Replicated blood biomarkers for ME/CFS?
ME/CFS needs well-defined, quality cases stored in Biobanks
Last week, Dr. Chris Ponting, PhD, Research Lead of Decode ME, published the largest ME/CFS blood biomarker study to date.
The study used 1455 ME/CFS cases (sort of) and 131,303 controls from the UK Biobank. Only 55% of the “ME/CFS cases” had the hallmark symptom of ME/CFS - Post-Exertional Malaise (PEM). Meaning half did not meet the requirements for modern ME/CFS diagnostic criteria.
The study identified 116 trait differences in both female and male cohorts, but no single trait stood out as defining ME/CFS.
The researchers re-tested 14 blood traits in 903 ME/CFS cases and 75,943 Health Controls in the American All of Us Data set and were able to replicate 9 significant blood traits.
The team also tested Proteins and Metabolites
Proteins were tested in a much smaller cohort of 171 ME/CFS (126 female, 45 male) combined cases and 13,883 healthy controls (7963 female, 5920 male).
From the paper, ”2923 proteins were tested using antibody-based assays, yielding 1 protein, extracellular superoxide dismutase or SOD3.”
In the combined cases, 54 were significant. From the paper, “ Among these are 7 complement proteins (C1RL, C2, CFB, CFH, CFI, CFP and CR2) of the innate immune system, whose levels are all elevated in ME/CFS cases, including CR2 (complement C3d receptor 2), the receptor for Epstein–Barr virus (EBV) binding on B and T lymphocytes.”
Although underpowered, this portion of the paper is interesting because it may be a preview to future findings from Open Medicine Foundation’s BioQuest project which seeks to test 10,000 proteins and metabolites from 2 ME/CFS biobanks with ME/CFS patients characterized by clinical diagnosis by physicians from Harvard University and University of Uppsala according to the Canadian Consensus Criteria.
However, due to how ME/CFS patients are characterized at the UK Biobank, I have reservations of what this preview of proteomics could be worth.
Should ME/CFS Researchers be using the UK Biobank?
According to the paper, only 55% of the ME/CFS cases had Post-Exertional Malaise (PEM), which means the other half of the samples marked “ME/CFS” did not have ME/CFS. The UK Biobank also uses Self-Report rather than clinically diagnosed ME/CFS patients. There is no ME/CFS diagnostic criteria used by the UK biobank to clearly define and characterize ME/CFS patients.
The hallmark symptom of ME/CFS is Post-Exertional Malaise (PEM). PEM is also sometimes referred to as PENE (Post Exertional Neural Exhaustion) or PESE (Post-Exertional Symptom Exacerbation).
In all ME/CFS biomedical research, ME/CFS patient selection criteria can determine whether it is even worth the time and trouble to read. There are 25 ME/CFS patient criteria. In 2025, only ME/CFS criteria that recognize PEM as a mandatory symptom are considered good criteria to use for research. These main criteria are: Canadian Consensus Criteria (referred to as ME/CFS -CCC, published in 2003, and the M.E. International Consensus criteria (referred to as the M.E-ICC) published in 2011.
PEM is considered the disease within the disease of ME/CFS. PEM can be objectively measured by 2-Day Cardio Pulmonary Exercise Testing. The 2-Day CPET was recognized by the National Academy of Medicine as a diagnostic tool for ME/CFS in 2015. However, it is not mandatory because of the ethical issues of giving patients a test, that makes ME/CFS patients sicker, and that they may never recover from. Therefore, if a patient in a study for ME/CFS doesn’t have PEM, are the researchers really studying ME/CFS patients?
A new way to provoke Post-Exertional Malaise has also been proposed by Dr. Alain Moreau, PhD, Founder and Leader of IcanCME and lead of the ME/CFS ME/CFS Collaborative Research Centre, University of Montréal. To study and stratify ME/CFS patients using MicroRNAs and Random Forest Analysis, Dr. Moreau first provokes PEM in housebound and bedridden patients using a portable Cuff, and then takes objective measurements for five days using Hexoskin, blood, and other objective measurements. Dr. Moreau believes the Cuff provokes PEM, but in such a way that it is more gentle than a CPET, with less recovery time.
How is PEM defined?
Post-Exertional Malaise (PEM) is defined in the both the Canadian Consensus Criteria and the International Consensus criteria as a worsening of flu-like symptoms within 12-48 hours of exertion. Exertion can be rolling over in bed, brushing your teeth, or taking a walk, depending on whether you are mild, moderate, or severe ME/CFS. Flu-like symptoms can include fevers, sore throats, swollen and or painful lymph nodes.
The UK ME/CFS Biobank
There is a UK ME/CFS Biobank called Cure M.E. is a smaller biobank with ME/CFS samples, MS samples, and Healthy Control Samples. In this case, “ME/CFS cases must have a clinical diagnosis of ME/CFS and must meet CCC and/or CDC 1994 criteria.”
I think compared to the UK Biobank, the UK ME/CFS biobank is a better choice because it is using Canadian Consensus Criteria (CCC), with one caveat - that it is also using (and/or) the 1994 Fukuda which means non-ME/CFS patients are mixed in with ME/CFS patients.
CDC criteria (which does not require PEM as a mandatory symptom of ME/CFS), so again, same problem with mixing ME/CFS patients with Non-ME/CFS patients when they should be directly excluded from studies.
