NIH Responses Put Major ME/CFS Study On Right Track

[serotone9]

Exclusion criteria for all participants includes, "Current immunologic disorder (e.g. Type 1 diabetes, rheumatoid arthritis)", yet the IOM ME/CFS Clinicians Guide lists “Immune impairment” as an "additional symptom" on page 9 of the guide/page 13 of the PDF : https://iom.nationalacademies.org/~/media/Files/Report Files/2015/MECFS/MECFScliniciansguide.pdf. This seems inconsistent and a significant contradiction. Don't many/most/all M.E. patients have some form of an immunologic disorder - at the very least, autoimmune thyroid disease? What is the scientific justification and/or reasoning to exclude M.E. patients who have a “current immunologic disorder”?

Additional exclusion criteria for participants with CFS: "Underlying illness that may cause fatigue such as thyroid dysfunction..." - see observations and questions listed just above.

Why would NIH publicly mention Reeves - to what benefit? Did they not know how Reeves is thought of by expert physicians, M.E. researchers and M.E. patients - and if not, why did NIH not know this?

"Enrollees will meet all definitions for ME/CFS, including Canadian Consensus Criteria, IOM, Fukuda and Reeves, in addition to post-infectious onset." In all honesty, their list reads like the contents of the kitchen sink. Wouldn’t the study benefit from selecting more focused criteria, say the CCC and/or ICCC? What is being said by listing all of these different criteria? (struggling to make sense of this)


Has the NIH offered a meaningful explanation as to why their initial study does not focus on – or even include (!) – severely ill M.E. patients – instead of being limited to no more than moderately ill M.E. patients?

I suspect the most severely ill patients can't even get out of bed, let alone participate in a 2-day exercise test. It's likely that if we find out more about the disorder from those we can get data from, it can be applied to the people who have the disease to a more severe extent.

Including all versions of the criteria really produces no problem practically or even logically speaking. As long as everyone has to conform to the strictest criteria, the lesser criteria become irrelevant to the extent that they overlap the strict criteria, and only provide additional barriers to inclusion to the extent that they don't overlap.

Regarding the immune impairment issue, people with ME/CFS are not generally recognized as having immune impairment according to traditional diagnostic categories. Again, this will just serve to weed out people who don't actually have ME/CFS, but some other diagnosable disorder.

This comment isn't necessarily directed to you and your concerns, but generally I think people just need to chill and let the researchers do their work. Of course it's important to have NIH clarify that they're using proper criteria and studying PEM, but the majority of critiques I've seen (from non-scientists, moreover) have appeared mostly to be just noise at best, counterproductive at worst. Some group on facebook is even circulating a petition demanding that NIH stop the study! Are these people insane? This will be a great study, one we desperately need. The tone of NIH in taking this seriously has been impressive, imo. I'm looking forward to Tues to hopefully silence these patient-critics. Based on past experience (e.g., with XMRV), I suspect many will just continue looking for conspiracies and criticizing NIH for including Reeves (oh, horror), even though that doesn't matter in the least as long as stricter criteria is also being included. But hopefully it will shut down at least some of the critics and let these researchers do what they need to do.

 

[Catnap]

...It's likely that if we find out more about the disorder from those we can get data from, it can be applied to the people who have the disease to a more severe extent...

Serotone9, a great deal of data can be gotten from severely ill patients. Why would anyone think that it cannot? Are you aware of the work being done by the Open Medicine Foundation's (OMF) End ME/CFS Project with Dr. Ronald Davis and others? Dr. Davis’ team is beginning to study severely ill M.E. patients – not mildly or moderately ill ME/CFS patients – thanks to privately raised funds –– since NIH chose not to fund his proposals.

The OMF has three Nobel laureates on their scientific advisory board (http://www.openmedicinefoundation.org/scientific-advisory-board/). Dr. Davis in particular, his team, OMF scientific advisory board members, and doctors Kogelnik and Kaufman at the Open Medicine Clinic know far more about ME/CFS than anyone at NIH. Do you have any familiarity with Dr. Davis’s work? Here is a link to the November 2013 article in The Atlantic magazine that mentions him, “Who Will Tomorrow's Historians Consider Today's Greatest Inventors?”: http://www.theatlantic.com/magazine/archive/2013/11/the-inventors/309534/. It is an understatement to say that he is a giant in his field. Why didn't the NIH seek his input?

