Discriminating Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and comorbid conditions using metabolomics in UK Biobank, 2024, Huang et al

[Wyva]

Katherine Huang, Alex G. C. de Sá, Natalie Thomas, Robert D. Phair, Paul R. Gooley, David B. Ascher & Christopher W. Armstrong

Abstract

Background
Diagnosing complex illnesses like Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is complicated due to the diverse symptomology and presence of comorbid conditions. ME/CFS patients often present with multiple health issues, therefore, incorporating comorbidities into research can provide a more accurate understanding of the condition’s symptomatology and severity, to better reflect real-life patient experiences.

Methods
We performed association studies and machine learning on 1194 ME/CFS individuals with blood plasma nuclear magnetic resonance (NMR) metabolomics profiles, and seven exclusive comorbid cohorts: hypertension (n = 13,559), depression (n = 2522), asthma (n = 6406), irritable bowel syndrome (n = 859), hay fever (n = 3025), hypothyroidism (n = 1226), migraine (n = 1551) and a non-diseased control group (n = 53,009).

Results
We present a lipoprotein perspective on ME/CFS pathophysiology, highlighting gender-specific differences and identifying overlapping associations with comorbid conditions, specifically surface lipids, and ketone bodies from 168 significant individual biomarker associations. Additionally, we searched for, trained, and optimised a machine learning algorithm, resulting in a predictive model using 19 baseline characteristics and nine NMR biomarkers which could identify ME/CFS with an AUC of 0.83 and recall of 0.70. A multi-variable score was subsequently derived from the same 28 features, which exhibited ~2.5 times greater association than the top individual biomarker.

Conclusions
This study provides an end-to-end analytical workflow that explores the potential clinical utility that association scores may have for ME/CFS and other difficult to diagnose conditions.


Plain language summary
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an illness with severe fatigue without a known cause. Further symptoms of ME/CFS often overlap with other medical problems making diagnosis difficult. We wanted to find a way to easily identify people with this condition, so we used data from the UK Biobank to compare people with and without ME/CFS who had other medical problems. We developed a mathematical calculation, using 19 basic health factors and nine blood markers, which could classify ME/CFS and non-ME/CFS individuals correctly 83% of the time, and recognise this condition in individuals 70% of the time. This research could lead to a better way to diagnose ME/CFS and serve as an example for diseases lacking definite laboratory testing.


Open access: https://www.nature.com/articles/s43856-024-00669-7

 

[Nightsong]

A self-reported past or current diagnosis.

I've only just glanced at this very briefly but supplementary data table 3 appears quite interesting, as one can see a long list of patient group characteristics alongside comparators such as hypertension, depression, asthma, hypothyroidism, hayfever & IBS.

To give an indication of how currently & severely affected the UK Biobank CFS patient group was I think the answers to the "frequency of tiredness / lethargy in last 2 weeks" question are probably indicative: 41.4% replied "nearly every day" (compared to healthy 3%, hypertension 3.6%, hypothyroidism 5.4%, migraine 4.6%). But 37% of the CFS group said "several days" and 9.7% said "not at all".

The "alcohol drinker status (current)" is lower for the CFS group (81.6% vs 93.8% for healthy) and the "previous" status is higher (12.1% vs 2% for healthy and 5.9% for migraine).

 

[Hoopoe]

o give an indication of how currently & severely affected the UK Biobank CFS patient group was I think the answers to the "frequency of tiredness / lethargy in last 2 weeks" question are probably indicative: 41.4% replied "nearly every day" (compared to healthy 3%, hypertension 3.6%, hypothyroidism 5.4%, migraine 4.6%). But 37% of the CFS group said "several days" and 9.7% said "not at all".

I never have a day with no abnormal tiredness. If for some reason I had a day like that, I would think that excitement and exceptionally good mood were keeping the body in an unsustainable high and delaying the fatigue, and that the next day would probably be especially bad.

The 37% group could be mild cases or be misdiagnoses. The 9.7% group definitely does not have ME/CFS.

