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Article: The NIH on ME/CFS in 2012: Pt II the STUDIES!

Thank you Cort for this comprehensive report on ongoing NIH funded trials.

I am confused about how Dr. Natelson goes about dividing the patient groups as ones with depression and those without. Furthermore, saying that biological abnormalities only show up in the group without depression.
Is he talking about primary depression and fatigue without true ME/CFS?
My problem with this is that you can have patient x who is severely affected by ME/CFS. Patient x did not manifest with depression at outset of the illness but, as the illness progresses an grows in intensity, the patient develops adaptive depression. Is Dr. Natelson saying that patient x, in the beginning, before he manifested with depression symptoms, would have a positive biological (extra proteins in spinal fluid) outcome yet, later when his illness is more severe and he becomes depressed because of it, these proteins will disappear?
I really hope that he is not of the school of thinking that depressed people are being diagnosed with ME/CFS!
 
Thank you Cort for this comprehensive report on ongoing NIH funded trials.

I am confused about how Dr. Natelson goes about dividing the patient groups as ones with depression and those without. Furthermore, saying that biological abnormalities only show up in the group without depression.
Is he talking about primary depression and fatigue without true ME/CFS?
My problem with this is that you can have patient x who is severely affected by ME/CFS. Patient x did not manifest with depression at outset of the illness but, as the illness progresses an grows in intensity, the patient develops adaptive depression. Is Dr. Natelson saying that patient x, in the beginning, before he manifested with depression symptoms, would have a positive biological (extra proteins in spinal fluid) outcome yet, later when his illness is more severe and he becomes depressed because of it, these proteins will disappear?
I really hope that he is not of the school of thinking that depressed people are being diagnosed with ME/CFS!

It is a very confusing area and an intriguing one. My understanding is that he has found that people with ME/CFS with depression have different study findings - actually lower levels of the brain abnormalities that he is testing for - than people with ME/CFS without depression.

He's not talking about depressed people without ME/CFS at all and we know that depression is, in fact, quite different from ME/CFS; cortisol readings are bumped up (not down), they don't experience post-exertional fatigue, the metabolic abnormalities are not present; in most studies - CFS patients test differently than people with major depression....so people with ME/CFS and depression are quite different from people with major depression.

There are similariites as well...though. Learning that antidepressants can work quite well with chronic pain patients (who are not depressed) was kind of a revelation for me....These are really complex systems. It makes me wonder if these depression.....pain.....fatigue...... etc. fields all kind of weaves in and out of each other in ways that we don't understand. Researchers are now, for instance, really beginning to get excited about immune processes in the central nervous system that effect or cause depression. Of course they are interested in them in ME/CFS as well...

I can see how this could work.....there could be a depression prone subset of ME/CFS who are different, for some reason, than people with ME/CFS who do not become depressed.

You bring up a good point though about people who start off with CFS who are not depressed but later become depressed...It could be that Natelson has a group of patients who have been ill long enough that those people who are going to get depressed do so (?)
 
It is a very confusing area and an intriguing one. My understanding is that he has found that people with ME/CFS with depression have different study findings - actually lower levels of the brain abnormalities that he is testing for - than people with ME/CFS without depression.

He's not talking about depressed people without ME/CFS at all and we know that depression is, in fact, quite different from ME/CFS; cortisol readings are bumped up (not down), they don't experience post-exertional fatigue, the metabolic abnormalities are not present; in most studies - CFS patients test differently than people with major depression....so people with ME/CFS and depression are quite different from people with major depression.

There are similariites as well...though. Learning that antidepressants can work quite well with chronic pain patients (who are not depressed) was kind of a revelation for me....These are really complex systems. It makes me wonder if these depression.....pain.....fatigue...... etc. fields all kind of weaves in and out of each other in ways that we don't understand. Researchers are now, for instance, really beginning to get excited about immune processes in the central nervous system that effect or cause depression. Of course they are interested in them in ME/CFS as well...

I can see how this could work.....there could be a depression prone subset of ME/CFS who are different, for some reason, than people with ME/CFS who do not become depressed.

You bring up a good point though about people who start off with CFS who are not depressed but later become depressed...It could be that Natelson has a group of patients who have been ill long enough that those people who are going to get depressed do so (?)

Thanks for your reply Cort,

I still have a problem though with the term "depression prone ME/CFS". Who in their right mind would have a debilitating illness that leaves them house/bedbound for ten years, be in pain most of the time and NOT BE SOMEWHAT DEPRESSED! He is kind of saying (from my understanding) that if someone is in this position and is not depressed = they are truly sick but the same person with the same circumstances who doesn't get depressed at all, well then - he is really sick.

Am I reading this all wrong?

