Stratifying patients for ME research
Important step to speed up treatment options
Note: If you are reading this before March 8 (the deadline to submit comments for the NIH Roadmap) this article is the basis of my input. If you want to show support, my comment should be found on the IdeaScale Roadmap Priorities HERE. I write about how to give feedback HERE.
Science taught in grade school stresses the importance of minimizing variables as well as stratifying data.
One of the biggest variables in ME research has been patient selection. Patients have been used in “ME” research who were selected based on a vague description of fatigue but not screened for ME.
Researchers need to understand that doctors lump patients under a vague umbrella for clinical diagnosis, but this is insufficient for research purposes. My article ME/CFS is an umbrella term, discusses the various criteria and the importance of classifying patients accurately.
The International Consensus Primer for ME explains the importance of screening for ME (pg iv):
“Research on ME: The logical way to advance science is to select a relatively homogeneous patient set that can be studied to identify biopathological mechanisms, biomarkers and disease process specific to that patient set, as well as comparing it to other patient sets. It is counterproductive to use inconsistent and overly inclusive criteria to glean insight into the pathophysiology of ME if up to 90% of the research patient sets may not meet its criteria (Jason 2009). Research on other fatiguing illnesses, such as cancer and multiple sclerosis (MS), is done on patients who have those diseases. There is a current, urgent need for ME research using patients who actually have ME.”
Stratify by criteria
Using the 2011 International Consensus Criteria (ICC) will ensure the most effective patient selection for researching ME
Educating doctors on how to verify an ICC diagnosis would help researchers know how to categorize each patient. The ME International Consensus Primer offers thorough guidance. See the ME-ICC Table of Contents for links to the IC Primer in multiple languages.
Patients can help researchers by utilizing one of these helpful tools to begin the screening process for the ME-ICC.
Webform from Swiss Society for ME & CFS
● English https://sgme.ch/icc/en/
● German https://sgme.ch/icc/de/
● French https://sgme.ch/icc/fr
ICC Questionnaire for patients over 18: "Do I fit the ICC?"
(Handout from MEadvocacy.org)
● English http://tinyurl.com/4ayanmnx
● Spanish http://tinyurl.com/prjjtxzh
● Dutch http://tinyurl.com/3vcvreyx
Post-exertional neuroimmune exhaustion (P.E.N.E.)
Researchers need to take into account the required symptom of post-exertional neuroimmune exhaustion for diagnosis and in the design of studies. This required symptom affects every aspect of the biological abnormalities in ME.
Leave no one behind
It is also important to know what criteria a person fits if they don’t fit the ME-ICC. As was seen in the recent NIH study discussed HERE, too many patients given an ME/CFS diagnosis were found to have something else. This is a serious problem not just for quality of research, but for those patients who have been given a misdiagnosis. I wrote about the serious problem of missed diagnosis HERE.
Stratify patients beyond criteria
The following are some stratification categories that have shown to be important in previous research:
Severity (mild, moderate, severe, very severe)
Gender
Onset type (gradual/sudden)
Pre/post menopause
Age
Length of time ill
Suspected pathogen at onset.
Note: As ME causes immune dysfunction, it is important to take into account that the suspected pathogen at onset may have been a reactivation of an earlier pathogen.
Examples of the importance of stratification
There is ample evidence that stratification of patients in research offers important insight into the biological abnormalities seen in ME. The following are a few examples.
Association of circulating biomarkers with illness severity measures differentiates ME/CFS and post-COVID-19 condition: a prospective cohort study 16 December 2023 (preprint) -
"Our results also suggest that ME/CFS and long COVID may have different origins of endothelial dysfunction, insofar as long COVID patients lack the sustained high cytokine/chemokine levels that are observed in ME/CFS.”
HERV activation segregates ME/CFS from fibromyalgia and defines a novel nosological entity for patients fulfilling both clinical criteria - 06 October 2023
"Worth noting are the results obtained in the comorbid group which, unexpectedly, presented a completely different HERV profile to those identified for ME/CFS and for FM while strikingly closer to that of healthy controls.”
HERV = human endogenous retroviruses
Symptom-based clusters in people with ME/CFS: an illustration of clinical variety in a cross-sectional cohort - 10 February 2023
“This study demonstrated that in ME/CFS there are subgroups of patients displaying a similar pattern of symptoms. These symptom-based clusters were confirmed in an independent ME/CFS sample. Classification of ME/CFS patients according to severity and symptom patterns might be useful to develop tailored treatment options... Almost 90% of the participants fulfilled the Fukuda case definition, compared to 80%, 59% and 39% fulfilling the IOM, CCC and ME-ICC case definitions, respectively. “
Volumetric differences in hippocampal subfields and associations with clinical measures in ME/CFS - 31 March 2022
“Our study found left hippocampal subiculum, presubiculum, and fimbria volumes were significantly larger in ME/CFSICC patients compared with HC, but not for ME/CFSFukuda patients. Furthermore, this study demonstrated that multiple hippocampal subfield volumes are different in ME/CFSICC patients meeting the strict ICC case definition, and they exhibited strong associations with clinical measures. Therefore, the strict case definitions are essential in investigation of the pathophysiology of ME/CFS. Subiculum and parasubiculum volumes were larger in ME/CFS in contrast to reductions seen in other neurological disorders.”
More evidence about the importance of stratification of patients for research can be seen in the stratification category in these ICC and CCC research lists. These lists are regularly updated.
Quality research = saving lives
We have spent decades wasting valuable resources (money and energy of patients) using sloppy criteria and ignoring the importance of stratification.
We need every ME research dollar to be used only for research that insists on careful stratification of patients.
I am grateful to those researchers who are doing quality work. If you are interested in seeing who is making the effort to carefully stratify by criteria and other factors, see the researchers listed in the ME-ICC Research List. They give me hope that we are moving in the right direction.
Colleen
Information provided here or in comments is not to be considered medical advice
Sources
The National Library of Canada Cataloguing-in-Publication Data: Myalgic Encephalomyelitis – Adult & Paediatric: International Consensus Primer for Medical Practitioners. ISBN 978-0-9739335-3-6 https://drive.google.com/file/d/1A0Bvtl4xRUkP3fEJSGMujdPaqQ1-QCIE/view
Joan Carles Domingo, Federica Battistini, Begoña Cordobilla et al. Association of circulating biomarkers with illness severity measures differentiates myalgic encephalomyelitis/chronic fatigue syndrome and post-COVID-19 condition: a prospective cohort study, 16 December 2023, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-3736031/v1]
HERV activation segregates ME/CFS from fibromyalgia and defines a novel nosological entity for patients fulfilling both clinical criteria, Karen Giménez-Orenga, Eva Martín-Martínez, Lubov Nathanson, Elisa Oltra, bioRxiv 2023.10.05.561025; doi: https://doi.org/10.1101/2023.10.05.561025
Vaes, A.W., Van Herck, M., Deng, Q. et al. Symptom-based clusters in people with ME/CFS: an illustration of clinical variety in a cross-sectional cohort. J Transl Med 21, 112 (2023). https://doi.org/10.1186/s12967-023-03946-6
Thapaliya, K., Staines, D., Marshall-Gradisnik, S., Su, J. & Barnden, L. (2022). Volumetric differences in hippocampal subfields and associations with clinical measures in myalgic encephalomyelitis/chronic fatigue syndrome. Journal of Neuroscience Research, 100, 1476–1486. https://doi.org/10.1002/jnr.25048