Pre-Illness Data reveals Differences in Multiple Metabolites and Metabolic Pathways in Those Who Do and Do Not Recover from IM, 2022, Jason et al

[Hutan]

The two groups of 18 are just the "severe" ME patients and 18 matched controls selected for this specific metabolic investigation. Their previous paper showed 23% meeting any one of the three criteria and 8% more than one criteria at six months. Still a lot, but not 50%.

Yes.

4501 - the prospectively recruited students
238 - the students who got IM during the study period

6 months after infection:
55 - students who met the requirements of at least one ME/CFS diagnostic criteria
>> 20 - students who met the requirements of more than one diagnostic criteria
157 - students who were asymptomatic
26 - students who had symptoms but did not meet any ME/CFS diagnostic criteria

So, two of the 20 students meeting multiple ME/CFS criteria weren't included in the study. This study does not set out the numbers of students - I had to look at the previous study (linked in a post above). I don't think this study explains why only 18 students were involved in this study. Probably the missing 2 just weren't available for logistical reasons.

But yes, I share the concerns of others that this very odd grouping labelled 'severe ME/CFS' might be a post-hoc creation to suit the data. Why would you not just choose (before data analysis) one criteria you believed was reasonable and analyse the data based on that? Or report results for each criteria separately. I'd really like to see the results for all the students reporting PEM at 6 months, and for all the students symptomatic at 6 months.

 

[LarsSG]

While the severe name definitely just confuses things, I don't think comparing the cohort who met IOM or CCC and Fukuda against controls is a bad thing. Some of the patients who only met Fukuda may not actually have the same disease or at least not in the same way as those who also met IOM or CCC. There were a few patients who met IOM or CCC and didn't meet Fukuda and so wouldn't have been included in the severe group (and I think it would have made sense to include them), but this doesn't seem like a huge problem to me.

I think the severe ME/CFS group is pretty similar to the group that has PEM, as anyone who meets Fukuda with PEM is highly likely to meet IOM or CCC or both. I'd imagine most of us wouldn't think it makes a lot of sense to lump patients without PEM in with those who do have PEM. But I also wonder if those with mild ME might not recognize PEM at six months either, so basing everything on PEM might not be as airtight as we'd want.

There was also another group who didn't recover fully after six months, but didn't meet Fukuda, so there was clearly a range of outcomes and they had to draw lines somewhere. There was a pretty big difference in the functioning and symptom scores between the severe and non-severe groups.

This isn't a treatment trial and I don't think one needs to apply the same standards here. We also don't know what the original study design was and this may have been included. If using the severe group helps find something interesting to follow up on, then that's great. Better to have some results that could lead to future study than null results and have to go back and start again with another eight years of work! Hopefully future studies can use this as a lesson in why using Fukuda is not a great idea.

I'd be really interested to find out what recovery rates looked like over the longer term (it has now been 3-8 years for these patients) and to see if the recovery rates differed between the no-ME but still not recovered, non-severe, and severe groups.

I don't think this study explains why only 18 students were involved in this study. Probably the missing 2 just weren't available for logistical reasons.

From the previous study: "For the behavioral and psychological survey measures, complete data were available for 109 participants at all 3 time points (18 S-ME/CFS, 31 ME/CFS, 60 Recovered). There were some data loss from the original sample; however, there were no sociodemographic differences between cases with missing data versus cases without missing data on gender, race, or received diagnosis (data not shown)."

 

[Hutan]

This isn't a treatment trial and I don't think one needs to apply the same standards here. We also don't know what the original study design was and this may have been included. If using the severe group helps find something interesting to follow up on, then that's great. Better to have some results that could lead to future study than null results and have to go back and start again with another eight years of work!

Yes, I was thinking that it would be very good to look at the study protocol. If they always planned to analyse the data in this way, then, even though the approach is a bit odd, I'd feel a lot happier that the reported results are solid. It would be great if an author of the paper could explain why they took the approach they did.

