Junk Science – Junk Ethics

In December 2012 ‘Unique immunologic patterns in fibromyalgia’ was published as Behm et al. BMC Clinical Pathology 2012, 12:25 http://www.biomedcentral.com/1472-6890/12/25. The authors measured cytokine levels in the blood of 201 subjects (110 with fibromyalgia). They concluded ‘The cytokine responses to mitogenic activators of PBMC isolated from patients with FM were significantly lower than those of healthy individuals, implying that cell-mediated immunity is impaired in FM patients. This novel cytokine assay reveals unique and valuable immunologic traits, which, when combined with clinical patterns [italics mine], can offer a diagnostic methodology in FM.’

In April 2012 a company called EpicGenetics filed a patent for ‘A method of diagnosing and treating fibromyalgia.’ (http://patentscope.wipo.int/search/en/WO2012051317) They wrote:

The invention provides methods, kits and reagents for diagnosing fibromyalgia (FM) in an individual by determining whether the levels of one or more cytokines in the individual are altered, as compared to control levels. The altered level(s) or patterns of expression of the cytokines measured in the affected individual compared to the level from the control is predictive/indicative of FM in the individual.

In March 2013, EpicGenetics started selling the ‘test’ for $744 to physicians and directly to patients (http://thefmtest.com/about-the-fm-test/). This test is unlikely to be reimbursed by insurance companies. In the BMC Pathology paper they `declared that they have no competing interests.’ Either they forget to tell the reviewers they were about to market the ‘test’ or they concealed it. There was a lot of money involved for the company and Dr. Gillis, and it is almost certain that the reviewers would have taken note of this fact. If the authors just ‘forgot’ and asserted no conflict, they still had a lot of time to correct the error and to tell the journal.

Cytokine levels are abnormal in many physical and mental conditions. The authors studied none of those conditions. They provided almost no information about patient selection or many other vital data for a comparison trial. The CONSORT statement on publishing trials offers guidelines on the reporting of data. They didn’t follow these guidelines. As a clinical study, it was very poorly planned and carried out. As a pathology report it might pass. But the data did not in any way addresses the validity and reliability of their ‘test’ to diagnose fibromyalgia. I conclude that they (EpicGenetics and Dr. Gillis) were trying to fool people into buying the scientifically unproven $744 test.

For such an ethical violation, BMC Pathology should withdraw the paper. Want to diagnose fibromyalgia? Talk to the patient. In less time than it takes to get the blood drawn you can have the diagnosis (free!).

16 Comments

  1. Fred, well spotted (as they say). No mention is made of the funding source, either! Was it Bruce Gillis Inc? I agree that the Editor(s) of BMC Pathology need to be made aware of their serious lapse in ethical behaviour. Those who were appointed as independent expert reviewers may also be at fault.

  2. Dear Fred, like you I am most surprised that the manuscript was accepted for publication, particularly when one reviewer commented:

    “The authors have addressed most of the reviewer`s questions, however, the
    reviewer still has some major concerns. This study investigates serum samples
    of FMS patients using one single method and claims to have found the “unique
    pattern” of cytokines in FMS patients. This title is misleading and not well based
    by the data shown and the methodology used. A second method is obligatory
    especially when investigating such a “fragile system” as cytokines that may be
    influenced by many factors and when investigating a non-well defined condition
    such as FMS with an inhomogenous patient cohort – even when using the ACR
    criteria. Otherwise this study will merely add another one to the large body of
    literature on cytokines in FMS, but of unclear significance.”

  3. Dear John, I agree. I have had notes from other rheumatologists sharing our viewpoint. The journal is looking into my complaint and suggestion that the article be retracted because of failing to disclose conflicts. It’s important here because there is an appearance of concealing things to make the sale of test go smoothly.

    Friedman et al. in 2004 studied articles from the New England Journal of Medicine and the Journal of the American Medical Association. They reported:

    “We observed a strong association between those studies whose authors had COI and reported positive findings (P < .001). When controlling for sample size, study design, and country of primary authors, we observed a strong association between positive results and COI (ICMJE definition) among all treatment studies (adjusted odds ratio [OR], 2.35; 95% confidence interval [CI], 1.08 to 5.09) and drug studies alone (OR, 2.64; 95% CI, 1.09 to 6.39)."