Given his professional stature, accomplishments and the fact that his son Whitney Dafoe has one of the most severe cases of ME/CFS, it is hard to imagine that Dr. Davis would approach ME/CFS research in any way that is anything less than optimal and efficient. He is trying to save his son’s life, after all.
Here is a link to the OMF’s ME/CFS Severely Ill Big Data Study: http://www.openmedicinefoundation.org/mecfs-severely-ill-big-data-study/. Quote about the OMF study: “The molecular biomarkers that reflect the symptom mechanism are expected to be strongest in the approximately 25% of ME/CFS patients who have a severe form of the disease and are home-bound or bedbound.”

Dr. Davis, his colleagues at Stanford University and the OMF board are far more knowledgeable about ME/CFS than NIH – yet NIH has not reached out to Davis. I believe that this is a huge mistake and a great loss for patients. NIH has not yet informed the public as to the reasons why they have chosen to study moderately ill rather than severely ill ME/CFS patients.

Regarding the immune impairment issue, people with ME/CFS are not generally recognized as having immune impairment according to traditional diagnostic categories. Again, this will just serve to weed out people who don't actually have ME/CFS, but some other diagnosable disorder.

I believe that this statement is not correct. For example, the IOM report and/or Clinician’s Guide state otherwise; people with ME/CFS are recognized as having immune impairment. Have you heard of NK cells and are you aware that NK cell counts tend to be very low in ME/CFS patients? There is a multitude of data on immune dysfunction/immune impairment in ME/CFS patients. Here's just one article but there are many: http://www.ncbi.nlm.nih.gov/books/NBK284894/.

This comment isn't necessarily directed to you and your concerns, but generally I think people just need to chill and let the researchers do their work. Of course it's important to have NIH clarify that they're using proper criteria and studying PEM, but the majority of critiques I've seen (from non-scientists, moreover) have appeared mostly to be just noise at best, counterproductive at worst.

Serotone9, No worries, none of this is about any one individual. However, my family and I are fully cognizant that my wife’s life depends on how well this study is designed, planned, and executed, and that is why it matters to us. Repeating: Her life depends on the quality of this study.

…the majority of critiques I've seen (from non-scientists, moreover) have appeared mostly to be just noise at best, counterproductive at worst.

Your statement reminds me of the way in which some physicians think about and communicate with ME/CFS patients… along the lines of, “You’re not a doctor so you can’t possibly know more than I do – I’m the physician and you are the patient.”

Have you ever had an experience like this with a doctor? We have many times over and at some of America’s most prestigious medical centers. And guess what? They were wrong. We didn’t want them to be, but sadly, they were. Sometimes we didn’t have answers either, other times we did, but at times the physicians felt uncomfortable or threatened by the situation and had temper tantrums. My wife has been on the receiving end of serious medical errors as a consequence. These experiences taught each of us to believe in ourselves. We learned that if you are an intelligent, well-educated person with good critical thinking skills and are willing to invest in learning, patients and their families can have valid and well-informed questions and feedback. Patients and their families can be right. You may disagree with this of course, but our own experiences have taught us this valuable lesson many times over. My experiences have also shown me that non-scientists can offer valuable input. For the record, I happen to be a scientist (are you? – just curious).

Some group on facebook is even circulating a petition demanding that NIH stop the study! Are these people insane? This will be a great study, one we desperately need.

There is no argument that we desperately need a study. But many of us object to a poorly designed study. Broadly speaking, quality and appropriateness are the concerns. Again, lives are at stake. But everyone is entitled to their own opinion and I respect your right to your views.
Best wishes.

 

[IrisRV]

Of course it's important to have NIH clarify that they're using proper criteria and studying PEM, but the majority of critiques I've seen (from non-scientists, moreover) have appeared mostly to be just noise at best, counterproductive at worst.

I think part of the problem is that many non-scientists, and more particularly non-researchers, don't really know how research works, or how to interpret things like research proposals. There's no reason they should; it's not their field.

