Recording of Lucinda Bateman MD March 4 talk: "New Clinical Definitions for ME/CFS"

[alex3619]

You're supposed to have, you know, large studies, replicated studies...there's some standards about what kind of evidence is kind of irrefutable evidence.

This confirms what I have been concerned about all along. EBM sets very high standards, and an under-researched field, particularly a controversial one, is not the place to be doing this.

One caveat: there is NO irrefutable evidence. There is only robust evidence.

 

[Ember]

EBM sets very high standards, and an under-researched field, particularly a controversial one, is not the place to be doing this.

According to Dr. Bateman:

The clinical diagnostic criteria in the report are core symptoms drawn directly from the published ME/CFS literature—much of which came from Dr. L. Jason’s works and the CDC multi-site study.... The symptoms must be of moderate to severe intensity and consistently present over time, an important parameter supported by Dr. Jason’s research.

The figures printed in the “Report Guide for Physicians” are based on Jason et al. (2013b), a study that applies the DePaul Symptom Quesionnaire (DSQ) to a SolveCFS BioBank population. Does that study meet very high EBM standards? Have Dr. Unger's interim analyses from the CDC multi-site study yet been published?

 

[alex3619]

@Ember, that question has been asked of me and I want to look into it. I think the standards were misapplied, but its hard to demonstrate. The multisite study is unpublished, and not peer reviewed. Jason's work is unreplicated so far as I know, and not backed by independent validation.

Where the EBM cutoff occurs is in the evidence review they are handed, compiled by bureaucrats. What the committee does with it after that is probably not standard EBM. Which might have been a good thing as this report could have been much much worse.

Do keep in mind that after the lit review was basically done, or in process, even more papers were added, either suggested by the experts or from patient suggestions.

In any case I am looking into this. Its probable though that there is insufficient evidence for me to determine if it was or was not improperly applied. Which in itself would be disturbing. These processes need to be transparent.

Let me repeat something again which I think we have to always keep in mind. This whole thing is a managerial process, not a scientific one.

 

[Ember]

Where the EBM cutoff occurs is in the evidence review they are handed, compiled by bureaucrats.

Thanks, Alex. Drs. Jason and Unger both made early presentations to the Committee. In his presentation, Dr. Jason (16:40) highlights primary symptoms based on Fukuda criteria: PEM, sleep and neurocognitive issues. To Dr. Clayton's question concerning what data set he used (17:25), he replies that the results are from the biobank collected by the CFIDS Association. He then highlights PEM, sleep dysfunction and neurocognitive impairments from the CCC as the most frequently reported and therefore the core or cardinal symptoms of this illness. Here he neither describes his data set nor states that he used a DSQ algorithm to substitute for the CCC.

Dr. Unger presented her unpublished findings to the Committee in public. As part of its charge, HHS requested that the Committee coordinate with two ongoing HHS efforts concerning ME/CFS in order to minimize overlap and maximize synergy. The Committee was thus charged with considering unpublished data from the ongoing CDC multi-site study.

Do EBM standards apply then only to the evidence review compiled by bureaucrats?

 

[alex3619]

Do EBM standards apply then only to the evidence review compiled by bureaucrats?

That is something I would like an answer to. I think it still applies but with some leniency. Why have experts at all if you don't give them some latitude to apply their training and experience?

The EBM process is subject to huge bias in how it is applied, and on subjects it is improperly applied to, but sometimes this may not be a bad thing. I am seeing it more and more as a management tool, not as science.

I am however still investigating all this. Its not a simple topic especially for someone with cognitive challenges. I think even most docs misinterpret it. Its very much becoming a shortcut through Evidence Based Practice which shares a similar philosophy.

Such a shortcut is great because a review panel can review thousands of papers. Its bad because inadequate reviews lead to poor review recommendations. Meta-analyses of flawed studies can also lead to entrenched flawed conclusions. I think we see that in some psych analyses.

I think Nancy Klimas got it right when she opposed the process, and she said an IOM review was premature. I think she joined it because its better to have people who know the science involved, and issues can be mitigated. However I am interpreting her intentions, and so I could be completely wrong ... someone should ask her.

The flaws in the EBM process might be used by HHS to scuttle the recommendations. Its a risk. In which case expect another IOM review in a year or two. If this happens we may have to start asking if they are fishing for a particular result.

 

[Nielk]

According to Dr. Bateman: The figures printed in the “Report Guide for Physicians” are based on Jason et al. (2013b), a study that applies the DePaul Symptom Quesionnaire (DSQ) to a SolveCFS BioBank population. Does that study meet very high EBM standards? Have Dr. Unger's interim analyses from the CDC multi-site study yet been published?

I have been concerned about this as well. When you base your findings/results on patient questionnaires, the results will depend on the cohort one uses.

Had Jason"s study been on ME patients per ME-IC, the results would have been different.