    "CONCLUSION: COI is widespread among the authors of published manuscripts and these authors are more likely to present positive findings."

    There is general scientific consensus that patents represent conflicts of interest and must be reported, and that conflicts of interest are often associated with positive study results.

    And there are all the other problems that you noted. Conclusion: not so fast on a test for FM. And see my post on the continuum of polysymptomatic distress.

  4. Fred, there have been some changes made on the EpicGenetics website. The picture of Dan Wallace no longer appears and his reported comments have been considerably modified. There has also been a significant change in Dan’s designated role on their Scientific Advisory Board. Their Facebook page seems to have disappeared.

    The link to the Fox News report on the “test” now appears on the Face Book page of Arthritis and Osteoporsis WA and has been sent to our local FM Consumer organization.

    In the words of Sir William Osler: “When mammon enters the room, science jumps out the window.”

    • Dr Wolfe. I think I need to apprise you of John Quintner and how he is representing your work on my facebook page.

      In response to my announcement of the cover article in the Fibromyalgia and Chronic Pain Life regarding the Behm, et al study, “A unique immunological pattern has been found in fibromyalgia.”

      From John Quintner, “Save your money. It is NOT a test for Fibromyalgia. Junk Science – Junk Ethics! See Fibromyalgia Perplex, a blog by Professor Fred Wolfe.”

      I have given a commentary on the research, which you can access from my blog. Biological marker for fibromyalgia is challenged- No surprise
      http://fmcfstriggerpoints.blogspot.com/2013/03/biological-marker-for-fibromyalgia-is_8.html#.UTozlRx18yI

      Celeste Cooper, RN, BSN, author, http://TheseThree.com, Fibromyalgia expert http://www.sharecare.com/user/celeste-cooper, participant in the Pain Alliance to Implement a National Strategy http://www.painsproject.org

      • Dear Celeste. For the record, here in full is my response to your article on “the test”.

        “Yes, it is really a big deal Celeste. But one more in hype than hope. Failure of researchers to have disclosed their conflict of interest, as happened with the paper from Gillis et al., is inexcusable.”

        You and I have disagreed in the past, but this is an issue of great importance to your constituency and I felt it only fair to point out the flawed nature of the conclusions being drawn from the research by those who are marketing the test.

      • Dear Celeste. I revisited your website only to find that you are still promoting myofascial “trigger points” as a possible source of ongoing nociception in patients with Chronic Widespread Pain (Fibromyalgia Syndrome). As I have tried in vain to explain to you, this notion is highly speculative and is insufficient justification for well-meaning therapists to launch their “search and destroy” operations within the voluntary muscles of sufferers. I know that other “fibromyalgia experts” share your belief system but members of your large constituency deserve at least to be told that there are other respectable opinions out there that are not in accord with those that you are currently promulgating from your website.

  5. I strongly agree with Dr. Quintner. I addition, I do not see this a evidence of an immunological disorder. Here is a statement that I had written previously, but had not placed on this blog. I deal specifically with my objections to the FM test in a little more detail.

    My Coments

    Concerning patents, my objection is not to applying for or having obtained a patent, it is about the failure to disclose the patent. After an Internet search, I conclude that almost every medical journal that describes conflicts of interest in detail requires reporting of patents applied for, pending or received.

    Writing “A Common Standard for Conflict of Interest Disclosure” for the Center for Science in the Public Interest, Goonzner et al.1 write:

    Scientific discourse depends on objectivity. The conduct of science can be influenced by biases introduced by conflicts of interest, whether they are financial, professional, intellectual, or fueled by academic competition. The potential for bias is real, whether or not researchers believe those conflicts of interest influence their conduct.

    “Relevance for patents is defined as any invention or pending invention connected in any way to the subject. Since relevance is often in the eye of the beholder, you should err on the side of full disclosure in drafting the disclosure statement.”

    They require reporting of “Patents granted, pending and applications, whether or not generating royalties.”

    Friedman et al. in 2004 studied articles from the New England Journal of Medicine and the Journal of the American Medical Association.2 They reported:

    We observed a strong association between those studies whose authors had COI and reported positive findings (P < .001). When controlling for sample size, study design, and country of primary authors, we observed a strong association between positive results and COI (ICMJE definition) among all treatment studies (adjusted odds ratio [OR], 2.35; 95% confidence interval [CI], 1.08 to 5.09) and drug studies alone (OR, 2.64; 95% CI, 1.09 to 6.39).