Cherry-picking (not saying that that is what happened here) does have a down-side of course, even in exploratory analyses. If researchers spend a lot of time looking at hypotheses that fit with cherry-picked results, then they aren't looking at hypotheses that might be closer to the truth.

I'd be really interested to find out what recovery rates looked like over the longer term (it has now been 3-8 years for these patients) and to see if the recovery rates differed between the no-ME but still not recovered, non-severe, and severe groups.

yes, me too

 

[Mij]

But I also wonder if those with mild ME might not recognize PEM at six months either, so basing everything on PEM might not be as airtight as we'd want.

Everybody experiences M.E differently, I didn't have PEM until 6-7 years into the illness. MS is considered an episodic disability as well as progressive. And so that means that there are periods of wellness followed by periods of disability.

 

[LarsSG]

Reading though the paper again, it looks to me like for this study they had already grouped the participants into the severe ME group in their previous work and only actually carried out the metabolemics work on these 18 with severe ME and the 18 matched controls, so it doesn't look like cherry picking is an issue.

 

[Wonko]

Jason et al usage of 'severe' is bizarre and will cause confusion, if not downright derision (of us when we use it to mean what we, and everyone not included in Jason et al) and dismissal - IMO.

I had not seen anyone else use it in this bizarre way before he did a couple (few?) years ago, and I've not seen anyone else use 'severe' to mean 'meets more than one definition' as opposed to the way everyone else uses 'severe' to mean severe.

IMO it is not helpful, to anyone, apart from maybe Jason etal, and welfare agencies, insurance companies, etc., and then only because they can use it to downplay the meaning of 'severe' vs severe.

Starting to get a tad irked by it now.

 

[voner]

perhaps this will help shed some light on the wording these authors use…

this is from a previous paper they published in February 2022…(https://www.s4me.info/threads/predi...ectious-mononucleosis-2022-jason-et-al.24902/)

Predictors for Developing Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Following Infectious Mononucleosis

here is their definition section:

////////

ME/CFS Diagnosis

Participants’ six-month medical examination, and the results from their DePaul Symptom Questionnaire and MOS 36-item Short-Form Health Survey were used in the diagnosis of ME/CFS. While there are multiple ME/CFS case definitions, we selected three major ones including the Fukuda et al. criteria, the Canadian Consensus criteria and the Institute of Medicine criteria. A number of studies have found that the Fukuda et al. criteria are broader and identify a larger group of patients, with less severity, than those identified by the Canadian Consensus or Institute of Medicine criteria. Therefore, participants who primarily only met the Fukuda et al. criteria were defined as having ME/CFS. Those who met more than one case definition (i.e., the Fukuda and either the Canadian and/or Institute of Medicine criteria) were defined as having severe ME/CFS. Those who met more than one case definition also scored worse on the DSQ than those who met only a single case definition for ME/CFS six months following IM. Those who recovered were labeled controls. For participants with data at all stages of the study, 30 were classified as ME/CFS, 18 were classified as severe ME/CFS, and 58 were classified as controls.

/////////

I had to read this paragraph more than once. it certainly could be worded much better. By the way, DSQ, means the DePaul Symptom Questionnaire …(DSQ, a self-report measure of ME/CFS symptomatology). They don't seem to define "scored worse”. Maybe that data can be made avaiable.

 

[Andy]

So the core problem is that the authors in this and previous papers are happy to accept anybody who meets Fukuda, which doesn't require PEM, as having ME/CFS. Then, on the basis that anybody who also matches other criteria, the criteria that do require PEM, have higher severity then they should be defined as "severe ME/CFS".

So not only is it an issue of appropriation and mis-application of the term "severe", but in a time when it appeared that generally we might be moving away from use of Fukuda, this team use it in such a way as to encourage its continued use, because according to them Fukuda=ME/CFS.