If one is looking at patients with strong neurological abnormalities, myalgia, headaches, sore throat or if you are looking at patients who are fatigued and have trouble sleeping well, you will get very different results as to what their core symptoms are.

 

[Dolphin]

Somebody on Facebook saved the slide where she talks about the SF-36 vitality scores being much lower than in other conditions

 

[Ember]

What we are seeing here is a caring, honest, experienced physician who understands the illness and co-morbidities very well and wants the disease to move forward. The IOM contract was 'the' opportunity.

Dr. Bateman's understanding of co-morbid entities didn't make it into the "Report Guide for Clinicians." These co-morbid entities are listed in the CCC:

Fibromyalgia Syndrome (FMS), Myofascial Pain Syndrome (MPS), Temporomandibular Joint Syndrome (TMJ), Irritiable Bowel Syndrome (IBS), Interstitial Cystitis, Irritable Bladder Syndrome, Rynaud's Phenomenon, Prolapsed Mitral Valve, Depression, Migraine, Allergies, Multiple Chemical Sensitivities (MCS) Hashimoto's thyroiditis, Sicca Syndrome, etc. Such co-morbid entities may occur in the setting of ME/CFS. Others such as IBS may precede the development of ME/CFS by many years, but then become associated with it. The same holds true for migraines and depression. Their association is thus looser than between the symptoms within the syndrome. ME/CFS and FMS often closely connect and should be considered be be "overlap syndromes".

These co-morbid entities are listed in the ICC:

Fibromyalgia, Myofascial Pain Syndrome, Temporomandibular Joint Syndrome, Irritable Bowel Syndrome, Interstitial Cystitis, Raynaud’s Phenomenon, Prolapsed Mitral Valve, Migraines, Allergies, Multiple Chemical Sensitivities, Hashimoto’s Thyroiditis, Sicca Syndrome, Reactive Depression. Migraine and irritable bowel syndrome may precede ME but then become associated with it. Fibromyalgia overlaps.

The IOM Committee expects that clinicians will refer to the more thorough CCC and ICC documents:

The committee decided against developing a comprehensive list of potential comorbid conditions, but points to conditions that clinicians may wish to consider that have been identified by the ME-International Consensus Criteria (ME-ICC) and the CCC, including fibromyalgia, myofascial pain syndrome, temporomandibular joint syndrome, irritable bowel syndrome, interstitial cystitis, irritable bladder syndrome, Raynaud’s phenomenon, prolapsed mitral valve, depression, migraine, allergies, multiple chemical sensitivities, Sicca syndrome, obstructive or central sleep apnea, and reactive depression or anxiety.

 

[alex3619]

Somebody on Facebook saved the slide where she talks about the SF-36 vitality scores being much lower than in other conditions
View attachment 10252

Yes, this is a dramatic part of the recommendation, though has to be interpreted cautiously. I think what is good about it is that we also have evidence from exercise studies on some of these diseases, which tend to confirm the vitality finding. This is unlike PACE where the SF-36PF opposes the objective outcomes.

 

[alex3619]

All in all if you want to understand the IOM report to some extent, covering the highlights, this is what the first 45 minutes or so of the presentation is about. Its a lot easier than reading hundreds of pages, and probably better for many people. In addition many concerns about the report are addressed.

I have a suspicion that a lot of concerns we are having were discussed, and not all that discussion made it into the report. Interviewing panel members with these concerns in mind is a good way to elicit further information.

 

[jimells]

@Ember thanks for the excerpts. They are very helpful, since I can't see videos over my dial-up internet connection.

And the biggest problem with ME, as a name... not quite up to the standard of an evidence review to call it that in terms of inflammation, neuroinflammation...we're really, really close, but the timing was just not quite right.

This seems like a good argument for not changing the name, or the definition, at this time... it's just too soon.

people are not happy about this new name and.... But my...the way I look at this is...we have not made any progress really for two decades to speak of in this field. So something had to change.

If a name change could result in a flood of research money, I'm gonna guess there would be few objections. But changing the name just for the sake of

Don't just stand there... Do something!

doesn't seem very productive.

 

[Ember]

I think Nancy Klimas got it right when she opposed the process, and she said an IOM review was premature. I think she joined it because its better to have people who know the science involved, and issues can be mitigated. However I am interpreting her intentions, and so I could be completely wrong ... someone should ask her.

I had thought that the IOM process allowed committee members to register dissenting views. Dr. Bateman describes the challenge:

The IOM is respected in part because of its adherence to a process with high standards. The IOM process is not a transparent, publicly interactive or open process; it is a confidential, internally interactive, collaborative and “consensus building methodology” that was an intellectual and interpersonal challenge for those entrusted with the task.

 

[Ember]

If one is looking at patients with strong neurological abnormalities, myalgia, headaches, sore throat or if you are looking at patients who are fatigued and have trouble sleeping well, you will get very different results as to what their core symptoms are.