    CONCLUSION: COI is widespread among the authors of published manuscripts and these authors are more likely to present positive findings.

    From the above brief excerpts, I conclude that there is general scientific consensus that patents represent conflicts of interest and must be reported, and that conflicts of interest are often associated with positive study results.

    The FM Diagnostic Test

    As a preliminary report, your BMC paper is of considerable interest. You make some assertions about fibromyalgia that I might not agree with, but that is your right. My concern is with the extrapolation of the data from your study to a diagnostic test. I will only comment on a few problems.

    1) Diagnostic tests have an intended population: patients for whom the diagnosis is uncertain. So, patients with pain or some fibromyalgia symptoms would be the intended population. But your controls were “healthy donors.” It is not possible to estimate diagnostic properties of a test when the control population is not the population that the test will be used upon. Note the various American College of Rheumatology studies employed substantial pain controls.

    2) Second, it is necessary to explore illnesses that are similar to fibromyalgia or have symptoms that common to fibromyalgia to determine if the test is specific to fibromyalgia.

    3) The characteristics of the fibromyalgia subjects are important. We have no way of knowing how typical your subjects were.

    Based on these three items, I conclude that you do not have sufficient data to determine a measure of test accuracy regarding differentiating fibromyalgia from patients with similar non-fibromyalgia disorders.

    Here are some of your statements and claims that I found on your web site.

    Statement: This novel cytokine assay reveals unique and valuable immunologic traits, which, when combined with clinical patterns, can offer a diagnostic methodology in FM.

    Comment: “combined with clinical patterns?”

    Statement: FM/a® is a multiple biomarker-based test, which measures protein molecules called cytokines within white blood cells, a key part of your immune system. People with significantly lower cytokine levels have fibromyalgia. It uses a 1-100 point scoring system to determine diagnosis, and it calculates a positive fibromyalgia diagnosis as a score between 50 and100 points.

    Comment: Impossible from your study sample.

    Statement: FM/a® is more than 93 percent sensitive, a sensitivity comparable to the HIV blood test. By comparison the rheumatoid arthritis blood test is only 65 percent sensitive. No medical test is 100 percent accurate.

    Comment: Impossible from your study sample

    Statement: Fibromyalgia and Chronic Pain Questionnaire

    Comment: With your pain questionnaire you already have most of the diagnosis.

    Statement: Who should have “The Fibromyalgia Test – FM/a ®”

    If you have a personal medical background where you possess some or all of the recognized manifestations of fibromyalgia for several months or longer, then after discussing with your doctor and healthcare professionals your symptoms, you are a candidate for this test which can confirm the diagnosis of fibromyalgia in you. The specific traits of fibromyalgia include:

    Comment: you didn’t test those with some of the symptoms. Based on the data you have, you did not test how well you could diagnosis fibromyalgia.

    Statement: Those who have previously been diagnosed with FM may want to have the test because — until you have the test — you cannot be sure that your diagnosis has been accurately confirmed.

    Comment: simply not true.

    Statement: Also, once a baseline level of FM activity has been achieved via your test score, you and your doctor can monitor the effectiveness of your treatment via objective parameters- hence you will know whether you are improving due to that therapy or not versus just feeling better because of a placebo effect.

    Comment: You have no data on this point.

    Statement: One may also want to consider having the test to potentially eliminate other diagnoses — like depression — being made incorrectly.

    Comment: You have no data on this point.

    Stement: “The Fibromyalgia Test – FM/a ®” has made what will no doubt be the first breakthrough in diagnosing, understanding and treating this medical illness.

    Comment: No doubt?

    Statement: The FM/a® Test is the first test to objectively diagnose fibromyalgia via a simple blood test, with results usually available in one week or less.

    Comment: Simply not true with your data.

    Statement: The FM Test fundamentally shifts the way fibromyalgia is perceived. Previously, fibromyalgia was thought to be a syndrome (subjective collection of symptoms), but The FM Test proves that fibromyalgia is an immune system disorder and a real disease.

    Comment: Simply not true with your data.