In addition, he is looking at the neurological component of the illness. This makes sense since he is a neurologist. He can only test those that if on neurological meds, have to come off them for two weeks prior to testing. I don't know what neurological meds one is on (because they need it for their neurological problems) can just come off them for two weeks?

I was always perplexed about who is really being studied here but, I guess the same can be said about all studies. The most severe/bedbound patients can't participate and therefore are not represented in any of these studies.
 
Thanks for your reply Cort,

I still have a problem though with the term "depression prone ME/CFS". Who in their right mind would have a debilitating illness that leaves them house/bedbound for ten years, be in pain most of the time and NOT BE SOMEWHAT DEPRESSED! He is kind of saying (from my understanding) that if someone is in this position and is not depressed = they are truly sick but the same person with the same circumstances who doesn't get depressed at all, well then - he is really sick.

Am I reading this all wrong?

In addition, he is looking at the neurological component of the illness. This makes sense since he is a neurologist. He can only test those that if on neurological meds, have to come off them for two weeks prior to testing. I don't know what neurological meds one is on (because they need it for their neurological problems) can just come off them for two weeks?

I was always perplexed about who is really being studied here but, I guess the same can be said about all studies. The most severe/bedbound patients can't participate and therefore are not represented in any of these studies.

Agreed about not being somewhat depressed...My guess is that a level of subclinical depression is almost inevitable in any disorder that effects people as strongly as CFS for a long period of time. I think what Natelson is saying that based on his results thus far these two groups of patients are showing up very differently on neurological tests. It is kind of extraordinary that this same pattern has shown up in a variety of different tests. Whether or not the pattern persists in this new study is the big question - I don't think that anyone else has tried to validate Natelson's results.
 
Thanks for the summary Cort. This could be a very interesting year.

Results Thus Far Several papers have come out of this long study. Biaggioni has documented angiotensin abnormalities in some POTS patients and found that low doses of the beta blocker propranolol significantly reduced the racing heartbeats and symptoms found in POTS patients, while high doses may make some POTS patients worse. The big news were waiting for is whether Biaggionis theory that reduced NO levels are at heart of this disorder causing sympathetic nervous system over-activation, low blood volume, cardiovascular problems, POTS, etc. is correct.


Anecdotally; when I was still working I really needed some help from my GP to cope with my symptoms one of which was being unable to control my temperature even in a normally heated office. Frankly I was constantly sweating like a pig and on the verge of passing out.

My GP must have assumed a SNS problem and prescribed propranolol 80mg, 1 per day. Did it work? Oh yes and then some. I can't remember the details now but I do remember having never felt so ill in my life and rather than overheated I felt like an ice cube. I had to quit them after a few days. So low and slow would be the way to go.


You may have heard of 'statin myopathy' that may occur in a small number of vulnerable people (including the elderly and those with a mitochondrial defect).

One study looked at the effects on mitochondria of nearly 3000 compounds, half of which were FDA approved drugs :

Among them were six statins and, intriguingly, three of them -- fluvastatin (Lescol), lovastatin (Altoprev), and simvastatin (Zocor) -- caused ATP levels to fall and production of free radicals to increase, Dr. Mootha and colleagues reported.

This "toxicity signature" wasn't seen with other statins, although it was seen with another drug often used by the same patients - the beta-blocker propranolol (Inderal).

http://www.medpagetoday.com/Cardiology/Dyslipidemia/8489

Hmmmm!

Plus :

In this study, they looked through their 2,940 compounds to see if any had the opposite effect. In essence, Dr. Mootha said, the work has produced a "look-up table" that can now be used to find compounds that have desired effects.

In this case, they found six compounds that increased gene expression and reduced free radicals and two of them are known -- at least anecdotally -- to have anti-diabetic effects.

One is mebendazole (Vermox), a benzimidazole used to treat infestations by worms
."

Double Hmmm!

http://forums.phoenixrising.me/show...ent-for-worms-has-helped-my-gut-a-bit-but-why


Perhaps I should 'eats all my spinach'

In the 1990s, a research group at Karolinska Institutet demonstrated how the body can convert nitrate to NO, a molecule involved in many important bodily functions, such as blood pressure regulation, the immune defence and cell metabolism.

In this new study, the same team had healthy people take nitrate equivalent to 200-300g of spinach or lettuce for three days, after which they were given a cycling task to perform. The researchers then analysed samples from their thigh muscles and compared them with similar samples from the same subjects when they had taken a placebo instead. After nitrate ingestion, a significant improvement was seen in the efficiency of the mitochondria, which consumed less oxygen and produced more of the energy-rich substance ATP per consumed oxygen molecule.

http://insciences.org/article.php?article_id=9838


Sorry for digressing - again:angel:
 
Thanks Cort, interesting stuff, lets hope something useful comes of it all. As for the depression issue, i have (apart from post natal) never suffered from depression, other than some normal amount of grief due to losing out on the life i wanted for myself. But i do wonder why they dont study anxious patients alongside M.E patoients as so many M.E patients have severe anxiety rather than depression. This has never made sense to me, as there are many who (wrongly ) think of M.E as a type of anxiety disorder rather than a depressive disorder.
Justy.
 
