PHOENIX RISING

Cognizant of the important role these panels play the Center for Scientific Review (CSR) has laid down a series of guidelines and requirements that members of them must meet. A few are highlighted below.

• Candidates must be a principal investigator on a research project comparable to those being reviewed.
• Expertise is the paramount consideration when developing/updating a study section roster
• Each scientific area reviewed by the study section needs an appropriate expert representation.
• Study sections that review multidisciplinary or interdisciplinary applications have a greater need for scientists who have broader expertise.

Because this RFA calls for research exploring the relationship between two large fields, neurology and immunology, and a complex disease, CFS, the need for reviewers with broad and extensive expertise is paramount

The Process - Each reviewer will typically review two or three proposals. Typically about half the proposals are rejected outright, the rest are scored and given written reviews on the proposal’s significance, approach, innovation, investigator’s experience and ‘environment’. and then sent onto another review by the various government agencies involved in this RFA.

At the moment here are two CFS Review Panels; a standing panel that reviews all other proposals for CFS research, and one created specifically to review the proposals in the Neuroimmune RFA, and. We first examine the history of the standard review panel in order understand the context in which the neuroimmune review panel was created.

The CFS SEP’s mandate is to review applications that examine "the causes, manifestations and treatments of the Chronic Fatigue Syndrome, the Fibromyalgia Syndrome and other chronic polysystemic morbidity syndromes." It usually meets three times a year. Despite its title this review panel is not designed solely to review CFS grant proposals. Indeed, the qualifier at the end of the sentence (‘other’ polystemic morbidity syndromes) makes its purview quite open-ended. Still CFS makes up the title of the SEP, it always mentioned first, and it is the primary disease under consideration.

The difficulty with placing different diseases under the purview of one panel, of course, is assembling researchers with expertise in all these areas. This can beeasily achieved if these disorders are allied in significant ways and indeed, in this case, many of them are; fibromyalgia, irritable bowel syndrome, temporal mandibular syndrome and pelvic pain syndrome are all ‘pain diseases’. Pain is their major presenting symptom and the research into them mostly explores ways to explain the heightened pain their patients suffer.

CFS, however, is not a pain disease; it’s the major presenting symptom, the one that essentially defines the disorder, is fatigue. Recent studies indicate that it’s not just fatigue that is so important in CFS but a particular kind of fatigue – post-exertional fatigue – that is its hallmark.  This unusual symptom – not shared by the other diseases under consideration - strongly suggests the central pathophysiology in CFS is unique. While pain can be found in CFS it is only one of eight symptoms the CDC uses to define CFS. Because only four of these symptoms need to be present (in addition to fatigue) CFS patients need not suffer from increased pain in order to meet the criteria for CFS.

Indeed pain is not a major issue for most CFS patients, and has not been even a minor research subject. A review of PubMed citations over the past five years indicated that few studies directly addressed the subject of pain in CFS and none have directly explored its pathophysiology. A 2004 study found that examined the influence of pain on CFS patients determined that it was a not a factor in the activity restriction seen in CFS (Nijs et. al. 2004). That a key finding in FMS research – increased levels of the pro-pain compound substance P – is not found in CFS, suggests that the central pathophysiology of the two diseases is different.

Dr. Hofford, the CFS SEP's organizer, however, has stated that it’s to ‘everybody’s advantage to have them (the polysystemic morbidity syndromes)…. all considered together". This statement flies in the face of much of the current thinking on CFS. Instead of being subsumed into a larger disease category most thinking on CFS posits that CFS should be sub typed further (Jason et. al. 2005), and that our inability )or unwillingness) to do so has contributed to some of the heterogeneous findings found in CFS research (Spence, 2005). The CDC – which recognizes this concern – recently participated in several studies designed to delineate the heterogeneity present in CFS.  What is needed in CFS is lesser but greater differentiation.

The danger in lumping CFS in with a number of pain rather than fatiguing diseases is the creation of a review board that sees these diseases through a paradigm appropriate not for fatigue but pain. A shrewd organizer might be able to create a board diverse enough to accommodate the different research issues but a poor organizer will weight the board towards one of the different emphases present. As we shall see this is exactly what has happened. Researchers with expertise in pain and behavioral issues have dominated the SEP panels put together by Dr. Hofford and many areas of current research in CFS have not been represented.

A Continuing Source of Concern -The makeup of the Review Committee and its decisions have been an object of concern for CFS researchers and advocates for some time. Even as NIH funding has doubled in the past five years funding for CFS research has dropped. This in combination with low approval rates for CFS research proposals has lead CFS advocates to charge that the NIH in general, and the CFS SEP panels, in particular, exhibit bias.