    The FM Test is sensitive to more than 93 percent, a high degree of accuracy.

    Comment: Simply not true with your data.

    Statement: Q: Who should be tested for fibromyalgia? What are the symptoms?
    Individuals who experience two or more of the following symptoms should consider being tested for fibromyalgia:
    · Chronic pain
    · Poor sleep
    · Frequent headaches
    · Chronic fatigue
    · Depression
    · Joint aches
    · Leg cramps
    · Numbness
    · Tingling
    · Poor memory
    · “Brain fog”
    · Anxiousness

    Comment: Not true.

    Statement: Q: Is The FM Test the first test for fibromyalgia?
    Yes. The FM Test is the first conclusive test to objectively diagnose fibromyalgia via a blood test, usually providing results in one week or less.

    Comment: Simply not true with your data.

    Statement: Q: What are the implications for this diagnostic test for fibromyalgia?
    Conclusive research now establishes that fibromyalgia is an immune system disorder, not a syndrome. This creates a paradigm shift in the way fibromyalgia is perceived.

    Comment: Simply not true with your data.

    Statement: Q: Who has endorsed The FM Test?
    The FM Test has received support from leading experts in the fields of immunology and rheumatology, at universities such as Harvard, Cornell, UCLA, University of Texas and the University of Illinois at Chicago.

    Comment: You might tell just who is endorsing the test.

    To summarize, your data are insufficient to make any of the above claims. While your research may offer a path to better understanding of fibromyalgia, your diagnostic test is misleading and intellectually and financially harmful in my opinion.

    Fred Wolfe

    1. Goozner, M. et al. (Washington, DC: Center for Science in the Public Interest, 2008).
    2. Friedman, L.S. & Richter, E.D. Relationship between conflicts of interest and research results. Journal of general internal medicine 19, 51-56 (2004).

  6. Dr Wolfe, I appreciate your review of the FM test. You bring up many good points. First, this is not MY test. I have no affiliation with it, only to report on it via my blog. I hope you agree that it does however, open the door for more research on cytokines in FM. This is certainly not a new theory and I have followed this connection for over a decade.

    In the Preliminary Proposed Diagnostic Criteria, you define symptoms of several autoimmune disorders to be considered in FM. I believe, based on your own data, that there could certainly be a reason why certain disorders, such as AS, RA, Sjogrens, SLE, IC (possibly Hashimoto’s, there is some research, but minimal), hypothyroidism, etc. cluster with FM. Also noted in the PPDC are symptoms compatible with autonomic effects such as NMH, POTS, IBS, loss of HRV. Then we can kick in Raynaud’s and PLM during sleep. I believe there is a shared myofascial component with many pain disorders, but particularly with FM including migraine, IC, and restless leg, and I do believe there is a cervical connection (also having a strong myofascial component) in some subgroups of FM. I believe sleep studies should be a given for the FM patient, because non-restorative sleep is a primary symptom of FM, along with body-wide pain and cognitive deficit. More research is needed in how to target dysfunctional sleep stages, that seem to set FM apart from other pain disorders.

    Personally, I have a great pain management doctor who does the work of Travell and Simons. She is integrative in her approach, and has brought me a great deal of pain relief, and I don’t think consideration for comorbid MPS should be ignored. As most FM patients, I do not tolerate a great deal of medications used to treat it. I am now using a compounded cream prescribed by the pain specialist. It is composed of Baclofen, lidocaine, gabapentin, flexeril, a calcium channel blocker, and some other medications. It is the first topical agent to really work. I understand that this is purely an anecdotal remark on my behalf, but I suspect because Medicare does cover it, when they seldom cover compounded agents, I am not the only one to benefit from it.

    I couldn’t agree more that all these things you mention should be considered, but I do believe we should embrace science with guarded optimism, have an open mind and a willing heart. I do have reservations regarding the FM test being released so early in the phase, and I don’t want to see what happened with XMRV and CFS/ME to reoccur with this test and FM. I did revise my blog, once my initial enthusiasm calmed down. As a fellow educator, I am sure you can appreciate that all considerations are subject to revision.