Thanks for the summary Cort. This could be a very interesting year.

Anecdotally; when I was still working I really needed some help from my GP to cope with my symptoms one of which was being unable to control my temperature even in a normally heated office. Frankly I was constantly sweating like a pig and on the verge of passing out.

My GP must have assumed a SNS problem and prescribed propranolol 80mg, 1 per day. Did it work? Oh yes and then some. I can't remember the details now but I do remember having never felt so ill in my life and rather than overheated I felt like an ice cube. I had to quit them after a few days. So low and slow would be the way to go.

You may have heard of 'statin myopathy' that may occur in a small number of vulnerable people (including the elderly and those with a mitochondrial defect).

One study looked at the effects on mitochondria of nearly 3000 compounds, half of which were FDA approved drugs :
http://www.medpagetoday.com/Cardiology/Dyslipidemia/8489


http://forums.phoenixrising.me/show...ent-for-worms-has-helped-my-gut-a-bit-but-why

Perhaps I should 'eats all my spinach'

http://insciences.org/article.php?article_id=9838

Interesting on the mitochondrial stuff Marco - I had no idea they were able to test mitochondria that way and what an interesting finding on diabetes. Oddly enough spinach is one of the vegetables that I often feel more relaxed after eating...it can be quite noticeable at times.
 
Thanks Cort, interesting stuff, lets hope something useful comes of it all. As for the depression issue, i have (apart from post natal) never suffered from depression, other than some normal amount of grief due to losing out on the life i wanted for myself. But i do wonder why they dont study anxious patients alongside M.E patoients as so many M.E patients have severe anxiety rather than depression. This has never made sense to me, as there are many who (wrongly ) think of M.E as a type of anxiety disorder rather than a depressive disorder.
Justy.

Hah! Justy my thoughts exactly and Dr. Baraniuk's as well. He feels researchers missed the boat when they focused on depression (I imagine because fatigue is common in depression) and that if they focused on anything they should have focused on 'anxiety' and this is coming out in the science with findings suggesting that ME/CFS is associated with increased sympathetic nervous system (fight or flight) activity; ie increased arousal.

I imagine I do have some subclinical depression but then again I would place lots of people in that category -quite a few of whom who do not have any chronic illnesses - so my definition of that may be a little warped but the 'anxiety' or 'arousal' issue - tightened muscles, clenched jaw, thoughts flying like around like mad - is very, very apparent to me. When I can use treatments that increase my energy levels (temporarily) those issues just disappear....
 
He feels researchers missed the boat when they focused on depression (I imagine because fatigue is common in depression) and that if they focused on anything they should have focused on 'anxiety' and this is coming out in the science with findings suggesting that ME/CFS is associated with increased sympathetic nervous system (fight or flight) activity; ie increased arousal.

That's exactly what they have focused on for the last 20 or so years and it hasn't resulted in much. They talked about 'atypical depression' and anxiety in CFS patients as a potential causative factor.

See this conference report from 1993 (ignore the front cover which is currently the wrong image).
http://books.google.com.au/books?id=9cAa038ka1QC&printsec=frontcover#v=onepage&q&f=false
 
Hi Snow - i think what i mean by focusing on anxiety is not that i believe it is causative in our illness (although i know many, including patients do) b ut that when they compare us in studies to healthy controls and then to people with major depression i wonder iof they shouldnt compare us instead with those with anxiety disorder - i dont have
any depression at all - just get a bit fed up occassionaly, but it would be nice to see that there are differences between us and anxiety patients - that might get the psychs of our backs!
 
That's exactly what they have focused on for the last 20 or so years and it hasn't resulted in much. They talked about 'atypical depression' and anxiety in CFS patients as a potential causative factor.

See this conference report from 1993 (ignore the front cover which is currently the wrong image).
http://books.google.com.au/books?id=9cAa038ka1QC&printsec=frontcover#v=onepage&q&f=false

I think there have multiple focuses in CFS ranging from the HPA axis to cytokines to EBV to the sympathetic nervous system - to the brain.....and recently on XMRV....If you look at the current slate of studies the NIH is doing - you don't see a focus on anxiety at all; instead you see a focus on how the sympathetic nervous system is interacting with the blood vessels; one kind of 'arousal' - along with the immune and other studies. The brain studies show reduced ability from the brain to turn off attention to background noises - that is another kind of increased 'arousal'.....While there are behavioral trials there are no personality studies, no 'anxiety', so to speak, studies in the current slate of studies and I am actually hard pressed to remember the NIH doing those - so they must be coming from another source.
 