In particular, CFS advocates propose that the review panels created by Dr. Hofford lack the expertise to review the grants before them. They believe the presence of a review panel top loaded with researchers knowledgeable in pain and frequented by reviewers with no knowledge of the issues concerning CFS gives many CFS researchers little confidence that their grant proposals will be given a fair hearing. Some believe that has lead some CFS researchers to simply pull out of the process.

Craig Maupin’s review of the 2004 CFS SEP found few reviewers with research interests in CFS (6), a predominance of reviewers with a background in pain, and containing reviewers with expertise in subjects like drug abuse, opiate management, retardation, spiritualism, psychosis and urological disorders. Of the six with CFS research interests half focused on behavioral aspects of the disease.

The review panels for 2005 CFS SEP fared no better; more than half the reviewers have a background in pain/fibromyalgia, and only two of the thirty-seven had published on CFS (click here). Only nine of the 37 reviewers have expertise in fields relevant to CFS and almost half of these are focused on sleep abnormalities, few of which have been identified in CFS. It is remarkable given the rich field of CFS immunology that only three of 37 reviewers have immunological expertise. Even the reviewers with immune research backgrounds have little expertise (e.g. brain mast cells, asthma) in the immunological issues relevant in CFS. Even more startling are the large number of reviewers (15) whose research interests had no discernable connection to CFS (dental pain, chiropractic, law and autism, exercise and smoking, hypertension/micturition, chronic pain, migraine, pain and alcoholism, etc.).

A December 2005 letter from the Chairman of the Board (Susan Jacobs) and President/CEO of the CFIDS Association of America (CAA) (Kim McCleary) to Vivian Pinn, the Asst. Director of the ORWH, indicated that the CAA had objected to the makeup of the SEP Panel ‘on multiple occasions’. The CAA concluded that despite their attempts to be ‘collaborative’ and ‘reasonable’ their concerns had, once again, been ‘largely ignored’. They noted the dismay expressed by CFS researchers at the limited understanding of CFS the reviewers comments on their applications reflected. The inability of some researchers with long track records of success in other fields to get their CFS studies approved suggested that the SEP panel was riddled with bias or incompetence or both

Dr Hofford implies the review panels makeup may not reflect many CFS research interests because they are dealing with cutting edge research. "If it is brand new to being applied to this particular syndrome, then we need to have people who have used it in related conditions". It is certainly true that in rapidly evolving interdisciplinary fields such CFS the pace of knowledge may at times outpace the expertise of some researchers. Indeed a panel composed solely of CFS researchers might lack sufficient breadth to rapidly move the field forward. The NIH can hardly be accused of providing cutting edge research in CFS. however. In fact a lack of innovation is one of the key complaints that CFS advocates have towards the NIH.

One area the NIH has been ahead of the curve has been on circulatory issues and orthostatic intolerance. Yet only one out of some 30 odd reviewers in 2004 and 2005 had expertise in this field. One wonders how the few immune studies, one of which resulted in an important 2005 paper on NK cell function, managed to get funding given the low levels of immunological expertise found on the panels. Several of the innovative studies the NIH has funded in the last five years appear to have occurred despite the review panel expertise not because of it.

Dr. Hoffield asserts that if the CFS community does not like the kinds of studies being funded it is because the review panel is not getting the kinds of proposals the CFS community wants. He contradicts his former statement regarding ‘brand new’ research when he suggests that field of CFS research is actually in a kind of stasis. "My study section can only evaluate the applications being submitted. And, the applications being submitted are emphasizing palliative care more than they did in the past, and that is simply because that is what people are thinking about these days. They are sort of waiting for the next breakthrough in the technology to be able to study new things like biomarkers or diagnostic approaches".

It is hard to understand how this can be so given the rapid growth of the field over the past several years. Many of the studies now being released were funded not long before Dr. Hoffield made this statement. Recent papers in CFS have uncovered a possible biomarker in the brain, reduced brain blood flows, altered patterns of brain activation, evidence of increased serotonin levels in the brain, increased oxidative stress, altered post-exercise muscle activity, etc..  Either the NIH is not receiving proposals that could lead to breakthroughs because the researchers engaged in that kind of research do not feel it is viable source of funding for them, or the NIH often hasn’t recognized that kind of proposal when confronted with it.