Unfortunately, if they read research documents as newspaper articles or political documents, it can lead to a lot of misunderstanding. Many of their questions or complaints don't make much sense in the research context which then confuses or puzzles the researchers. Some of it makes us look a little silly, unfair as that may be. The patient community sometimes does the equivalent of demanding to know why the painter is standing on a ladder when a chair is what everyone knows is the way to reach high places. It's not that the patients are trying to be obstructive. They're trying to help. The problem is that all they know about is chairs. The painter, on the other hand, is puzzled by the demand. He understands his business, knows what tools work best, and can't understand why he's asked to use the chair. It just won't make sense to him.

I think people just need to chill and let the researchers do their work.

To the extent that I think you mean this, I agree. Of course we need to keep an eye on what's going on and to offer any information that we have that might help. Patients need to be involved and kept informed, but we can't micromanage them. They know how research works (not referring to BPS researchers who appear to have no clue at all how research works). We look ridiculous trying to tell them their business when we really don't know what we're talking about.

Take something like this:

Exclusion criteria for all participants includes, "Current immunologic disorder (e.g. Type 1 diabetes, rheumatoid arthritis)

What I hear as a researcher is that they want to exclude people with known immunological disorders (Type 1 diabetes, RA) which are independent of our illness and could confound (def: mix up (something) with something else so that the individual elements become difficult to distinguish) the data. I do not hear, "We are going to test in advance for every immunological abnormality we can possibly imagine and eliminate anyone with any sign of immune abnormality"

The second sounds pretty silly for ME research, but the first makes perfectly good sense. If we don't know what they mean, we should ask politely for a clarification. We shouldn't jump to the conclusion that they are doing something stupid and then yell at them about it. It doesn't make us look like intelligent partners in research.

If we go to them yelling, "You can't eliminate everyone with any sign of any kind of immune abnormality because there are some nonstandard immune abnormalites i ME", they're likely to do the researcher equivalent of "Well duh, we weren't going to. Sheesh!" [eyeroll] It doesn't encourage the researchers that we are going to helpful rather than just pests who don't know what we're talking about.

Now if we ask politely for a clarification and they say, "Our intention is to eliminate any patient who has any sign of any kind of immune abnormality, because we don't think immune issues play any part in ME whatsoever so people with immune abnormalities can't possibly have ME", then by all means leap up and hand them information about immune abnormalities in ME, especially the ICC which they claim they are using to identify patients.

Based on past experience (e.g., with XMRV), I suspect many will just continue looking for conspiracies and criticizing NIH for including Reeves (oh, horror), even though that doesn't matter in the least as long as stricter criteria is also being included. But hopefully it will shut down at least some of the critics and let these researchers do what they need to do.

What he said.

 

[serotone9]

Serotone9, a great deal of data can be gotten from severely ill patients. Why would anyone think that it cannot? Are you aware of the work being done by the Open Medicine Foundation's (OMF) End ME/CFS Project with Dr. Ronald Davis and others? Dr. Davis’ team is beginning to study severely ill M.E. patients – not mildly or moderately ill ME/CFS patients – thanks to privately raised funds –– since NIH chose not to fund his proposals.

The OMF has three Nobel laureates on their scientific advisory board (http://www.openmedicinefoundation.org/scientific-advisory-board/). Dr. Davis in particular, his team, OMF scientific advisory board members, and doctors Kogelnik and Kaufman at the Open Medicine Clinic know far more about ME/CFS than anyone at NIH. Do you have any familiarity with Dr. Davis’s work? Here is a link to the November 2013 article in The Atlantic magazine that mentions him, “Who Will Tomorrow's Historians Consider Today's Greatest Inventors?”: http://www.theatlantic.com/magazine/archive/2013/11/the-inventors/309534/. It is an understatement to say that he is a giant in his field. Why didn't the NIH seek his input?

Given his professional stature, accomplishments and the fact that his son Whitney Dafoe has one of the most severe cases of ME/CFS, it is hard to imagine that Dr. Davis would approach ME/CFS research in any way that is anything less than optimal and efficient. He is trying to save his son’s life, after all.
Here is a link to the OMF’s ME/CFS Severely Ill Big Data Study: http://www.openmedicinefoundation.org/mecfs-severely-ill-big-data-study/. Quote about the OMF study: “The molecular biomarkers that reflect the symptom mechanism are expected to be strongest in the approximately 25% of ME/CFS patients who have a severe form of the disease and are home-bound or bedbound.”