I still have a problem though with the term "depression prone ME/CFS". Who in their right mind would have a debilitating illness that leaves them house/bedbound for ten years, be in pain most of the time and NOT BE SOMEWHAT DEPRESSED! He is kind of saying (from my understanding) that if someone is in this position and is not depressed = they are truly sick but the same person with the same circumstances who doesn't get depressed at all, well then - he is really sick.

(...)

I was always perplexed about who is really being studied here but, I guess the same can be said about all studies. The most severe/bedbound patients can't participate and therefore are not represented in any of these studies.

I agree with these two points. I have always been curious as to how physicians/researchers distinguish between a normal reaction to all the losses ME/CFS brings (especially in the cases at the more severe end of the scale) and a clinical depression. How much grief/sadness is "normal" when one is house- or bed-bound, suffering from terrible symptoms and has lost most of one's life? If a person is put into prison and then isolated, not knowing if he/she would ever get out, would it be normal to not have "depressed" feelings and thoughts in that situation?

(This issue of defining depression could perhaps be a theme for a blog post, Cort? ;))

Also, I too wish researchers would make their studies more available to severely affected patients. I think I read that for this study, one would preferably do tests in one day in two different sites in NY City, so the patient would need to manage two tests plus travelling between the sites (?) - that means that only rather mildly affected ME/CFS patients can be considered. Guessing that more severely affected patients would give clearer results, I wish they/we would be included in all studies.

As always, thanks Cort for keeping us updated!
 
Cort said:
With grant success rates at less than 20%, grants are hard to come by. The NIH estimates that grant success rates of about 30% are about right; anything lower than that suggests the NIH has other priorities for its funds. First time grant success rates in the mid-late 2000s, for ME/CFS, however, were only around 8%. Nevertheless, the money, when they can get it, is so good thats its well worth the effort. The CFIDS Association, for instance, has been able to parley their recent small grant packages into millions of dollars of NIH funded studies.

You write, Cort, that the first time grant success rates in the mid-late 2000s, for ME/CFS...were only around 8%. At the last CFSAC meeting, Dr. Cheryl Kitt, Deputy Director of the NIH/CSR, reported that recent success rates are really quite high in the CFS study section because the number of applications is low:

In the last two years there were no new investigators in chronic fatigue syndrome that were reviewed. None. So that's a problem. I mean, it's a problem for the field that for some reason new investigators are not even submitting applications. I would urge you to encourage people to do that (http://www.youtube.com/watch?v=nf2yOxf74bE).

Dr. Kitt says that what she's noticed, particularly in the past few years, is that if an individual is funded the first time, they tend to not come back in the second time, for some reason.... We're not getting competitive renewals very often. Overall, she says, We receive very few applications.... The NIH really can't fund applications it doesn't see. The success rate is pretty high for applications to be funded because the denominator is small. There aren't that many.

Dr. Kitt's report suggests, then, that these grants aren't so difficult to come by, after all. In an earlier article, you wrote, Researchers probably dont feel they can make progress in what they feel is a wastebasket disorder (http://forums.phoenixrising.me/content.php?526-Ottawa-IACFS-Conference-IV-CFS-and-the-Immune-System). Doesn't that assessment better account for our recent situation?
 
Hats off to you again, Cort, for another excellent review summarising a vast amount of very useful information.

I think the Fletcher Good Day/Bad Day study is very exciting and, as you say, could change the way research is done if it finds a real difference between the two. It could lead to far more consistent results than we currently see in biologial abnormalities research.

I was also delighted to see that the Lights will be trying to repicate their very interesting findings
its first goal will be to validate the results of the old study with new patients
from earlier coments you reported from Alan Light, I had thought they felt they'd done enough and were moving on to drug testing.
 
You write, Cort, that the first time grant success rates in the mid-late 2000s, for ME/CFS...were only around 8%. At the last CFSAC meeting, Dr. Cheryl Kitt, Deputy Director of the NIH/CSR, reported that recent success rates are really quite high in the CFS study section because the number of applications is low

Dr. Kitt says that what she's noticed, particularly in the past few years, is that if an individual is funded the first time, they tend to not come back in the second time, for some reason.... We're not getting competitive renewals very often. Overall, she says, We receive very few applications.... The NIH really can't fund applications it doesn't see. The success rate is pretty high for applications to be funded because the denominator is small. There aren't that many.

