Sunday, April 24, 2011

There are many flaws in the XMRV review / editorial by Wainberg and Jeang

by Danny Ze-dog on Sunday, 24 April 2011:

There are many flaws in the short review piece/ editorial by Wainberg and Jeang (2011), "XMRV as a Human Pathogen?"

You can find the full text on Dr. Speedy's blog here

I can't go into everything that's wrong with it, as a full critique would be longer than the original article itself. But here are some responses I have on their commentary:

"Aside from a single study that reported finding polytropic murine leukemia virus sequences (a virus related to but different from XMRV) in 87% of CFS samples (Lo et al., 2010)..."

The original study (Lombardi et al) involved multiple centers and multiple methodologies that found concordant results, a powerful argument in itself. Then we turn to the virus definition question - the insistence of many pundits to define XMRV by a tiny range of genetic variation. Neither HIV nor HTLV are defined so narrowly. The other 'virus', as these authors call it, is represented by MLV-related sequences that are 96% homologous to XMRV identified by Lombardi et al. That's far closer than different viral strains that are all given the name HIV-1, i.e. considered the same virus. The continued, obsessive insistence on defining XMRV by such a tiny range of diversity is truly bizarre.

"The original study that identified a link between XMRV and CFS (Lombardi et al., 2009) remains unconfirmed and has been questioned in regard to the prevalence of in vivo XMRV infection and its causal disease relationship to CFS."

There are a number of mistakes here. The original study has not been replicated, period. It's essential finding HAS been confirmed by Lo et al - the presence of MLV-related viral sequences in the blood of CFS patients. The negative studies cannot be called failures to replicate the original study's results because they did not attempt to replicate it. Further, neither Lombardi et al nor Lo et al made any claims about causality.

"Like the connection between XMRV and prostate cancer, several studies now claim that the identification of XMRV sequences in CFS samples has resulted from laboratory contamination involving either faulty primers that were used in PCR analyses or laboratory tainting of human-tissue samples by mouse cells containing XMRV sequences (Smith, 2010; van der Kuyl et al., 2011)."

None of those studies has offered proof of their assertions, but only speculation based on bits of evidence and extrapolation therefrom. Crucially for the purposes of scientific inquiry, not one of them has offered an explanatory hypothesis to defend their claims. Without a falsifiable, testable explanatory hypothesis, these arguments carry far less weight than the positive data compiled by the WPI, NCI, FDA and NIH scientists.

"Others have failed to identify antibodies to XMRV in the sera of individuals suffering from CFS (Satterfield et al., 2011)."

Which means, in scientific terms, that they have failed to identify antibodies and not necessarily anything more. Again, more compelling evidence could be provided if authors of negative studies were to faithfully replicate the WPI methodologies and still fail to replicate their findings. As for the serological assays used in this study, they are brand new and untested/ unvalidated, in a fresh field of inquiry; negative studies under such conditions are far more frequent as scientists find their way along the learning curve. It is very important to bear this in mind when attempting to assess the value of negative non-replication studies at this early stage in XMRV research.

"Moreover, there has been no clarification on the causal mechanism(s) by which XMRV is responsible for CFS."

How could there be? The first report of an association was only published a year and a half ago!

"There is significant uncertainty in postulating a link between XMRV and either prostate cancer or CFS. Unless and until more definitive reports of in vivo prevalence and disease causality are published, it is probably judicious to assume that some of the currently reported findings may be erroneous."

This statement is logically and scientifically bankrupt. It is NEVER "judicious" to assume uncontested positive data is "erroneous" when replication studies have not been attempted - never! What would be judicious is to do a few studies that faithfully replicate the methods of Lombardi et al and Lo et al, after consulting the researchers in those groups on the exact specifications of those methods. It would be judicious for the federal government to involve itself in such work regarding the safety of the blood supply - which it has already done. It would be judicious, in the meantime, to follow the advice of the FDA's own scientific advisory panel (which included one of the most vocal advocates of contamination arguments) and temporarily defer all persons who have ever been diagnosed with CFS from donating blood.

"Decision makers should be scrupulously cautious that some individuals and/or companies might stand to gain financially from the notion that XMRV is a human pathogen."

It seems to be that this is a not-so-veiled smear of a number of companies and organizations, including the WPI and Cerus. It also does not consider the alternative - that there are individuals and/or companies (and perhaps larger entities) that might stand to lose financially from the notion that XMRV is a human pathogen. Decision makers, when in doubt, should look at scientific evidence rather than trust in individuals or companies. There is no reason to be swayed by anyone or anything else.

In the interests of declaring conflicts of interest, it should be noted that one of this piece's authors, Kuan-Teh Jeang, is the Editor-in-Chief of the journal Retrovirology, which published five separate articles suggesting the possibility of contamination in XMRV research in a single issue - an almost unprecedented publishing event that surprised a number of fellow scientists.

"In regard to CFS, the possibility that XMRV may be a causal pathogen has led many affected individuals to turn to ARVs as possible remedies for their conditions."

This is a perpetuation of a growing bit of propaganda in the medical community and the media. The number of individuals involved is, as those who are on the inside of these discussions know, insignificant relative to the scale of Wainberg and Jeang's argument.

"Even if XMRV is linked to some CFS cases, it is almost certain that many and perhaps most CFS cases are not caused by XMRV since CFS is a heterogeneous entity."

A largely unsubstantiated and highly speculative statement of opinion, unworthy of a professional scientific review.

"Scientific and regulatory communities might have a responsibility to endorse the appropriate drug therapy if some cases of XMRV-CFS could be established and to strongly discourage the use of ARVs in cases where it is shown beyond a reasonable doubt that an XMRV-CFS link does not exist."

Another baffling statement. What is "beyond reasonable doubt" at this stage in clinical detection of XMRV? Would they have argued for such "reasonable doubt" in the early days of HIV testing, when HIV-2 had not even been discovered, and whole clades of HIV viruses could not be detected by the existing assays?

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