Dr. Davis, his colleagues at Stanford University and the OMF board are far more knowledgeable about ME/CFS than NIH – yet NIH has not reached out to Davis. I believe that this is a huge mistake and a great loss for patients. NIH has not yet informed the public as to the reasons why they have chosen to study moderately ill rather than severely ill ME/CFS patients.



I believe that this statement is not correct. For example, the IOM report and/or Clinician’s Guide state otherwise; people with ME/CFS are recognized as having immune impairment. Have you heard of NK cells and are you aware that NK cell counts tend to be very low in ME/CFS patients? There is a multitude of data on immune dysfunction/immune impairment in ME/CFS patients. Here's just one article but there are many: http://www.ncbi.nlm.nih.gov/books/NBK284894/.



Serotone9, No worries, none of this is about any one individual. However, my family and I are fully cognizant that my wife’s life depends on how well this study is designed, planned, and executed, and that is why it matters to us. Repeating: Her life depends on the quality of this study.



Your statement reminds me of the way in which some physicians think about and communicate with ME/CFS patients… along the lines of, “You’re not a doctor so you can’t possibly know more than I do – I’m the physician and you are the patient.”

Have you ever had an experience like this with a doctor? We have many times over and at some of America’s most prestigious medical centers. And guess what? They were wrong. We didn’t want them to be, but sadly, they were. Sometimes we didn’t have answers either, other times we did, but at times the physicians felt uncomfortable or threatened by the situation and had temper tantrums. My wife has been on the receiving end of serious medical errors as a consequence. These experiences taught each of us to believe in ourselves. We learned that if you are an intelligent, well-educated person with good critical thinking skills and are willing to invest in learning, patients and their families can have valid and well-informed questions and feedback. Patients and their families can be right. You may disagree with this of course, but our own experiences have taught us this valuable lesson many times over. My experiences have also shown me that non-scientists can offer valuable input. For the record, I happen to be a scientist (are you? – just curious).



There is no argument that we desperately need a study. But many of us object to a poorly designed study. Broadly speaking, quality and appropriateness are the concerns. Again, lives are at stake. But everyone is entitled to their own opinion and I respect your right to your views.
Best wishes.

So if Davis is already studying severely ill, why should the NIH replicate that? Maybe we can find out something different from studying people who aren't as ill that would also be helpful, the same way we found differences between people who had been ill for different time periods. If we can't get information from 2-day exercise tests - which as I said, would be very unlikely from the severely ill - that in itself is a huge limitation, it seems to me.

Sometimes it's better not to collaborate directly with others so that you don't "contaminate" your own thinking with possible groupthink. Often a fresh set of eyes can see things that even the most knowledgeable and experienced person can miss, precisely because they've become so accustomed to looking at things in a particular way.

Respectfully, I don't think anyone's life rests in the balance of any one particular study. I could be wrong, but my sense of this NIH study so far is that it's not exactly designed to find out the "cause" of ME/CFS, but rather to distinguish it as a legitimate entity once and for all. That in itself would be a huge step forward, regardless of whatever else it was able to find. All things can't be included in a single study anyway. Like it or not, it's one step at a time until ultimately we can find the cause and possible treatments.

I don't dispute anything you said about patient experiences with doctors, and I fully appreciate your points about how we need well-designed studies rather than poorly designed ones - as we have often had in the past (PACE, etc.) On the whole, however, this one on the surface seems fairly well designed to be able to "prove" that ME/CFS is an actual physiological thing, which is one thing we desperately need -- so that we can be taken seriously by researchers and the kind of doctors you describe. I hope we'll find out even more, and that we'll learn more about it during the conference today.

Best regards to you and your wife.

 

[Catnap]

So if Davis is already studying severely ill, why should the NIH replicate that?

To answer your first question, Davis and team are literally just beginning their proposed five year study of severely ill patients. The OMF Severely Ill study requires a minimum of $5 million per year for 5 years - but hearing from Davis himself, the study would be more appropriately funded at $10 million per year. The OMF raised about $1.75 million last year to kick off the study; but to state the obvious, having to rely on raising private funds for the entire $25 - 50 million is tough, to say the least. This information is publicly available - anyone who is interested in the facts can read what I'm repeating here.