Dr. Kitt's report suggests, then, that these grants aren't so difficult to come by, after all. In an earlier article, you wrote, Researchers probably dont feel they can make progress in what they feel is a wastebasket disorder (http://forums.phoenixrising.me/content.php?526-Ottawa-IACFS-Conference-IV-CFS-and-the-Immune-System). Doesn't that assessment better account for our recent situation?

All I can say is that Dr. Cheryl Kitt is wrong and right. I did a FOIA request on all studies reviewed by the CFS SEP from 2003 to 2007 and it showed very low grant acceptance rates for grants applied to program announcements. I would be astonished if anything has changed.

The next article in the NIH series will show that the NIH has tended to fund the same investigators over time and has not been funding new investigators.

She is right, on the other hand, that they get very few applications - that is a big part of the problem. On the other hand there is a way to fix the low grant applications and that is to fund an RFA with guaranteed money - that worked in 2006 - it brought in alot of grants - and it had a pretty percentage of grant approvals - and it would work even better now. Dr. Kitt can wring her hands and say - we don't have anything to fund - or she and the NIH can do what they know will bring in researchers and produce an RFA.

Scientific Workshops like the State of the Knowledge Workshop are done to prepare for RFA's - one should have been produced alongside the one last year.

I've always been a bit surprised at what appear to be ad hoc pronouncements by agency officials. I actually question whether they take the time to really review the stats...I will post the FOIA findings in the next comment.
 
FOIA Findings


CFS Specific Grants Submitted to CFS SEP 2003-2007 (FOIA Cort Johnson)

Background

The FOIA was submitted in an attempt to figure where the roadblocks in the CFS grant funding process at the NIH are. The very low numbers of awarded grants of the past five years (8) suggested that success rates of CFS grant proposals were either very low or very few researchers were applying for grants or both.

This document charts the fate of CFS specific grants to the CFS SEP and the Neuroimmune RFA Review Panels from 2003-2007.

First Time Grant Success Rate: A primary reason of the FOIA was to determine the success rate of first-time CFS grant applications. NIH officials have stated that the CFS grant success rates are similar to those found NIH-wide but its been unclear whether they were lumping in CFS grants with FM and other grants or if they were including continuation grants; i.e. already approved grants whose funding need at some point to be renewed by the panel in their statistics. Both of those would likely increase the grant success rate. This FOIA specified that only CFS-specific grants be included.

(*Unfortunately since the NIH refused to provide titles, authors, etc. of the rejected grants its impossible to tell how many of those were first-time grants and how many were rejected renewals. Several factors argue against having many rejected renewals; renewal grant acceptance rates are generally much higher than first time grant success rates and the low numbers of active grants suggests few renewal grants would be present. I assume that all of the rejected grants are first-time grants. An appeal of the NIHs decision is underway)

A Very Low Reward Rate - Based on the supposition that all the rejected grants were first time applications the first-time grant success rate for CFS researchers was 8/57=14%. Even with the special grant package of 2006 (RFA) the NIH managed to fund on average just over I new grant a year on CFS.

High Levels of Rejection Early in the Process the most common fate of a CFS research grant application (@30%) was to be triage reviewed non-competitive (see below for explanation)/ These are grants that the review panel unanimously agreed fell into the bottom fifty percent in terms of quality. They are given comments but not a full review and are returned to the applicant unscored.

CFS advocates have repeatedly raised the specter of high rates of grant rejections before review panels composed of few researchers with experience with CFS issues. A grant application by Andrew Lloyd provides a case in point. Dr. Lloyds application before an RFA review panel with more CFS expertise reportedly just missed the cutoff point. After Dr. Lloyd reconstituted his application to incorporate the RFA reviewers suggestions it was judged non-competitive by a subsequent CFS SEP review panel and was returned unscored.

Difficulty Getting Past the CFS SEP Review Panel
- The biggest single roadblock for CFS researchers was getting past the initial review panel. Of the 57 new CFS grants over half (29) were stopped at the review panel stage for various reasons (triage reviewed non-competitive/application withdrawn (see below)).

High Rejection Rates at the Institute Level
the last stage of the review process, the final review before an Institute panel, was even more difficult. The last review for a CFS grant is before an Institute review boards. The FOIA data indicates that over the past five years 28 new CFS grants (ICD Withdrawn/Pending Award/Awarded (see below)) appeared before Institute Review Panels. A CFS grant application had about a 25% of getting funded at this stage; the Institutes funded 28%, rejected 46% and placed 26% in an unfunded holding category (Pending Award).

RFA Acceptance Rates vs. PA Acceptance Rates. Greatly reduced acceptance rates for Program Announcement initiated grant proposals (8%) indicates that CFS researchers have only a small chance of getting their grants funded under the dominant funding mechanism they available to them at the NIH. RFA initiated grant proposals, on the other hand, had a 31% chance of getting funded.