Dr. Hofford assures us that "There are certainly always people in the room who have hands on experience with the disease [CFS]." That Dr. Hofford felt the need to make a statement like this regarding a review panel for CFS in itself speaks volumes. A few CFS experts in a sea of pain researchers can hardly have a substantial effect. The scoring that is so important to a grants success is carried out by individual reviewers not the panel as a whole. Since grants with low scores are almost automatically rejected a CFS grant given low initial scores will not be aided by the presence of a few CFS researchers in a large panel.

Aside from the new funding it provided the CAA was particularly interested in the Neuroimmune RFA because it allowed for the creation of a review panel outside the purview of the Center for Scientific Review. In this case the overseer of CFS research for the NIH - the Office of Research for Women’s Health (ORWH) - had the option of creating the new review panel. The depth of the CAA’s concern at the current review process can be seen in the ‘enormous disappointment’ the CAA expressed to Dr. Pinn when they learned that the CSR and Dr. Hofford had been slotted to create the review panel for the RFA,

We know Dr. Hofford’s past review panels have had a heavy emphasis on pain. But this is a new review panel with a more specific mandate. The RFA was largely focused on immune activation, endocrine dysregulation and altered neurotransmitter levels (See Reading the Grant). Only indirect notice was given to FMS and/or pain (e.g. polysystemic disorders). The types of researchers Dr. Hofford has emphasized in the past are clearly not appropriate for this panel.

Researchers with A Background in Chronic Fatigue Syndrome (4) – As noted earlier the CAA has been particularly perturbed by the CFS researchers on the panels reviewing proposals for CFS research. The ideal reviewer for this RFA would have expertise in CFS and neuroimmunology. Unfortunately few researchers with experience in all three fields are available. Many researchers have, however, have examined the neurological or immunological aspects of CFS. Dr. Hofford, however, did not take advantage of this resource, only four of tne 25 reviewers had expertise in CFS. Three meet the grounds for expertise in neurological or immunological issues, one, Taylor, despite being well published in CFS, did not.

Researchers with A Background in Neuroimmunology (8) – The researchers with a background in neuroimmunology have a strong focus on cytokines – a focus that is welcome and germane to the issues at hand. Their perspective on cytokines is heavily slanted, however, towards their role in contributing to mood disorder, a secondary consideration in CFS not fatigue, the primary consideration. A recent study found that the rate of depression is no higher in CFS patients than in multiple sclerosis, a disorder in which increased fatigue has recently been linked to increased cytokine production.

A rich field of cytokine/fatigue research was ignored both on this panel and in the Neuroimmune Conference. Cytokines are believed to contribute to fatigue in infection, cancer, multiple sclerosis, rheumatoid arthritis, hepatitis C and cholestatic liver disease and are believed to contribute to cognitive impairment in multiple sclerosis and cancer. Furthermore, cytokine production in the brain following muscle damage has been tied to delayed recovery, perception of effort and pain. It is remarkable given the richness of this field that Dr. Hofford has been unable to find one reviewer with expertise in it.

Researchers with A Background in Pain/Fibromyalgia (7) –Outside of two brief references to FMS (e.g. a ‘spectrum disorder’), nothing in the RFA suggested the NIH was interested in pain research. Yet there are almost as many reviewers with an expertise in pain/FMS on the SEP than on neuroimmunology. This board, in fact, shows greater expertise in pain than in its putative subject CFS.

This was not entirely surprising. As noted above Dr. Hofford has consistently packed the CFS SEP’s with large numbers of pain/FMS specialists. It suggests that Dr. Hofford either deliberately ignored the emphasis of the RFA when assembling the review panel or that it was never wholly intended for research into CFS. If the later turns out to be the case it will be disappointing for CFS patients and their advocates but not entirely surprising. The CDC misappropriation of millions of dollars of funds earmarked for CFS in the late 1990’s resulted in a congressional investigation ead to the imposition of a independent review panel. The NIH has increasingly attributed to ‘CFS research’ projects with only a peripheral connection to it. It would be unfortunate if this apparent ‘breakthrough’ in CFS funding that was so eagerly greeted by the CFS community became a means for further estrangement but it would not be entirely surprising.

