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Archive for the ‘XMRV’ Category

Professor McClure

Professor Myra McClure is a retrovirologist from the Imperial College, London. Professor McClure exhibits an impressive resume encompassing a large portion of published studies: https://www1.imperial.ac.uk/medicine/people/m.mcclure/publications/

                                                                                                                                                                                                                                Professor McClure was a co-author of the paper published in Plos One in January 2010 titled, “Failure to Detect the Novel Retrovirus XMRV in Chronic Fatigue Syndrome.” As the paper’s name suggests, this study found no evidence of XMRV or MLV in CFS patients or controls. This study can be found here: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0008519

                                                                                                                                                                                                                                Professor McClure has publically stated on many occasions that there is a high possibility that the XMRV/MLV related virus findings being implicated in CFS are a consequence of contamination.

 

The Usefulness of Critiquing Professor McClure’s Statements

It can be argued that Professor McClure is just an arbitrary retrovirologist whose opinions on XMRV/MLV related viruses will not have an influence on the final scientific consensus. This is true and Professor McClure has publically stated that “Nothing on God’s Earth could persuade me to do more research on CFS.” The XMRV/MLV related virus- CFS paradigm shift will likely stem from several USA government departments working in unison. The question is then posed, “What is the value is criticising Professor McClure’s viewpoint?”

                                                                                                                                                                                                                                   Professor McClure has recently been the leading proselyte reviving the contamination hypothesis as an explanation for the Lombardi et al. results. She has appeared in a flurry of media interviews and seems to be driven by the purpose of spreading the contamination hypothesis. She has recently appeared in a Medpage Today interview, addressed the American Society for Microbiology, been interview for This Week in Virology and presented the contamination argument at the International XMRV conference. Professor McClure’s recent string of media interviews and conference talks will unquestionably influence the short-term research plans of some scientists. She has made ad nausium contamination accusations in her talks although some of these accusations are subtle and contamination is implied. Professor McClure’s underwhelming ‘Science Media Centre’ press release synopsis of the Lo et al. study may have contributed to the UK media boycott of the story that was covered by hundreds of media groups worldwide (this press release can be found here: http://www.sciencemediacentre.org/pages/press_releases/10-08-23_cfs_virus_pnas.htm)  Professor McClure has undeniably had a significant number of scientists, ME/CFS patients and the public hear her comments.

 

Professor McClure’s contamination accusations would be useful if there was a high likelihood of contamination in this situation. If contamination was the cause of the XMRV/MLV results then her media interviews may be of benefit due to

  1. Reducing the number of ME/CFS patients taking anti-retrovirals
  2. Inhibiting the false hope that the ME/CFS community has somewhat projected on the XMRV/MLV outcome.
  3. Stopping research scientists waste their funds on research that is based on contamination

 

If the contamination likelihood was negligible, then Professor McClure’s recent media comments may have caused some harm. If contamination was not the cause of the XMRV/MLV results then her media interviews and conferences may be counterproductive due to:

  1. Causing scientists to delay XMRV/MLV research studies
  2. Causing patients to delay taking anti-retrovirals when this may be a useful treatment (although this is also contingent on XMRV/MLV causing CFS which is a separate debate.)
  3. Causing scientist such as Dr. Mikovits to focus her attention on disproving the contamination theory rather than focusing on the pathogenesis and possible treatment of XMRV/MLV
  4. Delaying the paradigm shifting realisation that ME/CFS is a purely organic illness.
  5. Short term research projects reconfirming the Lo et al. and Lombardi et al. results rather than researching pathogenesis and possible treatment of XMRV/MLV
  6. Dashing the hopes of ME/CFS XMRV/MLV positive patients by ruling out this as the etiology of their disease.
  7. Focusing the debate on the presence of XMRV/MLV in ME/CFS patients. This is as opposed to the more pragmatic debate concerning whether XMRV/MLV causes or plays some role in the development of ME/CFS.

                                                                                                                                                                                                                                                 I have presented a somewhat simplified analysis above. The actual implications of Professor McClures’ talks may be more subtle and nuanced. Essentially the usefulness of Professor McClure’s remarks are contingent on whether the XMRV/MLV results are due to contamination. As the link between XMRV/MLV and ME/CFS has not been ruled out and contamination has not been ruled out definitively then the usefulness of Professor McClure’s comments can be assessed according to the likelihood of contamination causing the aforementioned results. I will attempt to determine the likelihood of this contamination hypothesis being correct and consequently whether Professor McClure’s comments are justified and productive.

 

My First Email to Professor McClure

On the 15th of September 2010 I emailed Professor McClure, posing six questions.

