Clearly, issues concerning reliability of clinical diagnosis are complex and have important research and practical implications. Jason et. al
In the beginning of his overview on the IOM definition and name change Jason notes the numerous false starts and botched definitions that have plagued chronic fatigue syndrome. Because the Fukuda definition did not require core symptoms of the disease be present it selected out a heterogeneous group that may have differed from study to study.
Both the Canadian and International Consensus Criteria did require core symptoms of the disease to be present but they required so many other symptoms they ran the risk of increasing rates of psychiatric disorders – something ME/CFS surely does not need at this point. (There was also the Holmes definition which had too many symptoms as well, the Oxford definition which has too few, and the ME definition which requires infectious onset.)
Nobody has gotten it right so far. The IOM definition would seem to be the closest. It requires some core symptoms but not too many. It was not derived statistically but relied heavily on statistical analyses.
Tony Komaroff asserted it was the best definition yet. He stated
“It will likely encompass a more homogeneous and sicker group of persons than the past case definitions.”
The IOM definition requires the following criteria to be met:
- substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities accompanied by fatigue which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest, and
- post-exertional malaise
- unrefreshing sleep;
- one of the two following symptoms: cognitive impairment or orthostatic intolerance.
It’s quite similar to the statistically derived symptom set Jason et. al came up with in a 2015 study. (This study was probably not available to the IOM panel.) Using several statistical techniques Jason found the following symptom set most accurately selected out ME/CFS patients with more severe symptoms
- fatigue or extreme tiredness
- difficulty finding the right word to say or expressing thoughts
- physically drained/sick after mild activity
- unrefreshing sleep
Jason’s “empiric definition” – not to be confused with the CDC’s “Empirical Definition” (which was not derived empirically) probably provides the best symptom criteria yet.
Given that these two definitions are pretty darn close, though, why is Lenny Jason – our resident expert on defining ME/CFS – publishing all these critiques? Jason had the opportunity to be on the panel but declined. Since it’s come out he’s published at least four commentaries/studies that have been critical of the definition and/or the name.
Leonard A. Jason, Madison Sunnquist, Abigail Brown, Stephanie McManimen, Jacob Furst. Reflections on the IOM’s systemic exertion intolerance disease. Polish Archives of Internal Medicine.
The IOM definition was, as Komaroff noted, designed to produce a more homogeneous, probably smaller set of ME/CFS patients. It doesn’t always seem to be producing a smaller, more tightly defined set of patients, however.
Jason’s analysis of different large patient/control sets indicates the IOM criteria – at least in some instances – plucks out about the same sized group as the Fukuda criteria and a smaller group than the CCC, ICC and Jason’s empiric criteria do.
Only 66% of the patients who meet the IOM criteria meet Jason’s statistically derived four symptom empiric criteria. Plus, the IOM criteria selected more patients with less impairment and fewer symptoms than does Jason’s empiric criteria.
If the definitions are so similar what could account for these major differences? The IOM criteria do add orthostatic intolerance to the mix. OI is common in ME/CFS but it’s not nearly as common as some other symptoms. Jason’s analyses indicated, however, that adding OI as a supplementary symptom added only about 2% more patients to the mix.’
Something else is going on.
The Exclusionary Criteria Question
Jason data suggests that the lack of exclusionary conditions in the IOM definition could, in some circumstances, allow more patients, in fact many more patients into research studies than even the Fukuda criteria do.
We should note that the IOM panel was tasked with producing a clinical definition not a research definition. Clinical definitions and research definitions in ME/CFS have a way of morphing into each other though.
Most ME/CFS research definitions have had a fairly long list of exclusionary conditions but IOM definition listed none. Jason reported that “no medical or psychiatric conditions were considered exclusionary for the SEID criteria, as the IOM criteria state that conditions are only exclusionary if they explain all of an individual’s symptoms.”
Exclusionary diagnoses in past ME/CFS definitions have ranged from untreated hepatitis B infections and thyroid conditions to Addison’s disease to diabetes to rheumatoid arthritis, lupus, anemia, etc. Some psychiatric disorders such as depression with melancholic features, bipolar disorders and schizophrenia have always been considered exclusionary but depression and anxiety have not.
Jason points out that the IOM core symptom complex (fatigue, unrefreshing sleep, post-exertional malaise) can be found in other chronic illnesses. His sample set was a small one but Jason’s 2015 finding that significant percentages of patients with multiple sclerosis and lupus (35-45%), major depressive disorder (24%) and melancholic depression (47%) could all meet the IOM criteria was alarming.
The IOM definition does appear to work very well at distinguishing ME/CFS patients from healthy controls who do not have chronic illnesses. This is an important point as most studies use healthy controls and/or patients with specific illnesses as controls. ME/CFS doctors tasked with providing patients for ME/CFS studies are not going to provide lupus or rheumatoid arthritis or bi-polar disorder patients to researchers. The risk of those patients ending up in most studies is probably quite small.
In larger-scale community studies that include a wide range of participants, however, Jason’s studies suggest the IOM definition would likely add in significant number of patients with a range of chronic illnesses – possibly increasing ME/CFS prevalence rates threefold. (One wonders as well, absent exclusionary factors, if some psychiatric researchers might add-in more patients with psychiatric disorders for whom ME/CFS is a secondary diagnosis.
Defining a condition is obviously a complex process. Jason noted that even the decision to categorize an illness as a comorbid or exclusionary illness is a complex decision that’s often been treated as a simple one.
Thus far, Jason’s published at least four studies/papers critiquing the IOM panel report. The fact that he’s the only one to publish anything on the IOM report emphasizes how much this is his field. He was clearly missed on the panel and hopefully he will be on the next one.
The fix he proposes, however, is not a large one. If the IOM definition ends up being used in research exclusionary criteria simply need to be added in. If they are then the rest of the definition – the symptom criteria – are close. Jason’s 2015 empiric definition study suggests some symptom criteria might be better.
The authors of the IOM report knew that the field is a fluid one. The report is probably doing just what the authors of the report hoped. It’s a significant body of work that can’t be ignored which is prompting more work in this area. That work is helping to clarify the nature of ME/CFS. Even as it’s being critiqued the report is working…
The IOM saga also emphasizes just how vital the work of Lenny Jason and his research team have been. His work laid much of the groundwork for a new definition. His studies highlighted the mostly unforeseen and paradoxical problems the CCC and ICC definitions posed. His close monitoring and study of the IOM definition is making it stronger.
Defining a disease is more complex than we knew. In just the past six months Jason has published papers suggesting that people with lifelong fatigue should not be excluded from an ME/CFS diagnosis and how even subtle differences in wording can alter whether people believe they have post-exertional malaise.
In the future Jason wants to provide structured interviews to make a ME/CFS diagnosis bullet-proof, to produce guidelines for exclusionary vs comorbid disorders, and create mental health evaluations to ensure that people with mood disorders but not ME/CFS are not finding their way into studies.
Hopefully the IOM and P2P reports will help him and others get the funds needed to further put the study of ME/CFS on a firm foundation.