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XMRV: A Week In Review

Posted Jul 03 2010 7:05am
Last week, the Dutch magazine, ORTHO, leaked a copy of a presentation from a lecture given by Dr. Harvey Alter, a highly respected scientist (discoverer of hepatitis C) from the National Institutes of Health (NIH).

Within the obtained presentation slides, Dr Alter stated that "the data in the Lombardi, et al Science manuscript [the Whittemore Peterson Institute's study findings linking the retrovirus XMRV to ME/CFS] are extremely strong and likely true, despite the controversy." Dr. Alter also claimed that the NIH and the Food and Drug Administration (FDA) had "independently confirmed the Lombardi group findings."

Furthermore, Dr Alter’s study also allegedly estimated XMRV and other Murine Leukemia viruses to be within the blood donation supply at between 3% and 7%.

The study paper was apparently set to publish in the Proceedings of the National Academy of Sciences of the USA (PNAS).

The leak was also reported by The Wall Street Journal (WSJ) in an article entitled Further Evidence of an XMRV-Chronic Fatigue Syndrome Connection?

Not long after this leak, the WSJ later reported that the Centers for Disease Control (CDC) had also completed a study on CFS that was ready for publication. However, the CDC study findings were the opposite of the FDA and NIH: no XMRV at all. Not in CFS, and not in healthy controls.

This, of course, was not surprising to the ME/CFS community, nor to anyone familiar with the CDC and its history with CFS. Bill Reeves, the former head of the CFS division at the CDC (he has since been removed, though is oddly still one of the authors of the paper) was long ago quoted as saying he did not think they'd be able to find XMRV in CFS.

Nevertheless, as a result of these conflicting studies, the WSJ stated that both papers were being put on hold until the discrepancies could be sorted out -- a decision that created quite a bit of controversy.

In a surprise turn, however, very early Thursday morning, the CDC went ahead with their publication , while the FDA/NIH's positive study remained at a standstill.

There's a lot of conflicting information on why the FDA/NIH study remains on hold, and I don't want to speculate here when I don't know the full story with certainty. So, I will only refer to what was reported. Yesterday morning, Nature.com stated the following
Although a PNAS spokeswoman reportedly told The Wall Street Journal that the study had been accepted for publication, press officers at PNAS refused to comment on the matter today. One scientist familiar with the issue said that the journal's editor-in-chief, cell biologist Randy Schekman of the University of California, Berkeley, sent the paper out for further review after government agencies requested the publication delay. That review came back with requests for additional studies, the scientist says. Schekman declined to comment, noting that it is the journal's policy not to discuss papers in progress.
Another source, Science Magazine , provided a different update yesterday
The authors of the PNAS paper have decided it needs more work. Corresponding author Harvey Alter of the NIH Clinical Center, who is in Berlin this week, issued this statement on 30 June: "Our paper has not yet been accepted for publication. My colleagues and I are conducting additional experiments to ensure that the data are accurate and complete. Our goal is not speed, but scientific accuracy." NIH spokesperson John Burklow explained to Insider that the paper had been accepted, but Alter and his co-authors decided to "pull it back" and revise it in response to questions raised by reviewers.
Either way, it seems that those at the FDA/NIH will re-examine their data, whether on their own accord or by another person/agency's request, in order to ensure that their findings are fully accurate.

Reportedly, the CDC also took a brief pause to re-evaluate their data (though, it seems, not very successfully, as their study contains some major flaws in its subject sampling and methodology, which I will discuss shortly). According to the WSJ, the lead scientist of the CDC study stated that "after the FDA/NIH team submitted a paper with results different from their own, the CDC group decided to take a 'scientific pause' to look at both papers, compare study methods and do additional experiments. After this review, they decided to proceed with publication—and he says no changes were made to their original manuscript."

Now, let's look at that CDC study .

