patients for the gene expression data in the intramural study and those in WASF3 study), we also have data for males and females vs controls separate. I have found the following things to not be present in the data

WASF3 - not found (this includes the aliases WASF3, Brush-1, SCAR3, WAVE3, any terminology related to WAS, nor can its entrez id 10810 nor its ensemble id ENSG00000132970 be found)
PERK - not found (this includes the aliases PERK, EIF2AK3, PEK, WRS, nor can its entrez id 9451 nor its ensemble id ENSG00000172071 be found)
BiP (GRP78) - not found (this includes the aliases BiP, HSPA5, GRP78, HEL-S-89n, MIF2, nor can its entrez id 3309 nor its ensemble id ENSG00000044574 be found)
MTCO1 - not found (this includes the aliases MTCO1, COX1, COI, nor can its entrez id 4512 nor its ensemble id ENSG00000198804 be found)
COX17 - not found (this includes the aliases COX17, nor can its entrez id 10063 nor its ensemble id ENSG00000138495 be found)

Other than that I also looked for some genes that have appeared in different hypotheses, namely IDO1, IDO2 and AHR (both motivated by this study which however focused on the proteins rather than genes) and STAT1.

IDO1 - only data for female cohort, p=0,033324508 (adj p=0,999938353), t=-2,378861446,
IDO2 - not found (this includes the aliases IDO2, INDOL1, nor can its entrez id 169355 nor its ensemble id ENSG00000188676 be found)
AHR - only data for the male cohort, p=0,029088036 (adj p=0,996544964), t=-2,452823722
STAT1 - not found (this includes the aliases STAT1, CANDF7, IMD31..., ISGF-3, STAT91, nor can its entrez 6772 nor its ensemble id ENSG00000115415 be found)

Of course the raw data might be slightly different, but I haven't requested access to that (yet).

 

Brilliant. That's important.

 

I don't see these results as leading to anything new. The studies on T and B cells are not significant with such a tiny sample.

T cell sequencing I think would be a complete waste of time even if we knew what antigen might be around. There is no evidence of antigen being around so there is nothing to look for. If you sequence the peptides that bind to receptors on T cells cloned out of patients you are likely to find they could be from a million different organisms. It isn't a serious strategy to my mind.

 

Mods, feel free to move or delete if this was already shared (as I assume it was).

Sharing this interview today from David Tuller with Michael VanElzakker on the NIH study. Sharing some notes (I know this will be critiqued, but sharing):

Dr. Michael VanElzakker:

“they have reported antigenic stimulation in the immune system, which to me was the take-home message that I wish people were amplifying”

“I would like to see patient advocacy groups demanding a follow-up for that – okay, what is my antigen? What are the antigens? What is that’s driving the immune system responses? Is it the same in everybody?”

“Those are questions that could be answered. They found evidence of activated T-cells. We have techniques now, further at the cutting edge, that are more expensive and difficult, where you can do T-cell sequencing, you can work backwards if you have isolated T-cells and figure out – to what is the T-cell responding? These are answerable questions that we can figure out."

"That is the kind of follow-up if I were in this study, I would be demanding. Okay, if my T-cells were activated, what is my T-cell responding to? Is it a pathogenic antigen or what? That is the thing I would want to be finding out.”

“I would be focusing on the antigen part – there is evidence of this antigenic stimulation – what is the antigen? Can we do biopsies? Can we do T-cell sequencing? Let’s figure out the actual cause what is happening to."

https://www.youtube.com/watch?v=CIeXa5cYHiU

 

Was there any evidence of antigenic stimulation?
A few stray T cells possibly but T cells get activated by things other than antigens.

Brain biopsy is not a terribly good idea!

 

Of course, I myself have no idea what the answer is here--smarter people will have to figure that one out! In general, I appreciated Mike's pragmatic perspective on the study.

 

I had a look at the paper again. The B cell findings are unremarkable and we have similar studies from the past that showed nothing much. An increase in naive cells is hard to make much of. The key finding for brain seems to be "Markers of T-cell activation, PD-1+ CD8 T-cells, were elevated in the cerebrospinal fluid of PI-ME/CFS participants (Fig. 7c)." But figure 7c relates to peripheral blood mononuclear cells. It doesn't seem to say CSF. And anyway the box plot shows the patients and controls are much the same, just skewed a bit, which is probably due to one or two odd outliers.

I cannot persuade myself so far that there are any meaningful data here.

 

Wouldn't a pragmatic perspective be like ours - the samples are so small and the findings so marginal that nothing very much can be concluded?

These are actually quite good negative findings in that there are no clear cut population shifts in values for the two groups. Pathogenetically relevant data tend to look as different as ducks and swans.

Lucibee made the valid point that claims of immune abnormalities might encourage physicians to hand out antivirals. I would have hoped that nobody would take the data seriously enough. But vanElzakker seems to be doing just that.

 

Perhaps, but I was thinking "pragmatic" more in the sense of the larger public discussion of focus--not necessarily on the specifics of the meanings of the findings.