1.     XMRV from patient samples has been seen from a transmission electron microscope. Does this rule out contamination?

2.    XMRV has been grown in a petri dish and uninfected human cells have been infected by it. Does this rule out contamination?

3.    The Lo et al. paper saw the MLV related virus mutate over a 15 year period in 7 individuals. Does this rule out contamination?

4.    XMRV has produced antibodies in CFS patients. Does this rule out contamination?

5.    XMRV from ME/CFS patient samples has been sequenced and it has been deemed to be distinct from every known murine ERV. It is almost identical to XMRV found in prostate cancer patients. Does this rule out contamination?

6.    You seem open to the possibility of XMRV/MLV related virus and the ME/CFS association being a product of contamination but not the XMRV-prostate cancer connection being due to contamination. What is the reason for this?

 

Professor McClure responds to my First Email

On the 16th of September 2010, Professor McClure responded to my questions. I’d like to thank Professor McClure for taking time to reply to my emails. Professor McClure’s response appears below.

“The answer to all the questions you pose , with the exception of the last is, No. In answer to your last question, the flanking sequeces to the integration sites for XMRV in prostate cancer cells have been shown to be human sequeces and not murine, suggesting this is not a laboratory contaminant.”

 

I was perhaps rather naive in my definitive phrasing of the questions that I posed to Professor McClure. In hindsight I would have phrased the question aspect differently.

 

My Second Email to Professor McClure

I posed the question pertaining to the accumulation of evidence of the following five factors:

1.      “XMRV from patient samples has been seen from a transmission electron microscope.

2.         XMRV has been grown in a petri dish and uninfected human cells have been infected by it.

3.    The Alter et al. paper saw the MLV related virus mutate over a 15 year period in 7 individuals.

4.    XMRV has produced antibodies in CFS patients.

5.    XMRV from ME/CFS patient samples has been sequenced and it has been deemed to be distinct from every known murine ERV. It is almost identical to XMRV found in prostate cancer patients”.

I then wrote,

“Do you believe that

  • the totality in weight of the aforementioned 5 factors
  • in combination with the non-ubiquitous and comparable levels of MLV related virus in CFS patients and controls from several studies (and almost a dozen independent research institutions)
  • also in combination with the multiple negative contamination tests including Switzer’s real time PCR assay (performed on the WPI samples) with two fluorescent mouse mitochondria DNA specific probes

provide solid evidence against the contamination possibility? If no, then why not?”

 

Professor McClure’s Response to my Second Email

 “I wish I had time to go into detail, but to answer your question directly. I believe the weight of evidence indicates laboratory contamination. There have now been 4 major papers published in reputable journals from highly reputable laboratories who have been unable to confirm the Lombardi findings. In fact, if you read the Bill Switzer paper from CDC, you will see that this paper actually describes, not just one study from CDC, but 3 since they had the samples independently tested in 3 laboratories (and blinded the samples). This effectively means that there were 3 studies described in this paper, all giving the same negative result . Hence, although I say 4 papers, the total number of investigations is actually 6.  I would think that the onus is now on the Whittemore Institute to prove beyond all doubt that they are right when the rest of the world cannot reproduce their findings.

 

My view (confirmed at the XMRV workshop) is that the US government agencies (NIH, CDC, FDA) will organise multi-centre trials with a blinded and randomised panel of samples and reagents in the near future and this will settle the matter once and for all.

 

I do believe that part of the problem for the misleading results in both the Science paper and the PNAS paper by Lo et al is the fact that CFS samples and control samples have not been blinded, randomised and treated in exactly the same way at the same time. Lo et al say their samples were “coded”, but that might just mean that the patient identity was removed, it doesn’t say that the samples and controls were simultaneously subjected to the same  procedures and that the person doing the experiments was blinded as to which were CFS samples and which were controls. In fact, if you look at Fig 1 and Fig 2 in this paper, you can see that a different primer set was used on the CFS patient samples and the control samples. This suggests that the study was not blinded. 

 

Professor Robin Weiss who is the UK’s leading retrovirologist has a very readable article coming out in the next couple of weeks addressing why different laboratories are getting different results and discussing the problems  retrovirologists face in isolating contaminating viruses that they think are new human viruses. I have copied my PA into this reply, so that when the article appears in print, she can send a copy to you. If nothing else, it will give you information about how claims like this are not a new phenomenon in retrovirology and the steps that were taken previously to settle similar arguments. I think you will find it interesting.”

 

My Analysis of Professor McClure’s Arguments

Let me preface this section by stating that I am not very well versed in retrovirology and I apologise in advance if I have made any erroneous statements pertaining to the retrovirology specifics.