 

[Mij]

The M.E doctor who diagnosed me co-authored the 2003 Canadian Consensus Criteria. He didn't diagnosis patients within 6 months of illnesses based on symptoms, or even severity, his diagnostic criteria was based on 25+ years of experience. The term PEM wasn't used or even talked about back then.

My diagnoses was based on onset, history, relapsing-remitting episodes and r/o M.S.

 

[Andy]

The M.E doctor who diagnosed me co-authored the 2003 Canadian Consensus Criteria. He didn't diagnosis patients within 6 months of illnesses based on symptoms, or even severity, his diagnostic criteria was based on 25+ years of experience. The term PEM wasn't used or even talked about back then.

My diagnoses was based on onset, history, relapsing-remitting episodes and r/o M.S.

I don't understand the point you are trying to make. As a co-author of the CCC, he must have attempted to distill his 25+ years of experience into the criteria surely, otherwise why was he involved? His experience must have been used to inform the decisions that resulted in the CCC as we know it.

 

[dave30th]

I'm less concerned about the use of the word "severe" and more intrigued by the fact that they had some findings that could be leads for further investigation into possible dysfunctional pathways. The Dubbo studies were also prospective but only started tracking patients after they got an acute illness. So it was smart to track the full undergraduate sample pre-illness.

 

[Andy]

I'm less concerned about the use of the word "severe" and more intrigued by the fact that they had some findings that could be leads for further investigation into possible dysfunctional pathways. The Dubbo studies were also prospective but only started tracking patients after they got an acute illness. So it was smart to track the full undergraduate sample pre-illness.

It's not a binary thing, I can be concerned about their use of 'severe' as well as interested in their actual findings. And I can understand that it might appear to be less of a concern from a non-patient perspective.

 

[Mij]

I don't understand the point you are trying to make. As a co-author of the CCC, he must have attempted to distill his 25+ years of experience into the criteria surely, otherwise why was he involved? His experience must have been used to inform the decisions that resulted in the CCC as we know it.

My point was that severity wasn't considered a criteria. Some of his pts were in wheelchairs and he did not give them an M.E dx.

History, onset, remitting-relapsing episodes was the reason I was dx with M.E, even if he suspected that I would recover in 5 years.

 

[Andy]

My point was that severity wasn't considered a criteria.

I would be concerned if burden severity didn't have a bearing on diagnosis. If not then we should accept anybody "tired all the time" as having ME.

Some of his pts were in wheelchairs and he did not give them an M.E dx.

Being in a wheelchair should have had nothing to do with it, it should have been whether they met a criteria for having ME, even if that predated the CCC.

History, onset, remitting-relapsing episodes was the reason I was dx with M.E, even if he suspected that I would recover in 5 years.

Yes, history of symptoms, including how much they affected you, i.e. the severity of symptoms. And the anticipated possibility of recovery shouldn't have affected the diagnosis you were given at that moment in time.

 

[Hutan]

Further on the interesting spermine/spermidine finding,
The Stanford lab has funding to explore this (related to manganese), it's discussed in a video from Ron Davis:
Dr Ron Davis - Updates on ME/CFS research - September 2019 onwards

Mn is involved in a number of enzymes in the mitochondria. It's involved in:
1. the glycolysis pathway - and we know that people with ME/CFS have problems with this pathway, with burning glucose
2. the urea cycle - When you burn amino acids (and that seems to be an important source of energy in ME/CFS), nitrogen is produced. If the nitrogen is not eliminated via the urea cycle, then it can make ammonia, which is toxic.

Further on the urea cycle: it is involved in the making of spermine and spermidine. Abnormal levels of these two molecules were identified as risk factor in going on to develop ME/CFS after mononucleosis (in the Jason college student study - it's discussed here). Both spermine and spermidine can block ion channels and potentially affect how Mn gets in [to cells?].

The plan is to run experiments to see if the enzymes are functioning normally. If they aren't, Mn will be added to see if it improves function. They will look at metals other than Mn a bit, but Mn is the focus. With the grant being for three years, there is scope to follow leads and explore.