 

[Sly Saint]

Diagnosing an unknown disease with a common symptom
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a condition shrouded in mystery, defined by debilitating fatigue—a symptom so common it often masks the profound complexity and severity of the disease.
Published in Cell & Molecular Biology, Biomedical Research, and General & Internal Medicine
Nov 27, 2024

Katherine Huang
Post-doctoral researcher, University of Melbourne

Fatigue is one of the most universally reported symptoms in medicine. As a subjective experience, it is incredibly difficult to quantify and even harder to define in scientific terms. This problem becomes even more pronounced when fatigue is not just a symptom but the core feature of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). In ME/CFS, fatigue is an overwhelming, unrelenting exhaustion that does not resolve with rest. The cause of ME/CFS remains elusive and is one of the most misunderstood, overlooked medical conditions. There is no definitive diagnostic test, and for many patients, the diagnosis process can take years—sometimes even decades—marked by frustration, misdiagnoses, and dismissal by healthcare providers.

The urgency to address ME/CFS is growing. With COVID-19 and the increasing prevalence of long COVID, the number of individuals with conditions resembling ME/CFS is likely to rise significantly. Both conditions share overlapping features, such as debilitating fatigue and “brain fog”, with long COVID bringing renewed attention to the long-term impact of post-viral syndromes. Understanding ME/CFS not only holds the key to improving care for millions already suffering but could also provide critical insights into managing long COVID.

Diagnosing, treating and researching a complex illness like ME/CFS is no small feat. We often find ourselves navigating a labyrinth of overlapping symptoms and comorbidities, trying to identify biomarkers that can truly define this enigmatic condition. Our study tackled this challenge by using machine learning to develop multi-variable biological signatures that can distinguish heterogeneous ME/CFS patients from non-ME/CFS individuals with similar comorbidities.

Behind the Scenes: The Research Journey
When we began this project, our primary goal was to see beyond ME/CFS as an isolated diagnosis. We wanted to understand how comorbid conditions—such as hypertension, depression, asthma, irritable bowel syndrome, hay fever, hypothyroidism, and migraine—interact with ME/CFS and whether these interactions could inform more accurate differential diagnostic tools. The UK Biobank dataset was a core resource, providing blood plasma nuclear magnetic resonance (NMR) metabolomics profiles of deeply phenotyped individuals with and without ME/CFS. Having access to such a comprehensive dataset was critical, as independently collecting data on this many comorbid conditions, along with their unique patterns, while ensuring enough statistical power for meaningful analysis, would have been an almost impossible undertaking. For an overview of our research, check out this 3-minute summary below.

Diagnosing an unknown disease with a common symptom | Research Communities by Springer Nature

 

[MelbME]

Yes we've been patiently waiting for this publication to come out for a long time!

We submitted almost a year ago but felt it was important to get ME/CFS research in to a nature journal.

We showed a lot of great things in this publication. A pathway to a differential diagnostic marker is the key translational piece. We think we've shown a novel concept around creating a score that suggests the % chance someone has ME/CFS vs a background of common comorbid conditions. A question that is very relevant to the diagnosing GP. We will be following this concept up with different datasets in the coming years.

 

[MelbME]

A self-reported past or current diagnosis.

I've only just glanced at this very briefly but supplementary data table 3 appears quite interesting, as one can see a long list of patient group characteristics alongside comparators such as hypertension, depression, asthma, hypothyroidism, hayfever & IBS.

To give an indication of how currently & severely affected the UK Biobank CFS patient group was I think the answers to the "frequency of tiredness / lethargy in last 2 weeks" question are probably indicative: 41.4% replied "nearly every day" (compared to healthy 3%, hypertension 3.6%, hypothyroidism 5.4%, migraine 4.6%). But 37% of the CFS group said "several days" and 9.7% said "not at all".

The "alcohol drinker status (current)" is lower for the CFS group (81.6% vs 93.8% for healthy) and the "previous" status is higher (12.1% vs 2% for healthy and 5.9% for migraine).

Yeah the supplementary files are loaded with data, worth perusing. A lot of work went into them but couldn't present them all in the main paper.

The comorbid conditions chosen were those that were most common in those that identified as having me/cfs in the dataset. We required a minimum for statistical power, those that were significantly elevated in ME vs general population were used as comparator groups. We also kept hypertension as the metabolite dataset used in the biobank was slanted towards a profile that would highlight hypertension (this was a positive control).

 

[MelbME]

I never have a day with no abnormal tiredness. If for some reason I had a day like that, I would think that excitement and exceptionally good mood were keeping the body in an unsustainable high and delaying the fatigue, and that the next day would probably be especially bad.

The 37% group could be mild cases or be misdiagnoses. The 9.7% group definitely does not have ME/CFS.