 

“I believe the weight of evidence indicates laboratory contamination.”

During the most recent ‘This week in Virology’ podcast, Professor McClure made several comments that reiterate her above opinion. These include,

“There is no point in me going back (to the laboratory) I’d just get the same result.”

“I have no plans to revisit those samples because I’m quite confident of the result and the result we would get.”

“Nevertheless in the interests of science, I’ve asked if we could get a few fresh blood samples from chronic fatigue (sic) patients. Following all of the recommendations which are now coming out from the Whittemore Peterson (sic) and we are getting sort of drip fed little hints of how to do it, then I’m very happy to try and I’m very happy to say alright by this method we can find it if we can find it but you know, I have err, I have doubts about that.”

                                                                                                                                                                                                                                Professor McClure seems to support the hypothesis that both the Lo et al. study and the Lombardi et al. study found a CFS link to XMRV/MLV due to contamination. I will now examine “the weight of evidence” of the Lo et al. study and determine if the study processes and results “indicate laboratory contamination.”

                                                                                                                                                                                                                                             The Lo et al. study provides several arguments against the contamination claims. These include specific tests and steps that Lo et al. performed in order to rule out contamination.

  1. Every sample in the Lo et al. study that tested MLV positive (based on gag gene sequences), was tested for traces of mouse DNA contamination. The PCR used in this MLV contamination test was designed so that it was more sensitive to registering mouse DNA than MLV gag sequences. It follow that if MLV by contamination was detected, mouse DNA would have also been detected. This PCR contamination test didn’t detect any mouse DNA in the reaction mixtures or clinical samples included in the study. Lo et al. concluded that this rules out the possibility of contamination by mouse DNA.
  2. Lo et al. then assessed the likelihood that the clinical samples or assays used may have been contaminated. The blood samples used in this study were obtained from clinical laboratories that had never contained or worked with mice or retroviral vectors. The blood from these clinical samples was drawn from needles into empty vacuum tubes that were only opened for the blood drawing process. The Lo et al. laboratory in which the PCR tests were performed had also never worked with murine cells, murine blood samples or MLV vectors.
  3. The MLV gag sequences that were detected in the study cohort’s blood comprised at least six distinct types of MLV sequence. Lo et al. hypothesise that if contamination is the mechanism behind results then the same sequences arise in most, if not all of the positive samples. The Lo et al. study also determined that these six plus sequences had “significant variations” when compared to all other known exogenous MLVs and viral vectors.
  4. This Lo et al. study also set up 300 negative controls for the multiple PCR amplification aspect of the study. This step involved attempting to detect the MLV gag gene however all results were negative.
  5. Lo et al. also strengthened their anti-contamination argument by obtaining fresh blood samples from 8 patients. These fresh samples were obtained approximately 15 years after the original drawing of the samples. Seven out of the eight patients still had MLV gag sequences detected. Lo et al. found that these newly obtained sequences were significantly varied from the original patient sequences. Lo et al. wrote that this “would be expected in retroviral infections, but not from contamination.”

 

The two lead study authors, Dr. Lo and Dr. Alter have publically made several statements emphasising their confidence in the result they obtained. Dr Alter made one of these comments to CFS Central, “There were no changes in the conclusions, but we added data that made the conclusions stronger…For one thing, we did some further work to feel confident that there was no contamination.” (Dr Alter is referring to the delay in publication of the Lo et al. study.) (http://www.cfscentral.com/2010/08/fdanihharvard-xmrv-study-same-thing.html)

 

During the study’s teleconference, Dr. Alter said, “The retroviruses…exist in big families of viruses…Hepatitis C is a very good example, nobody’s infected with one variant… they have a whole huge family of variants…and if you take any given patient the patient will have multiple variants in them, and different patients will have different variants, so it’s very characteristic of these kind of RNA viruses.” These comments emphasise the MLV sequence heterogeneity, as found by Lo et al., that is typical of a retroviral infection and not of contamination.
Lombardi et al. went to equally as impressive measure as Lo et al. to discredit the contamination theory explaining their own studies results. I can no longer access the Lombardi et al. paper in its entirety hence I cannot explain in detail the contamination- specific tests that Lombardi et al. performed. Despite this, I can state that all of the Lombardi et al. tests came back negative for contamination. Dr. Switzer, lead author of the CDC’s study that failed to detect XMRV/MLV designed his own contamination test that was performed on the Lombardi et al. samples. This test was a real time PCR assay that contained two fluorescent mouse mitochondria DNA specific probes. This test, created by Dr. Switzer failed to detect any signs of contamination amongst the Lombardi et al. samples.