Seventy-five percent of PA grants were halted at the review panel (Non-competitive -9, Withdrawn for Amendment 12); fifty percent of RFA grants were.

While withdrawn for amendment was a common fate (@30%) of a grant initiated through a program announcement (PA), none of the neuro-immune grant applications were withdrawn for amendment.

PA initiated grants also far lower acceptance rates at the last step in the grant acceptance process; the Institute Review. While all five of the RFA grants that made it to the final review were funded (100% success rate) a PA initiated grant had a less than 1 chance in four of being funded (23%).

The differing outcomes for RFA vs. PA grant applications indicate the Institutes are unlikely to fund CFS research grants if they have not specifically committed funds to do so ahead of time. It implies that under business as usual conditions CFS grants get lost in the competitive grant review process and suggests that special circumstances (e.g. RFAs) are needed to get the Institutes to concentrate their focus on CFS. It also indicates that if the NIH is committed to building a viable CFS research program it needs to institute programs with dedicated funding such as RFAs, Research Centers or Centers of Excellence.

The Missing Neuro-immune RFA Grants? Dr. Hanna reported the NIH was pleased with the response of the researcher community to the one funded grant effort for CFS the NIH has produced over the past five years the Neuroimmune RFA of 2006. At one point relatively early in the process Dr. Hanna reported that 29 applications had been received. But the FOIA only lists 16 applications (code (0D06-002) eight of which were rejected immediately (non-competitive), three of which were pending award and have not been funded, and five which were funded.

Its known that early in the process Dr. Hoffeld returned grants he felt did not fit the subject matter of the grant. This raises the question whether Dr. Hoffeld rejected almost half the grants submitted to the RFA panel before they made it to the first review.

Conclusions. CFS researchers have little chance of getting their grants funded under the dominant funding mechanism used in the CFS program at the NIH the program announcement. According the FOIA from 2003 through the first part of 2007 the NIH funded only eight new grants on CFS. These are remarkably low figures for a disease the Department of Health and Human Services own studies shows afflicts approximately a million Americans, causes high rates of disability and costs the economy tens of billions of dollars a year.

Summary Table

Grant Status
Number
Triage Reviewed Judged Non-Competitive
17
Administratively Withdrawn by Institute or Center Director
13
Applications Withdrawn For Amendment
12
Pending Award ($0 Funded)
7
Funded Grants (First time) Awarded
8
Continuation/Enlargement Grants Awarded
9
To Be Paid
4
Total Grant Reviews By CFS SEP 70


*Grey = not-funded
Green = funded


Grant Status Explanation

Triage Reviewed Non-Competitive (17) These grants are given comments but not a full review and are returned to the applicant unscored.

Administratively Withdrawn by the Institute or Center Director (13) these grants made it through the review process and to a final review by the Institutes where they were rejected.

Applications Withdrawn for Amendment (12) These applications were withdrawn for amendment by the applicants. Why this occurred is unclear.

Continuation/ Enlargement Grants (9) These are already awarded grants which came up for review again and were rewarded again. In one case a small (R21) grant was turned into a large (RO1) grant.

Funded Grants (8) As opposed to continuation grants these are new first time applications which were rewarded.

Pending Award ($0 Funded) These are grants which may or may not receive funding in the future but which have received no funding.

To Be Paid (4) These are grants whose funds have been awarded but had not yet been disbursed. Most appear to be continuing funding for first time grants originating in the Neuroimmune RFA; they are not new grants.

_______________________________________________________

APPENDIX: FOIA DATA

NON-FUNDED GRANTS

Triage Reviewed Judged Non-Competitive (17)

Grant Title Investigator PA/RFA Year Award Grant Status
X X X PA02-034 2003 $0 Non-Competitive
X X X PA02-034 2003 $0 Non-Competitive
X X X PA02-034 2005 $0 Non-Competitive
X X X PA02-034 2005 $0 Non-Competitive
X X X PA02-034 2005 $0 Non-Competitive
X X X PA05--03 2006 $0 Non-Competitive
X X X OD06-002 2006 $0 Non-Competitive
X X X OD06-002 2006 $0 Non-Competitive
X X X OD06-002 2006 $0 Non-Competitive
X X X OD06-002 2006 $0 Non-Competitive
X X X OD06-002 2006 $0 Non-Competitive
X X X OD06-002 2006 $0 Non-Competitive
X X X OD06-002 2006 $0 Non-Competitive
X X X OD06-002 2006 $0 Non-Competitive
X X X PA05--03 2006 $0 Non-Competitive
X X X PA05--03 2006 $0 Non-Competitive
X X X PA05--03 2007 $0 Non-Competitive