It's possible that people said they were diagnosed but had since improved to a significant degree while still holding the CFS diagnosis.

There will of course be misdiagnosis, as there will be in vast majority of studies. The point is capturing a large enough scale of people to form a reliable normal distribution for what ME/CFS looks like.

You could say we took the opposite approach of NIH, where they carefully ruled out every comorbid disease and potential complication so that they had 17 from an initial 500, we kept in everyone identified at a scale of 1000 people.

In fact when we did this we found that a strong predictor of ME/CFS was actually having multiple comorbid diseases. A disease of comorbid conditions indeed.

 

[Sean]

...marked by frustration, misdiagnoses, and dismissal by healthcare providers.​

Not to mention outright hostility and abuse.

 

[DMissa]

I remember Kathy presenting this at stony brook last year, talking with her afterwards and being very impressed, good to see it landing in an appropriately great journal. Congrats are in order for Kathy, Chris & team.

 

[wigglethemouse]

@MelbME : The paper sticks to facts and not hypothesis about mechanisms (quite rightly). Can you comment on the hypothetical - do the findings in the paper reinforce any hypothesis your team has, or provide clarity on where to put more focus?

This section struck me as a finding that has been replicated many times.

Surface lipids including total cholines, phosphatidylcholines, sphingomyelins, and phosphoglycerides were significantly decreased in the UKB ME/CFS cohort. These results are consistent with prior research10,13, suggesting potential membrane destabilisation, altered cell signalling and dysregulated immune cell function53. Our study contributes further evidence with a TG/PG association showing increased core lipid content relative to surface area, which may reduce membrane fluidity.

What would be the next steps to try and confirm that there are actual changes in cell membranes - do you know of anyone working in that area?

 

[wigglethemouse]

I was struck by the fact that hypertension was reported as present in 24% of those with ME/CFS and 26% of Control - no statistical difference. Yet the messaging for years from medical professionals has been that Orthostatic intolerance in ME/CFS is due to hypotension in the majority.

There must be another mechanism behind orthostatic intolerance in ME/CFS that is NOT blood pressure related for a large number of people.

 

[Trish]

Yet the messaging for years from medical professionals has been that Orthostatic intolerance in ME/CFS is due to hypotension in the majority.

There must be another mechanism behind orthostatic intolerance in ME/CFS that is NOT blood pressure related for a large number of people.

There is also evidence some have POTS without hypotension.

 

[Yann04]

I was struck by the fact that hypertension was reported as present in 24% of those with ME/CFS and 26% of Control - no statistical difference. Yet the messaging for years from medical professionals has been that Orthostatic intolerance in ME/CFS is due to hypotension in the majority.

Sorry I wonder if you made a mistake or I misread your comment.

You say they found similar levels of hypertension but then go on to say it is weird because POTS is associated with hypotension?

I’m not sure I understand.

 

[wigglethemouse]

Sorry I wonder if you made a mistake or I misread your comment.

You say they found similar levels of hypertension but then go on to say it is weird because POTS is associated with hypotension?

I’m not sure I understand.

They found 1/4 of people with ME/CFS had hypertension as did 1/4 of the people in the Comparison group.


I've been led to believe for many years by the media, papers, and advocacy that people with ME/CFS have orthostatic intolerance and a major cause of that is hypotension. In fact it is my understanding that orthostatic intolerance has been thought to be almost universal in ME/CFS. If that is the case I would have thought this data would show that there was a significantly lower % of PwME with hypertension which is not the case.

That makes me wonder what is the reason for orthostatic intolerance for those with hypertension, and why have we not seen more research asking that question. I feel that could hold an important clue to this disease.

I don't think I mentioned POTS. By definition POTS has a definition of an increase in heart rate WITHOUT a drop in blood pressure. However it seems clinicians and patients use POTS as a name for any sort of increase in heart rate above 30ppm, regardless of blood pressure. That muddies the water.

 

[horton6]

The 37% group could be mild cases or be misdiagnoses. The 9.7% group definitely does not have ME/CFS.

I have very severe ME/CFS and have been fully bedbound for 3 years, and I would answer that question with "a few days" or "not at all". It only happens in a crash for me now. I used to experience that crushing fatigue most days when I was still working and up and about, and it would be very wrong to say that my condition is better now than it was then.