 

There is no evidence that the Lombardi et al and Lo et al. studies were contaminated and all of the subtests in these studies came up negative for contamination. Both studies took every precaution to avoid contamination and to test for contamination. To be justified in believing that the weight of evidence indicates laboratory contamination” one would expect at least one positive test result for contamination in the aforementioned tests. In a subsequent section I will also address Professor McClure’s statement that “The weight of evidence indicates laboratory contamination.” This subsequent section is titled, ‘Explanatory Power and Mechanisms.’

 

There have now been 4 major papers published in reputable journals from highly reputable laboratories who have been unable to confirm the Lombardi findings. In fact, if you read the Bill Switzer paper from CDC, you will see that this paper actually describes, not just one study from CDC, but 3 since they had the samples independently tested in 3 laboratories (and blinded the samples). This effectively means that there were 3 studies described in this paper, all giving the same negative result . Hence, although I say 4 papers, the total number of investigations is actually 6.”  Professor McClure recently gave a Medpage Today interview (found here: http://www.medpagetoday.com/MeetingCoverage/ICAAC/22166) During this interview she stated that “there’s no point in having a league table of those who can find the virus and those who can’t find the virus and see who wins out.” Although Professor McClure doesn’t implicitly state this in the above bolded quote, she does imply that the negative studies are ahead, according to her own “league table.” The very fact that Professor McClure mentions the several premises in the bolded quote implies the conclusion that there are many more studies not finding XMRV/MLV than there are finding XMRV/MLV. Professor McClure may argue that this implied conclusion was not her intention hence I will examine her quote.

                                                                                                                                                                                                                                   Professor McClure’s bolded quote is a series of mainly factual statements (some are normative, including the sentences containing “reputable journals” and “highly reputable laboratories.”) If no conclusion is implied from her statements, then they are superfluous statements that she has added for no purpose. Professor McClure may argue that scientific statements are factual hence her quote. This is true however scientific ‘factual’ statements require the author to draw conclusions from the statements. This is part of the reason why scientific journal articles include a section for ‘discussion’ and a separate section for ‘conclusion.’ Scientific and factual statements that are used in an argument should be tied in to the author’s conclusion. If they are arbitrarily added to an argument and not linked to a sub-conclusion or a conclusion then they can be deemed as superfluous and irrelevant.

                                                                                                                                                                                                                                            Her statement “Hence, although I say 4 papers, the total number of investigations is actually 6” may be deemed to be the sub-conclusion of her previous premises. This ‘sub-conclusion’ does not relate to the rest of her argument unless the implied conclusion that the negative papers have more weight than the positive papers is introduced. Professor McClure’s other statement which may be a sub-conclusion is “There have now been 4 major papers published.” She does not relate this to her argument that contamination is a likely hypothesis.

                                                                                                                                                                                                                                Professor McClure’s above full bolded quote is therefore either

  1. Superfluous and irrelevant as she does not link it with her conclusion, or
  2. Has an implied conclusion that the negative XMRV studies are leading the positive studies and this supports the contamination hypothesis.

                                                                                                                                                                                                                                                If 1. is the case then there is no purpose in my analysis of her quote due to its non-relation to her overall conclusion. If 2. is the case then she has committed an explicit contradiction. This is due to her quote in the Medpage interview that “There’s no point in having a league table of those who can find the virus and those who can’t find the virus and see who wins out.”

                                                                                                                                                                                                                                        Despite this conclusion I have reached pertaining to Professor McClure’s quote, I will now analyse it from an accuracy perspective. “There have now been 4 major papers published in reputable journals from highly reputable laboratories who have been unable to confirm the Lombardi findings.” Professor McClure has used the terms “reputable journals” and “highly reputable laboratories” in a meliorative manner to support the implied conclusion that studies performed by quality laboratories, that are peer reviewed and accepted by eminent journals would have accurate results. This is not an argument for accepting a scientific paradigm. The studies should be judged on science alone, regardless of the highbrow nature of the institution or journal. Having said this, there is a general correlation between accuracy of science articles and the impact of the journal they are published in. I will therefore examine the impact factors of the XMRV related studies. The Lombardi et al. study and the Lo et al. study were published in journals with a higher impact factor than the negative studies. The top 5 scientific journals in descending order of Impact factor are 1. Nature (51.97), 2. Science (48.78), 3. New England Journal of Medicine (19.84), Cell (15.34), PNAS (14.88). The Lombardi et al. study was published in Science, the second highest impact rating journal and the Lo et al. study was published in PNAS, the fourth highest impact rating journal. None of the XMRV negative studies were published in the top 5 journals. The CDC study that Professor McClure perpetually mentions in her quote was published in ‘Retrovirology’ which has an impact factor of 4. I am not claiming that the journals the studies were published in necessarily influences their validity. I am only countering Professor McClure’s implied argument that the “reputable” nature of the journals of the negative XMRV studies adds to their validity over the positive XMRV/MLV studies.