First, the CDC admits to using archived blood samples from their Wichita and Georgia study cohorts -- subjects obtained by random telephone interviews who fit under the CDC's empiric definition of CFS. This definition, sometimes referred to as mere "chronic unwellness," is a much broader, vague and rather inaccurate definition of CFS. In fact, a 2008 study by Dr. Jason et al demonstrated that 38% of those with a diagnosis of a major depressive disorder were erroneously misclassified as having CFS using this new CDC definition. That is, many of the patients included in this definition did not actually have CFS. Furthermore, the CDC is alone in using the empiric definition to determine their patient/research sampling. All other researchers use what is referred to as the 1994 Fukuda criteria, or the stricter Canadian Consensus Criteria . The CDC, however, apparently opposes the use of the latter definition of CFS for the following reason (found on page 16 of their paper)
The 1994 International CFS case definition and the Canadian Consensus Criteria are different and do not necessarily identify similar groups of ill persons. Most notably, the Canadian Criteria include multiple abnormal physical findings such as spatial instability, ataxia, muscle weakness and fasciculation, restless leg syndrome, and tender lymphadenopathy.
This quote was quite revealing to me in a couple of ways. First, as Dr. Suzanne Vernon, medical director for The CFIDS Association of America writes in her analysis of the paper:
... the physical findings listed are those commonly experienced by CFS patients, and one (tender lymphadenopathy) is a case-defining symptom of the 1994 criteria.
Second, the authors of the study appear to essentially admit that their patient subjects did not present with these physical abnormalities often seen in CFS, and as such, it is apparent that the patients did not necessarily have CFS. As they themselves state in their paper
These CFS cases are different from CFS patients seen in general practice and referral clinics; of the participants from the population based study in Georgia, only half had consulted a physician because of their fatigue, about 16% had been diagnosed with CFS, and 75% described an insidious onset to their illness that had no obvious relation to an acute infectious disease.
This is indeed contrary to most cases of CFS, which often have a sudden, viral (i.e., infectious) onset. Also, I found it rather peculiar that a study of a specific disease would only have 16% of one of its study cohorts actually diagnosed with that disease. This can only mean that approximately 84% of the subjects in this study population had not been diagnosed with the very disease the CDC claimed to be studying.

Furthermore, I found it interesting that the CDC also state the following
The physical findings in persons meeting the Canadian definition may signal the presence of a neurologic condition considered exclusionary for CFS and thus the XMRV positive persons in the Lombardi et al. study may represent a clinical subset of patients.
First, ME/CFS is classified by the World Health Organization as a neurological condition. How can an illness classified as a neurological disease include neurological disease as exclusionary for diagnosis?

In addition, it seems the CDC are admitting that patients who fit the Canadian Consensus Criteria (which is actually the majority of ME/CFS patients) may indeed have XMRV as discovered by those in the Science paper, and this could possibly present as a neurological condition (i.e., what they seem to separate as ME). But they were not actually looking at patients who fit this definition in their study.

As someone who does fit the Canadian Consensus Criteria for ME/CFS and has tested positive for XMRV, my question then is this: if they didn't find XMRV in their flawed, empiric definition of CFS, are they at least now looking for it in what they seem to differentiate as ME? Something tells me that they are not. And maybe that's for the best, given what Dr. Suzanne Vernon said of their poor methodology
Further, the samples from these three study cohorts were collected using different types of tubes, each of which has a distinct way of being processed. As if this weren’t bad enough, none of the blood tubes used were of the same type used in the Lombardi study. (They used tubes containing sodium heparin that are intended for use with virus isolation). The blood tubes from the 18 Georgia registry patients are designed to collect whole blood and preserve nucleic acid; it is not clear where the plasma came from for these subjects since plasma cannot be obtained using these blood tube types. So the explanation for not finding XMRV in these samples is simple – this was a study designed to not detect XMRV using a hodge-podge sample set.
As Dr. Vernon, Dr. Mikovits (lead researcher at the Whittemore Peterson Institute) and other scientists have pointed out, XMRV is very hard to find. Highly specific testing methods are required. Dr. Mikovits provided a detailed, complicated overview of these methods in the Bulletin of the International Association of CFS/ME a few months ago. You can find that overview here.

The Whittemore Peterson Institute (WPI) issued a statement yesterday morning, which included the following
To correctly replicate scientific studies it is imperative that researchers use the same methods and patient criteria to ensure accurate results. The methodology used by the CDC was not the same as that used in the WPI study nor was the patient selection criteria. In September 2009, WPI sent the CDC twenty confirmed positive samples and the appropriate methodology to help them develop a clinically validated test. However, this team chose not to do this.

Until researchers use clinically validated tests to detect XMRV in patient samples, as WPI and their collaborators have successfully done, an accurate association of XMRV to any diseased population cannot be made. For this reason, WPI researchers and many others are currently validating more sensitive clinical assays to assist federal agencies in their search for the true prevalence of XMRV in the human population.

It's quite clear the CDC study is significantly flawed in multiple ways, and its a wonder to me it was even published. The CDC has a long history of being dismissive towards ME/CFS. This is undoubtedly frustrating. But, for those of us suffering with this devastating disease who are awaiting answers from legitimate studies of well-defined ME/CFS, perhaps in the end this will be a good thing. If the FDA/NIH study is rigorously checked and double checked, the data airtight, and the patient population representative of actual CFS (and, of course, the study is finally published), then the findings will be that much harder to dispute. In the meantime, as Dr. Vernon states, "studies such as this one from Switzer, et al., [the CDC] continue to absorb time, divert precious resources and fuel controversy instead of consensus."
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