Consider too that Dr. Jason's model requires symptoms to be moderately severe about half the time: “Symptoms were not asked about in relation to activity; as some patients may only experience certain symptoms in response to activity, the prevalence of these symptoms may be underrepresented in this study’s results.” PENE, the cardinal feature of ME, requires symptom exacerbation primarily in the neuroimmune regions as a post-exertional response.

 

[alex3619]

I had thought that the IOM process allowed committee members to register dissenting views.

Dissenting views in the report is my understanding. Dissenting views to the process itself? That might not be in the report.

 

[alex3619]

Symptoms were not asked about in relation to activity; as some patients may only experience certain symptoms in response to activity,

One of the problems with PEM and PENE, and fatigue as well, is that they are triggered issues. A mild patient with good pacing and generally good medical care might have minimal fatigue, and no chronic fatigue, and rarely encounter PEM and PENE. This is however a manifestation of their management, not the underlying disease process. Its a concern.

However I expect that nearly all patients with little obvious PEM, PENE or fatigue would show problems in the 2 day CPET. Whether such a patient should risk a CPET is a different question. I am hoping we can develop blood based biomarkers that can determine this.

 

[Ember]

One of the problems with PEM and PENE, and fatigue as well, is that they are triggered issues. A mild patient with good pacing and generally good medical care might have minimal fatigue, and no chronic fatigue, and rarely encounter PEM and PENE. This is however a manifestation of their management, not the underlying disease process. Its a concern.

Dr. Jason acknowledges that there's been no consensus in the field as to what the frequency and severity cut-off points need to be. But his presentation shows at 16:00 and 18:40 the apparent exclusion of those 50% or fewer SolveCFS BioBank patients with immune, neuroendocrine and autonomic symptoms when his cut-offs are applied.

Are those 50% or fewer SolveCFS BioBank patients ME-ICC patients? Dr. Jason provided the P2P Panel with his consistent findings among three data sets:

DePaul sample involved a convenience sample of adults self-identifying as having ME, CFS, or ME/CFS;
Solve CFS Biobank Sample included participants who had been diagnosed by a licensed physician specializing in the illness;
Newcastle Sample involved patients referred to the Newcastle-upon-Tyne Royal Victoria Hospital and given a complete medical workup.

Consistent findings among data sets:
About 95% met the CFS Fukuda et al criteria;
About 75% met the case definition for ME/CFS;
About 60% met the case definition for ME-ICC.

Frank Twisk estimated last year that only 30–50% of the subjects meeting the Fukuda criteria fulfill the more stringent criteria for ME-ICC:

Prevalence and Impact
Nacul et al. (2011) found that 0.19% of 143,000 individuals (18–64 years) met the commonly used Fukuda criteria for CFS (Fukuda et al., 1994), while 0.11% met the more strict criteria for ME/CFS (Carruthers et al., 2003), including post-exertional malaise. Prevalence rates of ME (Carruthers et al., 2011) remain to be investigated, but based upon (Nacul et al., 2011; Jason et al., 2012b; Maes et al., 2012a; Brenu et al., 2013) it is estimated that 30–50% of the subjects meeting the CFS (Fukuda et al., 1994) criteria fulfill the more stringent criteria for ME (Carruthers et al., 2011).

 

[Kati]

i had to fill questionnaires as of late, asking if in the last month I have had trouble falling asleep. We know pts with ME/SEID would say yes, however with the drugs I take I have no problem falling asleep. Does that make me cured? Hell no.

 

[usedtobeperkytina]

And I don't have trouble falling to sleep any more, even without meds. But I still have unrefreshing sleep. My trouble is getting up. I used to have insomnia and require meds. Years of limiting all stimuli helped me with that. Like pain, seems some of my central nervous system sensitivity has greatly reduced. But, I still meet the proposed new criteria.

 

[Ember]

Dissenting views in the report is my understanding. Dissenting views to the process itself? That might not be in the report.

The IOM Committee’s deliberation process has been called a consensus process, but the IOM criteria don't seem to represent the 100% consensus achieved by the International Consensus Panel. Consider Dr. Klimas' position on neuro-inflammation as presented to the P2P Panel. She cites a Watanabe study (Nakatomi et al. 2014) showing PET scan findings of neuro-inflammatory autonomic markers:

I know we talk a lot about how many thousands of people cumulatively were in the evidence base to accept something. But you know, even n of 1 things are influential. Watanabe published a paper this year that looked at PET scans using a marker that really marks inflammation, neuro-inflammation, and published a very pretty series, a case controlled series of abnormal PET scans that were positive for neuro-inflammatory markers. So do we have to argue about neuro-inflammation, or can we accept that general systemic inflammation is attached to the brain and that the brain is also inflamed and that these are the types of studies that are very compelling?

Neuroinflammation of patients with chronic fatigue syndrome/myalgic encephalomyelitis*

*As Jerrold Spinhirne points out, "It is vitally important to note that this important study used the 2011 ME-ICC to select subjects."