    ” We will continue on in our current treatment plan, just as those with other syndromes, such as rheumatoid arthritis, systemic lupus erythematosus, and many others for which we have no cure. The test may be cost prohibitive and maybe we should exercise patience until replicated and larger studies are implemented. If it bears out, then insurance companies should not deny reimbursement. But until then, this research and the test developed by Dr. Gillis is a really BIG deal, researchers have been working on a biological marker, have felt it was around the corner and the corridor of light could be staring us straight in the face, there is hope.”

    There must always be hope for the patient. I do not want to encourage false hope, and although JQ and I disagree on a great deal of issues, there are a few things on which we do agree.

    I strongly believe in the mind-body connection, thinking affirmatively, and the association of physical, socio-economic, psychological and spiritual effects of managing chronic pain from any source. It takes a balanced coping endeavor for optimal outcome, and our current thinking and cultural beliefs need some help as defined in the IOM Report “Relieving Pain in America.” You are welcome to see our work at http://www.PAINSproject.org

    In healing and hope, Celeste Cooper

    • You misread the ACR criteria when you write the criteria “define symptoms of several autoimmune disorders to be considered.” The criteria refer to symptoms that are present in humans irrespective of disease. There is no clustering between FM and the diseases and syndromes you cite. FM occurs in all diseases and illnesses, but more often in diseases that cause pain or are worrisome. And it is common in osteoarthritis and back pain syndromes, which are not autoimmune at all.

      In addition, the criteria do not ask about specific symptoms; they ask about the burden of symptoms. The long list attached to the criteria paper are presented as examples that physicians ‘might’ consider in assessing total burden.

  7. Celeste, we do indeed disagree on some important issues, not the least of which is your resolute espousal of the “myofascial pain/trigger point” hypothesis advanced by Drs Travell and Simons in the early 1980s. Despite the devastating critique of their work that we published in 1994,* the mythology of the “trigger point” as a source of nociception (i.e. primary hyperalgesia) has not disappeared. Your belief that “there is a shared myofascial component with many pain disorders” is completely lacking in scientific credibility. I have carefully followed the extensive literature published since 1994 and cannot find therein any evidence that would sway me towards your point of view. Moreover, systematic reviews have consistently failed to support the efficacy of “trigger point” therapy.

    *Quintner JL, Cohen ML. Referred pain of peripheral neural origin: an alternative to the “Myofascial Pain” construct. Clin J Pain 1994; 10: 243-251.

    • Celeste, having again reviewed the extensive literature this year my position has only been strengthened. Those who still believe in this nonsense (“myofascial involvement in FM”) have yet to publish any evidence that supports their claims for treatment success. The beauty of the work of Travell and Simons lies in the myriad factors said to perpetuate MPS and thereby release the conscientious trigger point therapist from any blame for treatment failure! Your espousal of an integrative approach is in my opinion only a smoke screen to hide the lack of scientific support for most or all the treatment modalities contained therein. By the way, the CDC website makes no mention of “trigger points” in its rambling review of Fibromyalgia. Closed minds, perhaps?

  8. “And it is common in osteoarthritis and back pain syndromes, which are not autoimmune at all.”

    Surely back pain syndromes are idiopathic and therefore you cannot know whether or not they are autoimmune, furthermore primary care practitioners regularly refuse testing of autoimmune disorders on the unfounded bases that they are mainly or entirely psychosocial as is the fate of many fibromyalgia patients.

  9. Even being an art student with zero medical background, when I had first heard of this FM/a test I knew it was just another catch-all way to diagnose fibromyalgia. I do have some questions though. Granted, irregular cytokine measurements are present in many different inflammatory disorders, if one were to get this test and yield normal levels, would that be a good way to rule out Fibromyalgia?
    It’s my understanding that:
    The FM/a test can only tell you whether or not you have an inflammatory disorder. Therefor, if you test negative for irregular cytokine levels, you can possibly rule out Fibromyalgia as a diagnosis.

    I’m going through a rough time in my life trying to figure all this out and I’d really appreciate comments on my (probably broken) theory. Hell, I’d pay 700 dollars to simply have peace of mind and a way to force doctors to take my case seriously – a thing so rare amongst those who worry they might have FMS.

    Thanks for being so level-headed and logical, Dr. Wolf. I would certainly LOVE to have a doctor as reasonable as you. I appreciate any responses.

  10. Pingback: Fibromyalgia Blood Test Accurate : FibroModem

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