Researchers with A Background in Neurology (4) – The backgrounds of the neurological researchers are remarkably varied. display little coherence. Hershey fails the test of expertise in two ways, subject matter and expertise. Primarily involved in the clinical not the pathophysiological aspects of migraine he lacks the expertise to review proposals of a pathophysiological bent. Malone’s current emphasis on lumbar disc degeneration has no discernable connection to CFS. Goolkasian’s emphasis on presentation and recall suggests she will be used to review projects involving cognition. Her focus on how presentation (i.e. words vs sounds vs types of formats) influences recall, however, has little connection to cognitive problems evidenced by CFS. It is surprising, given the amount of research devoted to the neuropyschological aspects of CFS, that no researchers involved in the field could be found. Despite the tenuous connection that marine neurotoxins have to CFS Sopori’s research in the effects of marine neurotoxins on rats, amazingly enough, makes him the most relevant researcher with a background in neurology, given the rapid growth of interest in this field in CFS. None of these researchers demonstrate expertise in aspects of neurology that are of current interest in CFS such as immune activation, reduced corticomotor excitation, depressed basal ganglia functioning, compensatory brain activation, etc.

Researchers with A Background in Immunology (3) – Dr. Hofford’s CFS SEP’s have always displayed little expertise in immunology and this one, despite its stated focus on immune issues, is no different. In contrast to the neurological researchers, however, these panelists do have the expertise to serve on this panel. Kenney’s research interests extend to EBV, a virus able to infect the brain, Taylor has published on viral gene expression, nitric oxide and IFN therapy.

Researchers with no expertise in CFS, neurology or immunology (4) - This grouping involves researchers without experience in any of the issues raised by the RFA. It is difficult to come up with a rationale for presence of any of these researchers on this review panel. Three have expertise in psychological/behavioral subjects (sexual content TV shows, HIV and anxiety, depression and CBT, adolescent mental health). One might have made a case for two of these reviewers on a general CFS panel given the psychological orientation some researchers have toward CFS but the Neuroimmune RFA specifically states it is designed to promote proposals examining neuroimmune mechanisms in CFS, not psychological ones. A last reviewer has expertise in cystic fibrosis.

Conclusion: This review panel is better than the 2004 and 2005 panels. More CFS researchers are present and the expertise of the panel better reflects its mandate. Better is not necessarily good, however. While this review panel is better than the 2004/2005 panels, it could be argued, given those panels, that it could hardly have been worse. Much of this panel still fails the first criteria of the CSR that "Candidates must be a principal investigator on a research project comparable to those being reviewed"

Assuming 30 applications were received the low number of CFS researchers on the panel indicates that about 60% of the grants will be decided by reviewers with no history of CFS research. Given the voluminous literature produced on CFS over the course of almost 20 years (>3,000 papers) this is clearly an unacceptably low number of researchers with expertise in this field.

Despite repeated requests by the CAA and others that the CFS review panel contain substantial numbers of CFS researchers and that the panel display an expertise appropriate to its subject matter Dr.Hofford has once again assembled a review panel light on CFS researchers, heavy on pain researchers and with a significant number of panelists with little or no expertise in the subject matter before them. If the goal of this panel were to review grants for studies on Fibromyalgia/pain then Hershey. Goolkasion, Mauderli, Pezzone, Plesh, Zhang are appropriate choices. If instead it was set up to review neuroimmune grant proposals on CFS l then these reviewers are clearly inappropriate.

Even if one stretches to include some panelists with peripheral connections to the research issues in CFS, it is impossible to make a convincing case for a substantial number of the panelists. About twenty-five percent of the panel ISandy Berry, Lucille Eller, (Andrew, Hershey, Andre Mauderli, Dan Malone, Robert Roberts, Robert Tarran) have no expertise in the issues they are likely to face. Others are quite marginal (Paula Goolkasian, Michael Pezzine, Octavia Plesh, Mohan Sapori) others are satisfactory (Michael Irwin, James Jones, Randy Nelson, Peter Rowe, Ann Silverman, Renee Taylor) and some appear to be excellent choices (Mahendra Kumar, Gundrun Lange, Jon Russell, Shannon Kenney, Charles Raison, Peter Rowe, Jerry Taylor).

Dr. Hofford has again assembled a panel in which specialists in the disease under review are under represented and with a significant number of reviewers with no expertise in the issues under review. While this panel is better than those before it does not meet the standards of expertise laid out by the Center for Scientific Review.

Should Dr. Hofford continue assembling review panels for CFS? It is important that the researchers studying CFS have the confidence that the proposals they submit for review will get reviewed by panelists with expertise in their field. CFS is a multi-dimensionary field in which studies on the brain, the cardiovascular system, metabolism, immunology, oxidation, etc are published every year. While virtually every paper on CFS begins with a short statement expressing the continuing mystery of its pathophysiology Dr. Hofford has apparently decided he knows better as he has consistently assembled teams that little reflect the rich milieu of CFS research. Entrusting review panels to an official who has repeatedly demonstrated he have no interest in much of CFS research is contrary to the strictures of the CSR that reviewers remain abreast of the fields they are overseeing.