Your mind is made up and we have opposing viewpoints that will not overlap. No sense in saying much more.

Respectfully, I don't think anyone's life rests in the balance of any one particular study.

serotone9: We disagree completely. Further, beginning a response with the word "respectfully" does not make a response respectful. Your statement is based in complete ignorance. It is anything but respectful.

 

[weyland]

So if Davis is already studying severely ill, why should the NIH replicate that?

They don't have to replicate it, but the least they could have done was actually review Davis' meritorious grant proposal instead of telling him to screw off.

 

[IrisRV]

They don't have to replicate it, but the least they could have done was actually review Davis' meritorious grant proposal instead of telling him to screw off.

Gosh! Did they?

 

[weyland]

Gosh! Did they?

More or less. The amusing part is that the new NIH study is not that different in terms of some of the omics work they want to do.

 

[IrisRV]

More or less. The amusing part is that the new NIH study is not that different in terms of some of the omics work they want to do.

Oh yeah, that. But that was a while back, wasn't it? Before whatsisname said that ME/CFS is a serious disease and they're going to work on doing something for us. It wasn't in direct competition with this research, right?

I'm trying to take a that was then, this is now approach. We can't blame this set of researchers for what some dumbass reviewers decided about a proposal a year (or whatever) ago.

I agree that they should have funded Davis' work. That they didn't doesn't invalidate this work. Apparently the NIH wants to do this in the way they know how to do it. First, confirm that the disease is a legitimate entity. Second, identify biomarkers to make sure the right patients are being studied. Third, identify the characteristics and abnormalities of the illness. Fourth, use those characteristic and abnormalites to identify a cause. Fifth, devlop and test treatments. It's a nice, neat, logical progression. Things will be clear and orderly when it's all done. And all of us will be long dead.

NIH looks at the long picture. Their in-house work is trying to get the science of the illness right, with all the i's dotted and the t's crossed. We want them to skip to step 4 because we know this is a legitimate illness. We know there are abnormalities that are likely biomarkers and that the top clinicians can diagnose ME correctly most of the time. That's good enough for us to move forward. We know there are a number of ME symptoms and abnormalities identified. So cut to the chase already, right?

That's not the way bureaucracies work. They don't know any of that because they haven't proven it themselves. Annoying, I know, but you can't expect an elephant to fly like a sparrow. It is what it is. Their research will be valuable ... eventually. It has to be done for this illness to be solved some day. They're starting. Good.

If we want something sooner, we have to fund our private research facilities. We have to help them get government funding separate from the funding for this big picture research. We will not get NIH to give up it's internal funding for the long-term plan in favor of shorter-term solutions.

We need to see this research for what it is and take advantage of it as much as we can. The NIH in-house team proving beyond a doubt that ME/CFS is a real illness will be huge for us. The media will start portraying us differently. Congresspeople will feel comfortable encouraging more funding for this disease. Many, many more private organizations and individuals will be willing to donate to the SolveCFS Initiative and the like. We might even become the new fashionable disease everyone want to be involved with -- researchers, philanthropists, politicians. We need this.

 

[weyland]

It wasn't in direct competition with this research, right?

Not really, no. Davis' study is going to be on severe patients where they can't do 2 day exercise tests or spinal taps. This NIH study by design will probably only include mild (and maybe lightly moderate) patients given everything that they're going to have to do.

Apparently the NIH wants to do this in the way they know how to do it. First, confirm that the disease is a legitimate entity.

Yeah, I get that. It's just too bad they couldn't fund Davis and do this study simultaneously. Instead we have to wait for Davis to do it piecemeal while he waits on private donations to trickle in.

I just really really hope they get the patient selection right for this study. You can design the most comprehensive study in the world, but if you run it on the wrong patients we end up nowhere. Actually we'd end up worse than where we started because if they fail to find abnormalities then we will look no different than the FMD control arm and we become a psychosomatic disease.