Made it to the Final Review Rejected (Administratively Withdrawn by Institute or Center Director) (13)

Grant Title Investigator PA/RFA FY Award Grant Status
X X X PA 02-034 2003 $0 Administratively Withdrawn by ICD
X X X PA 02-034 2003 $0 Administratively Withdrawn by ICD
X X X PA 02-034 2004 $0 Administratively Withdrawn by ICD
X X X PA 02-034 2004 $0 Administratively Withdrawn by ICD
X X X PA 02-034 2004 $0 Administratively Withdrawn by ICD
X X X PA 02-034 2004 $0 Administratively Withdrawn by ICD
X X X PA 02-034 2004 $0 Administratively Withdrawn by ICD
X X X PA 02-034 2004 $0 Administratively Withdrawn by ICD
X X X PA 02-034 2004 $0 Administratively Withdrawn by ICD
X X X PA 02-034 2005 $0 Administratively Withdrawn by ICD
X X X PA 05-030 2006 $0 Administratively Withdrawn by ICD
X X X PA 05-030 2006 $0 Administratively Withdrawn by ICD
X X X PA 05-030 2006 $0 Administratively Withdrawn by ICD

Applications Withdrawn For Amendment by Applicant (12)

Grant Title Investigator PA/RFA FY Award Grant Status
X X X PA 02-034 2003 $0 Application Withdrawn For Amendment
X X X PA 02-034 2004 $0 Application Withdrawn For Amendment
X X X PA 02-034 2005 $0 Application Withdrawn For Amendment
X X X PA 02-034 2005 $0 Application Withdrawn For Amendment
X X X PA 02-034 2005 $0 Application Withdrawn For Amendment
X X X PA 02-034 2005 $0 Application Withdrawn For Amendment
X X X PA 02-034 2006 $0 Application Withdrawn For Amendment
X X X PA 05-030 2006 $0 Application Withdrawn For Amendment
X X X PA 02-034 2006 $0 Application Withdrawn For Amendment
X X X PA 05-030 2006 $0 Application Withdrawn For Amendment
X X X PA 05-030 2007 $0 Application Withdrawn For Amendment
X X X PA 05-030 2007 $0 Application Withdrawn For Amendment

Pending Award - $0 Funded (7)

Grant Title Investigator PA/RFA Year Award Grant Status
X X X PA02-034 2006 $0 Pending Award
X X X OD06-002 2006 $0 Pending Award
X X X OD06-002 2006 $0 Pending Award
X X X PA 05-030 2006 $0 Pending Award
X X X PA 05-030 2006 $0 Pending Award
X X X OD06-002 2007 $0 Pending Award
X X X PA 05-030 2007 $0 Pending Award

FUNDED GRANTS

First Time Grants Awarded (8)

Grant Title Investigator PA/RFA Year Award Grant Status
I RO1 HDO43301-01A1 CF in Adolescents Taylor PA02-034 2003 509,257 Awarded
1 R21 AI054478-01 Sleep/Cytokines Natelson PA02-034 2003 629,309 Awarded
1 RO1 ES0115382-01 Proteomics CSF Baraniuk OD06-002 2006 379,720 Awarded
1 RO1 NS055670-01 ANS in CFS Biaggioni OD06-002 2006 385,500 Awarded
1 RO1 NS055672-01 CBT and CFS Antoni OD06-002 2006 342,219 Awarded
1 R21 AA16636-01 Neuropeptide Y Fletcher OD06-002 2006 200,321 Awarded
1 R21 AA167-1-01 Mast Cells Theoharides OD06-002 2006 275,906 Awarded
1 R01 A10565723-01A2 Biomarkers Fletcher PA02-034 2007 381,875 Awarded

Continuation/Enlargement Grants Awarded (9)

Grant Title Investigator PA/RFA Year Award Grant Status
2 RO1 A1054478-02 Sleep/Cytokines Natelson PA02-034 2004 334,904 Awarded
5 R01 HD043301-02 CF in Adolescents Taylor PA02-034 2004 567,009 Awarded
5 R01 A1054478-04 Sleep/Cytokines Natelson PA02-034 2005 643,2007 Awarded
5 R01 HD043301-03 CF in Adolescents Taylor PA02-034 2005 568,159 Awarded
5 R01 A1054478-04 CF in Adolescents Taylor PA02-034 2006 627,427 Awarded
5 R01 HD043301-04 Biomarkers Fletcher PA02-034 2006 499,114 Awarded
5 R01 A1054478-05 Sleep/Cytokines Natelson PA02-034 2007 572,643 Awarded
5 R01 ES015382- 02 Proteomics CSF Baraniuk OD06-002 2007 374,068 Awarded
5 R21 AA016636-02 Neuropeptide Y Fletcher OD06-002 2007 194,989 Awarded