Twenty-five people are reviewing the 30+ proposals reported received.

Chairperson – The chairperson, Dr. Peter Rowe, is indeed well versed in CFS research. The first researcher to uncover the orthostatic intolerance existing in some CFS patients, Dr. Rowe is a choice that most CFS patients and advocates will be happy to see.

James Jones – has been involved in variety of different studies involving orthostatic intolerance, gene expression, viral persistence in CFS patients for the CDC.

Gudrun Lange – has been involved in several neurological studies of CFS.

Peter Rowe – uncovered orthostatic intolerance in CFS

Renee Taylor – has published numerous papers on the clinical aspects of CFS (subtypes, attributions, diagnostic criteria)

Researchers With A Background in Neuroimmunology (8)

Michael Irwin –has a particular interest in cytokines and sleep and has authored several papers on alchoholism, African Americans, cytokines and sleep. He has also co-authored several papers on depression and cytokines.

Mahendra Kumar – has researched neuroimmune aspects of HIV, CRH (endocrinological) administration and depression and HIV.

Randy Nelson – Randy Nelson’s study on nitric oxide and the HPA axis was directed towards nitric oxides effects on psychological attributes (aggression).

Michael Pezzone – has published several studies on neurological and immunological aspects of chronic pelvic pain and/or irritable bowel syndrome.

Charles Raison – has published extensively on stress and depression; his particular focus is on interferon alpha, depression, hepatitis C and the HPA axis.

Jon Russell– is the editor of the Journal of Muscoskeletal Pain. He has done extensive research into Fibromyalgia involving interferon alpha, nitric oxide and substance P.

Mohan Sopori – has published several studies on the effects of inhaling the marine neurotoxins (brevitoxins) produced by red tides on laboratory rats.

Jun-Ming Zhang – has published on neuropathic pain and inflammation (tumor necrosis factor) and as such has a background in neuroimmune issues. His research has a strong focus on pain.

Researchers With a Background in Fibromyalgia and/or Pain (7)

Andre Mauderli – has an extensive resume involving the perception of pain that includes several on fibromyalgia.

Octavia Plesh – has extensive experience in dental pain.

Plus Goolkasian, Hershey, Pezzone, Russell, Zhang.

Shannon Kenney - has extensive experience in viral immunology (EBV).

Ann Silverman –has published extensively on the roles mast cells play in the brain.

Jerry Taylor – has published on the vascular effects of nitric oxide and sympathetic nervous system activation and nitric oxide/cytokine interactions.

Paula Goolkasian – for the past five years Paula Goolkasian has been mostly involved with studies focusing on how the format of a presentation affects recall; i.e. whether the spoken or written word leads to better retention of it – thus she has a background in cognition. She has also been involved in several projects measuring neck pain.

Andrew Hershey – has been the lead author in many studies involving pediatric migraine but, with the expression of some studies on gene expression in which he was not the lead author, has been entirely involved with clinical aspects of the disease; i.e. treatment, diagnosis, grading disease severity, etc. He has done no research on the neurological or immunological aspects of migraine.

Daniel Malone – has been involved in lumbar disc degeneration. In the early 1990’s he co-authored several papers on the role mast cells play in arthritis.

Sandy Berry – a putative specialist in research design, Sandra Berry has virtually no experiencing in designing biological studies. Her most recent project involved determining the effects of the sexual content of TV shows on teen behavior She’s also been involved in studies on HIV care giving and research costs and on stress levels after 9/11.

Lucille Eller – has been heavily involved with quality of life issues. Like Sandra Berry she has no experience in biological studies. The behavioral sciences studies she has been involved in include self care strategies for HIV patients with depression, HIV and anxiety, fatigue and HIV, and cognitive behavior therapy for people with HIV. Her resume does not indicate she has any experience with or interest in the very technical field of neuroimmunology.

Robert Roberts – has studied adolescent mental health.

Robert Tarran’s – research over the past five years has consisted almost entirely on the dynamics of the airway surface liquid layer in cystic fibrosis patients 

 Neuro-Immune RFA Intro / The Neuro-Immune Conference / The RFA Grant / Reviewing the Reviewers / Conclusion: Assessing the Grants

________________________________