 

[Katherine Autry]

Having just read a post from Jeanette B. re: the new Clinical Lead Investigator, Brian Walitt, I think we are all in trouble. Here is his response to one question from his interview:
Interviewer: What is fibromyalgia?
Walitt: That’s a hard one. Ah, time will tell. Uh, fibromyalgia appears to be a way that people experience suffering in their body. Um, both from the way that the bodies are interpreted and the problems of the body, as well as the problems in their lives, as well as how societies tell us how to experience things. All those come together to create a unique experience in different points in time, and right now, that experience, um, is a, one of those experiences is fibromyalgia. Ah. Is it a disease? Or is it a, uh, a normal way that we handle and are supposed to work is still to be determined. But it’s quite possible that the (frowns) tricky way that the brain works, is that we may create symptoms as part of how we’re supposed to operate, as opposed to this representing the system breaking down.

You can read more here

http://thoughtsaboutme.com/2016/02/...-as-normal-life-experience/walitt_patient_fm/


And of course, if this is just "how we're supposed to operate" we would not need to conduct any scientific research about it. What a nut job. It feels like we have taken a huge stride backward, like 30 years back. This is who they have appointed as the LEAD CLINICAL INVESTIGATOR. Here is the link to his interview.

http://www.familypracticenews.com/s...e-model/e913134880916685f3005dac5459ab88.html

 

[Janet Dafoe]

Ron would love to collaborate with the NIH study. He has called Dr. Nath and talked with him about this. Ron's team is studying severely ill patients and NIH is studying moderately ill patients. Ron offered that NIH could send him samples and Ron can do tests on their patients that NIH isn't doing. They could put their data together for analysis and get a better profile of the disease with this range of severeties. Collaborating like this would lead to answers faster. But alas, it seems there is no money to do this. So outrageous, in my opinion, when we have this opportunity and there have been decades of neglect. I think advocating for this would make the most difference in making the NIH study most powerful and on track.

 

[Katherine Autry]

I look forward to the NIH publicly posting the actual protocol. Unfortunately, they still have not addressed the other major concerns with the study. British and American research has shown that large percentages of ME patients have active, persistent enterovirus infections. This study design purposefully excludes patients with active infection. This means that a large percentage of very prototypical ME patients will be excluded from the study.

They have not provided justification for using a functional (psychogenic) neurological disorder as a control arm. If they fail to find statistically significant biological abnormalities, they risk improperly conflating this organic disease with a psychogenic disorder. This comparison arm is reckless and unnecessary in an exploratory study.

They have also not provided justification for using a post-lyme (not PTLDS) group as a control arm. There is no evidence in the medical literature that Borrelia spp. is associated with onset of ME or CFS. If they want to compare the difference between someone who recovers from infection and someone who develops ME or CFS from infection, it would make more sense to use the actual pathogens that have been associated with onset of the disease, such as enteroviruses or Epstein Barr virus. Diagnosis of these infections is far less controversial and error prone and incidence of these infections is more widespread which will make control recruitment easier and less error prone.

This concerns me as well. They need to explain the rationale for these choices.

 

[Cort]

Not really, no. Davis' study is going to be on severe patients where they can't do 2 day exercise tests or spinal taps. This NIH study by design will probably only include mild (and maybe lightly moderate) patients given everything that they're going to have to do.


Yeah, I get that. It's just too bad they couldn't fund Davis and do this study simultaneously. Instead we have to wait for Davis to do it piecemeal while he waits on private donations to trickle in.

I just really really hope they get the patient selection right for this study. You can design the most comprehensive study in the world, but if you run it on the wrong patients we end up nowhere. Actually we'd end up worse than where we started because if they fail to find abnormalities then we will look no different than the FMD control arm and we become a psychosomatic disease.

Hopefully with the renewed emphasis on ME/CFS at the NIH Davis's grant will go through the next time. I would be surprised if it didn't actually. We shall see!

 

[Cort]

Ron would love to collaborate with the NIH study. He has called Dr. Nath and talked with him about this. Ron's team is studying severely ill patients and NIH is studying moderately ill patients. Ron offered that NIH could send him samples and Ron can do tests on their patients that NIH isn't doing. They could put their data together for analysis and get a better profile of the disease with this range of severeties. Collaborating like this would lead to answers faster. But alas, it seems there is no money to do this. So outrageous, in my opinion, when we have this opportunity and there have been decades of neglect. I think advocating for this would make the most difference in making the NIH study most powerful and on track.

It's a great idea!