There are several metabolites that are involved in the regulation of spermine and spermidine. Mike Jensen who works in the Stanford/Ron Davis lab has worked ou an assay for the metabolites using the electrophoresis instrument that was purchased with funds from Whitney's birthday fundraiser.

 

[FMMM1]

Further on the interesting spermine/spermidine finding,
The Stanford lab has funding to explore this (related to manganese), it's discussed in a video from Ron Davis:
Dr Ron Davis - Updates on ME/CFS research - September 2019 onwards

I'm guessing that if manganese was relevant then the GWAS study should pick up a signal?
Haven't watched the video!

 

[FMMM1]

I'm guessing that if manganese was relevant then the GWAS study should pick up a signal?
Haven't watched the video!

Listened to the video - some garbled thoughts!

7.30 - 9.30 & 11.15 minutes bit about nitrogen (protein metabolism - urea - some evidence that protein is more important as an energy source in ME/CFS - Chris Armstrong 2015 onwards)

Assume that they'll look at the enzymes that are used to transport manganese into the cell and into the mitochondria.

Is there a role for manganese in the urea cycle?

Bit about mono & development of ME/CFS around 13 minutes. Possibly, given the current interest in post viral "syndromes", this would have been a significant benefit i.e. in getting the grant - well done!

13.17 bit about ion channels including calcium channel - think drug Whitney (abilify) is using/used is a calcium channel blocker. I'd like to see more research on calcium channels, but I've no real evidence to support that wish.

14.00 - 14.15 minutes I struggled to understand what he's referring to [couldn't transcribe the words to Google them!] but if there's access to the study protocol then that should help.

I'm still going back to my original post - there seems to be a lot of adding up dots here and I think GWAS would be a more objective way to direct research. Also, GWAS is more likely to identify the unknown unknowns.

Still, great to see this project - low success rate of grant applications is remarkable. Maybe, post covid, putting post viral into your ME/CFS application will help.

 

[dratalanta]

The Guardian has belatedly seen the appeal of that “95% accuracy” conclusion. Jason spoke about this paper for the Guardian’s “medical mysteries” piece today on Long Covid, post-viral illness and ME in their Long Covid series.

researchers seem particularly excited about the possibility that these post-viral illnesses could be predicted, mitigated or maybe even prevented before serious onset. Jason, at DePaul, has already started to identify risk patterns in his research. One recent study of college students who got mononucleosis found that pre-existing immune system deficiencies were a very strong indicator of which patients went on to develop ME/CFS.

“We could predict with over 95% accuracy who would recover or who wouldn’t,” said Jason.

Such information could allow doctors to better protect or prioritize vulnerable populations. But, he added, that still leaves the more basic questions of what’s causing these lingering maladies and what more can be done to help patients.

I notice the word “severe” didn’t appear in Jason’s summary. Did someone speak to him?

Hanging such a strong claim on such a small study is uncomfortable, but the apparent correlation does not seem obviously implausible, and to my ignorant eye it does look worth examining. This study surely could - and should - be repeated, preferably with a coherent, prospective definition of ME/CFS (such as that used by DECODE ME). And perhaps not just for EBV and ME, but with Covid - Long Covid too?

 

[chillier]

Despite the small n=18 sample size and weird issues with categorization of severe ME I really like this paper. I like that by looking at the metabolites prior to illness maybe you are looking at a risk factor for ME, instead of what could be fallout. They use Bonferroni multiple test correction with an adjusted p value cut off of 0.01. I respect the restraint, that might even be a little too strict. I've reanalysed it using Benjamini-Hochberg correction and a FDR cut off of 0.05 to see if there might be anything else interesting in there. Here are scatter plots for the 25 metabolites that meet those criteria ordered from most to least significant (from left to right).

 

[chillier]

Viewing the whole thing as a heatmap might be easier: