SMPDL3B a novel biomarker and therapeutic target in myalgic encephalomyelitis, 2025, Moreau, Fluge, Mella et al

Hutan said:
OMF's lever is the choice of who and what they fund. We need them to do better in making those choices. I think there could be a role for OMF in quality control - to have a panel that scrutinises protocols and manuscripts and provides comment, because careless and misleading work does reflect on the funders. If a researcher chooses to ignore the comments, that is fine, but it may mean that there is not further funding.
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I wouldn’t want pre-publication interference of the details by a funder, that creates all kinds of bindings (and there is no guarantee that the funder are more correct).

Post-publication termination of future funding is something else.
 
Hutan said:
OMF's lever is the choice of who and what they fund. We need them to do better in making those choices.
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I agree with a lot of what you say @Hutan. I'd just like to point out that this was funded by Canadian donations and OMF has only one Canadian research center. In the OMF financial reports major donations are often specified for a particular purpose. That may or may not be the case here, but could be the case. The Sibylla-Hesse Foundation is also a Canadian foundation.

Paper funding statement said:
This work was supported by grants from The Sibylla-Hesse Foundation and Open Medicine Foundation Canada, awarded to Pr. Moreau.
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I'm sure the politics of private research funding are complicated and I have no relevant information about relationships with major donors on which to speculate. I'm sure sometimes foundations and even researchers themselves have to swallow a rat. Everyone makes compromises sometimes, often they are necessary, I understand that.

My perspective is being exposed to the devastating direct effects of ME/CFS on a daily basis, compounded by the extraordinary and confident prejudice so many people, medical institutions and governments hold about sufferers of ME/CFS. We are relying on foundations like OMF to make the best choices possible as to where they direct funding to change that situation as quickly as possible. So, while I am sorry for any impact of my comments on the feelings of young researchers (I doubt my views will count for much anyway), I want to make it clear that this paper is not good enough. It must not be hyped as a breakthrough.

abstract said:
These findings warrant clinical trials to evaluate their potential in mitigating immune dysfunction and symptom burden in ME.
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The paper calls for money and effort to be spent on drug trials to correct a problem with SMPDL3B in ME/CFS that this paper does not prove exists. It also risks readers making unwarranted assumptions about the role of estrogen in the disease. I think the fact that there is no clear pattern of change in ME/CFS symptoms with age or menopause or even over the menstrual cycle (or even between men and women) makes a significant direct role for estrogen rather unlikely. I don't think there is much evidence for the idea of sexual dimorphism in ME/CFS - it just tends to be an easy refuge of post-hoc sub-setters.

There are a number of poorly evidenced background statements in the paper as well. I was happy to ignore those if the core finding was robust. But, it all contributes to a picture of a lack of rigour. I know I'm preaching to the choir here, but we need more rigour from everyone - funders, researchers and especially those in a supervisory role, clinicians, and people with ME/CFS too.
 
Paper: "Controls were frequency-matched to the ME patient group based on age and sex distribution at the group level."
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There was a massive sex difference between groups: 47% of controls were males compared to only 17% in the Canadian ME cohort. So what does frequency-matching mean in this context?

Pretty much all of their measures were affected by sex, suggesting that the difference between ME and HC could be due to the former group being more female. I don't understand why the authors didn't correct for this, it looks like they didn't even use a regression model in their analyses?

There is one graph that compares female ME/CFS with female HC (figure 3.c). Perhaps I'm misunderstanding but it seems to show no significant difference between the Canadian ME cohort and HC when you split it by sex. There is no line connecting these groups to suggest a significant difference, only between the Norwegian and other female groups.

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Murph said:
A large majority of those on contraception scored over 100 and therefore must be in the ME group. If I'm reading this right, almost everyone they got in their study who was on contraception also had ME.
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Good point. Frustrating that they didn't report the number of HC on contraception. I wonder if the analysis would still hold of they controlled for sex and contraception using a regression analysis. Seems rather irresponsible to not do this, given how large the effect of contraception is on the measures they report.
 
Just as a side note, I found the statistics about people in the Canadian ME/CFS cohort on the MFI-20 a bit interesting - see @wigglethemouse's post of the table upthread. A total score of MFI-20 of over 60 is regarded as indicating unusual levels of fatigue. There are 5 sub-sets of fatigue, each with a maximum score of 20 and a minimum of 4, and so a score of up to a bit over 10 on one of the subsets is still well within normal bounds.

General fatigue and physical fatigue are up around 16 and 17 out of 20 for the cohort, presumably way out on the end of a population distribution. Reduced activity is mostly around 16 out of 20. Mental fatigue is about 14.

But the scores for reduced motivation are way less than other measures of fatigue, for both men and women.
The female mean score (regardless of SMPDL3B levels) for 'reduced motivation' is 10.65. The male mean score is 12.23, with there looking to be quite a strong positive relationship with overall severity and a lot more individual variation.

So, self-reported reduced motivation does not seem to be a major component of self-reported fatigue in this ME/CFS cohort.

The exception is the group of 13 men who have a high mean overall fatigue level. Their mean score for reduced motivation is 15.1. Now, of course, this is a very small number of people and I know I'm somewhat torturing the data until it tells me what I want to hear. But, it looks as though there is a significant proportion of the male group with quite high reduced motivation scores. My personal experience contributes to me thinking that men may be more likely to explain their incapacity away by saying that they didn't really want to do the activity, that they could not be bothered. A sort of 'show no weakness' attitude, even to the point of preferring to be seen as lazy than explaining to people that they are ill. Not all men, of course. It's possible that that higher reduced motivation score is related to depression too.

A person who thinks that they are probably just unmotivated is less likely to go to see a doctor and even less likely to actually get an ME/CFS diagnosis. A man who reports feeling depressed as well may be even less likely to get an ME/CFS diagnosis, which is often seen as a female disease.

I think it's a phenomenon worth watching out for, because it may help to explain some of the sex ratio skew to female predominance in diagnosed ME/CFS.
 
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wigglethemouse said:
Here is the supplementary data attached. I've separated out Table S3 - Symptom scores split by SMPDL3B plasma levels. A wee bit underwhelming to say the least. What I don't get is why you hide away a supposedly main finding in supplementary info yet keep the conclusion in the abstract.

View attachment 26919
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What is SF-36 "Mental score"?

These are the categories of SF-36:

Physical functioning
Role limitations due to physical health
Role limitations due to emotional problems
Energy/fatigue
Emotional well-being
Social functioning
Pain
General health

"Physical score" must be what SF-36 normally calls "Physical functioning", right?

The most sensible category to include for a study about ME/CFS is "Energy/fatigue". Is that what they mean with "Mental score"? None of the SF-36 categories fit that name.
 
Liie said:
"Physical score" must be what SF-36 normally calls "Physical functioning", right?
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I suspect it refers to the physical component score.

The Sf-36 different subscales are grouped into a physical component score (PCS) and a mental component score (MCS).

PCS is calculated from:
Physical functioning​
Role limitations due to physical health​
Pain​
General health​

MCS is calculated from:
Social functioning​
Role limitations due to emotional problems​
Emotional well-being​
Vitality​
 
"In the logistic regression analysis accounting for age, sex, and plasma SMPDL3B levels, we found that ..."

Why would their covariates not have included i) contraception use, ii) co-morbidities (ME vs HC are wildly different)

I'm a non-scientist but even I would have done a multivariate logistic regression, controllling for these very significant covariates, and would have put the odds-ratio for SMPDL3B in my Abstract (rather than unsupported claims)
 
WildWoila said:
I'm confused, in the methods section it says "a multivariate logistic regression analysis was conducted to assess the influence of sex, age, and estrogen use on plasma SMPDL3B levels." But above everyone seems to be saying that contraception use was not controlled for. Which is it?
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It's a bit unclear but it seems that they used this model to see how these factors influence SMPDL3B but that they didn't use it for group comparisons.
 
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