To Be Paid (4)

Grant Title Investigator PA/RFA Year Award Grant Status
X X X PA02-034 2007 481,756 To Be Paid
X X X OD06-002 2007 383,750 To Be Paid
X X X OD06-002 2007 344,250 To Be Paid
X X X OD06-002 2007 153,281 To Be Paid

____________________________________________________________-

Institute Participation

AI National Institute of Allergy and Infectious Diseases (NAIAD) - $3,189,365
HD- National Institute of Child Health and Human Development (NICHD) - $1,644,435
NS- National Institute of Neurological Disorders and Stroke (NINDS) - $737,719
ES National Institute of Environmental Health Services (NIEHS) - $753,788
AA National Institute of Alcoholic Abuse and Alcoholism (NIAAA) - $671,216

Trans-NIH Working is comprised of representatives from nine Institutes with a purported interest in CFS.
 
Hats off to you again, Cort, for another excellent review summarising a vast amount of very useful information.

I think the Fletcher Good Day/Bad Day study is very exciting and, as you say, could change the way research is done if it finds a real difference between the two. It could lead to far more consistent results than we currently see in biologial abnormalities research.

I was also delighted to see that the Lights will be trying to repicate their very interesting findingsfrom earlier coments you reported from Alan Light, I had thought they felt they'd done enough and were moving on to drug testing.

Thanks! The Good Day/Bad study is due to finish up this year. In fact no less than 30% of the NIH funded studies are due to end this year! That means that unless the NIH does something to increase grant application or acceptance rates NIH funding for ME/CFS is likely to drop significantly next year. (That's not easy to do when you're only funding $6 million dollars worth of studies a year).....
 
Thanks Cort, interesting stuff, lets hope something useful comes of it all. As for the depression issue, i have (apart from post natal) never suffered from depression, other than some normal amount of grief due to losing out on the life i wanted for myself. But i do wonder why they dont study anxious patients alongside M.E patoients as so many M.E patients have severe anxiety rather than depression. This has never made sense to me, as there are many who (wrongly ) think of M.E as a type of anxiety disorder rather than a depressive disorder.
Justy.

I have no idea how exactly you would go about disaggregating the symptoms of depression or anxiety as a discrete illness or co-morbid condition from those understandable feelings arising from chronic illlness or depression and anxiety arising from an inflammatory milieu as in heart failure, COPD or indeed ME/CFS (the cytokine theory of depression).

The problem is compounded by instruments like the commonly used Beck Depression Inventory (BDI) that was presumably developed to discriminate cases of depression from healthy controls, not depression as a discrete illness (if there is such a thing) from the symptoms of depression in the chronically ill.

The fact is the BDI includes items that refer to physical somatic symptoms and functional/societal deficits as well as those relating to negative affect. For example :

The Beck Depression Inventory (BDI) is widely used to assess depression in chronic pain despite doubts about its structure and therefore its interpretation. This study used a large sample of 1947 patients entering chronic pain management to establish the structure of the BDI. The sample was randomly divided to conduct separate exploratory (EFA) and confirmatory factor analyses (CFA). EFA produced many satisfactory two-factor solutions. The series of CFA generated showed reasonable fit for ten of those solutions. All included a first factor identified as negative view of the self (items: failure, guilt, self-blame, self-dislike, punishment and body image change), and a second factor identified as somatic and physical function (items: work difficulty, loss of appetite, loss of libido, fatigability, insomnia and somatic preoccupation). The remaining items (suicidal ideation, social withdrawal, dissatisfaction, sadness, pessimism, crying, indecisiveness, weight loss, irritability) loaded infrequently or not at all in the CFA solutions. They did not form a coherent factor but comprised items associated with negative affect.

When compared with published data from samples of depressed patients drawn from mental health settings
the mean item scores for items reflecting the negative view of the self were consistently statistically lower that that observed in samples; there was no consistent difference between the samples on the items reflecting somatic and physical function; but the mean scores for the remaining affect items were significantly greater in the mental health samples. This version of depression is strikingly different from the psychiatric model of depression (e.g. DSM-IV or ICD-10), which is primarily defined by affective disturbance, and secondarily supported by cognitive and somatic symptoms
.

A quick look at the BDI shows how easily it would be to score highly on the depression scale due to physical symptoms and incapacity/doubts about future capacity while remaining resolutely not depressed. Even the one item likely to unambiguously point to depression (suicidal ideation) only scores the same as for the other items :

http://www.mydrrachel.com/docs/BeckDepressionInventory.pdf

Personally, I now just tend to ignore any studies that suggest elevated levels of 'depression' of 'anxiety' as for the reasons above I just consider them additional symptoms and otherwise meaningless.