We need stricter criteria for ME/CFS cases in Biobanks, so that Non-ME/CFS patients without PEM are not included as ME/CFS cases.
Commentary- Please choose Quality over Quantity for ME/CFS Biomarkers
In ME/CFS biomedical research, the quality of ME/CFS cases matters.
I can, even as a non-scientist, see the lure of the UK Biobank with its large amount of healthy controls and readily available datasets that can be generalized to larger populations. But it’s not worth it. Because the ME/CFS data sets are not well described and categorized, the results cannot be generalized to ME/CFS patients. And what are we teaching these machines for diagnostic models for ME/CFS on Non-ME/CFS cases labelled as ME/CFS?
I have been thinking about this all winter since the preprint for this study, and another study from Dr. Chris Armstrong from Open Medicine Foundation dropped within weeks of each other. That study sought to use machine learning to refine a diagnostic model using 1194 ME/CFS cases from the UK Biobank, along with patients from other diseases. I have to question how a machine can learn a refined definition of ME/CFS, with only half the cases being ME/CFS cases, and both ME/CFS and other cases being defined by self-report. It seems to me that allowing a machine to learn and refine a ME/CFS diagnosis should have been done on cases at a biobank with stricter criteria for definition of ME/CFS cases and co-morbid conditions.
In the search for a ME/CFS diagnostic blood test, the quality of ME/CFS cases and ME/CFS data is King. Having the most robust, well-characterized, well-defined ME/CFS cohort in any ME/CFS biomarker study has to be the main priority, because all of the analysis of the blood traits, proteomics and metabolomics, Immunobiology, molecular and cellular biology, will mean little at the end of the day if the samples are not quality samples- which is the case at the UK Biobank.
What we need
ME/CFS Biomarker research needs (in my Non-Scientist Opinion):
* A ME/CFS Biomarker Conference(s) to make decisions on how to design better biomarker studies and better Biobanks, showcase the ME/CFS biomarker studies that are now in various stages of development. A conference needs to decide on a biomarker protocol, a biomarker roadmap, Biobank criteria so that non-ME/CFS patients are not included (use of bad criteria) and begin the planning stages for how a ME/CFS diagnostic test will be tested against objective ME/CFS diagnostics (2-Day CPET) since that is likely what FDA/CIHR/NHS will require for regulatory approval.
* A strict biomarker protocol that outlines how ME/CFS cases should be characterized, defined, and clinically diagnosed for use in future ME/CFS biomarker studies. We need to our researchers to be able to compare apples to apples. But they have to be the best apples. If we set out a program of ME/CFS patient criteria that all ME/CFS Biomarker researchers must adhere to, it could help accelerate ME/CFS biomarker research.
* A ME/CFS Biomarker Roadmap modelled after the NIH ME/CFS Roadmap to showcase, and explain where we are in the development of a ME/CFS biomarker for a ME/CFS diagnostic blood test, and how far do we need to go to get that regulatory approval. We need Industry, and Media to publicly see ME/CFS diagnostic biomarkers in development, to find private and public partners for those biomarkers.
* A 2-Day CPET/ Hexoskin Biobank that includes ME/CFS blood samples collected at the time of 1-5 days of 2-Day CPET research, and blood samples from patients who have had PEM provoked by Moreau’s Cuff, and measured objectively with Hexoskin for 5 days. We need a biobank of blood, tissue, and medical records from patients who have had PEM provoked so that we A) Know they are ME/CFS patients B) Meet strict ME/CFS patient criteria C) So that ME/CFS biomarkers can be replicated against ME/CFS patient data sets with objective measurements of ME/CFS. In an ideal world, we would have recognized PET/MRI with TSPO tracer type of diagnosis for ME/CFS that was cheap and accessible so we could build up a biobank based on an imaging diagnosis, but I don’t know if that’s realistic or not. Dr. Michelle James, PhD, Scientific board member at Open Medicine Foundation, is working on clinical imaging for ME/CFS, but we haven’t had an update since 2023, as far as I know.
* We also need to consider Dr. Steven Deeks, MD’s advice that was given to LongCovid patients at PolyBio Symposium to model a Biomarker Program after the HIV Raven Program. Although, to my amateur eyes, the OMF way of Operating looks like VIPER already.
Original Paper
Beentjes, Sjoerd Viktor, Artur Miralles Méharon, Julia Kaczmarczyk, Amanda Cassar, Gemma Louise Samms, Nima S Hejazi, Ava Khamseh, and Chris P Ponting. 2025. “Replicated Blood-based Biomarkers for Myalgic Encephalomyelitis Not Explicable by Inactivity”. EMBO Molecular Medicine. Springer Science and Business Media LLC. doi:10.1038/s44321-025-00258-8.
Dr. David Tuller Ph.D. Coverage
https://virology.ws/2025/06/21/trial-by-error-edinburgh-study-links-me-cfs-to-blood-based-biomarkers/
https://virology.ws/2025/06/23/trial-by-error-an-interview-with-sjoerd-beentjes-lead-author-of-big-data-study-on-blood-based-biomarkers-for-me-cfs/
Media Coverage
Technology Networks (June 23, 2025)
BBC (June 20, 2025)
The Times (June 20, 2025)
The Independent
Medical Xpress (June 20, 2025)