I just want us to exercise some caution about saying that people don't have ME/CFS if they don't experience symptoms exactly the way we do. People are different, this condition varies greatly, but it could also have to do with how much people are pacing. To me, fatigue is a physical feeling, not simply the inability to do a task; it's not fatigue that is keeping me trapped in this bed, it's that if I do too much even within the bed I will get crazy debilitating symptoms that make it impossible to toilet, eat, or talk (i.e. PEM).

I really think that any study needs to use PEM as its main inclusion/exclusion criterion rather than any single symptom within PEM (like fatigue), and also include a FUNCAP-style assessment if they ever want to look at severity. Questions that ask "Can you do X/Y" also should specify whether they mean "Can you do this without causing any symptoms?" vs "Can you push through and do this, although it causes symptoms?" because from informal discussions among research participants, we are interpreting questions differently.

 

[Yann04]

They found 1/4 of people with ME/CFS had hypertension as did 1/4 of the people in the Comparison group.
View attachment 24390

I've been led to believe for many years by the media, papers, and advocacy that people with ME/CFS have orthostatic intolerance and a major cause of that is hypotension. In fact it is my understanding that orthostatic intolerance has been thought to be almost universal in ME/CFS. If that is the case I would have thought this data would show that there was a significantly lower % of PwME with hypertension which is not the case.

That makes me wonder what is the reason for orthostatic intolerance for those with hypertension, and why have we not seen more research asking that question. I feel that could hold an important clue to this disease.

I don't think I mentioned POTS. By definition POTS has a definition of an increase in heart rate WITHOUT a drop in blood pressure. However it seems clinicians and patients use POTS as a name for any sort of increase in heart rate above 30ppm, regardless of blood pressure. That muddies the water.

I won’t make any comments on the various theories, but another way to interpret this, would be that not everyone with ME has orthostatic intolerance, and likely not everyone with OI has hypotension. So if we compare an ME group with controls we might see an increase in hypotension but it wouldn’t be suprising if we had the same hypertension rate as controls.

 

[horton6]

I just want us to exercise some caution about saying that people don't have ME/CFS if they don't experience symptoms exactly the way we do. It could have to do with how much people are pacing.

Sorry for writing so much! The more I think about it the more frustrated I am that researchers and medical practitioners often have a different conception of how the severity scale works than I do.

It's not (only) symptom burden, in the sense of what symptoms do you get, how bad are those, and how often do you get them; it's also, or maybe even primarily, the activity threshold at which you trigger symptoms or deterioration. That's the primary way this condition is disabling. I was mild for years and just had a sore throat and flu-ish feeling, and that didn't really stop me from doing anything (because I didn't know what it was) but that was chipping away at my functional capacity by slowly making me worse (i.e. making the activity threshold required to cause symptoms lower and lower). On a questionnaire though, that would show up wildly differently - I used to have it every day, and now I get it once or twice a year when I really overdo things, so maybe it would seem better now. But I'm significantly, indisputably more disabled by the condition now.

There's some relationship between symptom burden and severity - the more severe I got, the more weird new symptoms I developed (and some of those were catastrophic ones that landed me in hospital). But now at very severe, I have some symptom-free days. I just do only a tiny fraction of what someone less severe does in a day.

 

[obeat]

Orthostatic intolerance is the SYMPTOM of feeling worse when in the upright position and needing to lie down. It doesn't have to have changes with blood pressure levels or heart rate and occurs in other neurological conditions eg multiple sclerosis.

 

[Mij]

Does severity matter at this point when mildly and severely affected patients all experience severe delayed PEM when we go over our own personal energy threshold?

I didn't experience severe delayed PEM for 8 years until I started exercising again when I became very mild almost symptom- free. I didn't have OI during that time period.

 

[horton6]

Does severity matter at this point when mildly and severely affected patients all experience severe delayed PEM when we go over our own personal energy threshold?

It matters to me insofar as:
1) More severely ill people may have more of whatever is wrong in their bodies, which may be important for detecting whatever it is
2) Most research up to this point has excluded us, and has found very little
3) researchers invent totally whackadoodle definitions of severity and publish misleading writing on it, like those ones that defined "severe" as people who would pass multiple sets of diagnostic criteria for ME/CFS
4) when researchers misunderstand severity as symptom burden/frequency, they haven't understood the condition or its classic defining feature (PEM), and that carries over into other assumptions they make, and doesn't bode well for them looking in the right direction.