                                                                                                                                                                                                                                Professor McClure alludes to the “highly reputable laboratories” that failed to detect XMRV/MLV. Similar to the aforementioned journal argument, the quality of laboratories (if one can measure or distinguish reputable laboratories) does not automatically add to the validity of the findings. Professor McClure’s quote seems to subtly imply that the quality of the laboratories not detecting XMRV/MLV is higher than the quality of the laboratories that can detect XMRV/MLV. She also fails to mention the laboratories other than the Whittemore Peterson Institute (WPI) that detected XMRV/MLV. The positive Lombardi et al. study was performed by the not only the WPI but also the National Cancer Institute and the Cleveland Clinic. The positive Lo et al. study was performed by both the National Institute of Health and the U.S. Food and Drug Administration. These laboratories are also considered to be “highly reputable” by many people within the scientific domain.

                                                                                                                                                                                                                                              “In fact, if you read the Bill Switzer paper from CDC, you will see that this paper actually describes, not just one study from CDC, but 3 since they had the samples independently tested in 3 laboratories (and blinded the samples). This effectively means that there were 3 studies described in this paper, all giving the same negative result .” This statement by Professor McClure uses the logic that three independent laboratories testing samples in their own laboratories under the one study umbrella can be counted as three separate studies. Using Professor McClure’s own logic, the Lombardi et al. study has been confirmed twice. The WPI, NCI and CC all performed unique tests forming the Lombardi et al. study at their own laboratories. Professor McClure’s own logic has therefore deemed that the Lombardi et al. study has been confirmed twice. During a recent American Society of Microbiology meeting, Professor McClure has stated that “So my position would be that in the absence of confirmatory evidence, there is… no confirmatory link of CFS and either of these Murine Leukemia Viruses. But of course, life changes and if there is evidence to the contrary then of course we would happily embrace it.” Using Professor McClure’s own logic that three laboratories performing tests under the one study umbrella counts as three separate studies, then the Lombardi et al. study has been confirmed twice. This confirmation is what Professor McClure stated she required to convince her of the XMRV-CFS connection. Therefore Professor McClure should believe the XMRV-CFS connection.

                                                                                                                                                                                                                                   Professor McClure made the statement that “There have now been 4 major papers published in reputable journals from highly reputable laboratories who have been unable to confirm the Lombardi findings ….Hence, although I say 4 papers, the total number of investigations is actually 6.” This statement seems to appeal (through the means of implying) to the high number of negative XMRV studies as evidence for the contamination hypothesis. Professor McClure has used the fallacy, argumentum ad numerum. Although multiple similar studies generally provide more weight for a specific outcome, multiple studies shouldn’t be cited as definitive proof of an outcome. This is especially true of studies which fail to detect anything, such as the negative XMRV studies. Due to the current discrepancy between the XMRV negative and XMRV positive results, a scientific consensus will likely be reached when a verifiable mechanism has been determined providing an explanation for the current discrepancy in XMRV results.

                                                                                                                                                                                                                                Professor McClure’s above quote is also problematic due to the precise nature of the negative XMRV studies. These negative studies have used dubious cohorts, flawed methodologies and questionable blood collection methods. I have detailed these erroneous aspects of the negative XMRV studies in detail elsewhere on this blog hence I will not cover these issues again here. If a flawed methodology is used ad nauseum, it does not add weight to the validity of the result. Albert Einstein made two quotes supporting the notion that I have mentioned here. Einstein said “Insanity is doing the same thing over and over again and expecting different results.” Also when a pamphlet was published titled ‘100 authors against Einstein,’ he retorted “If I were wrong, one would be enough.” These quotes emphasise the danger of using the argumentum ad numerum fallacy that Professor McClure has implied by her quote. 

 

“I would think that the onus is now on the Whittemore Institute to prove beyond all doubt that they are right when the rest of the world cannot reproduce their findings.”

Professor McClure was recently interview by ABC radio in Australia. The following is a transcript of part of her interview:

Norman Swan: And it’s not possible it’s a contaminant that it’s just crept into samples by accident? ( Norman Swan is referring to prostate cancer.)

Myra McClure: That’s always a problem with retroviruses and their association with disease – this time it’s not and I’ll tell you why, because the people who published the American studies have been very careful to sequence this virus and the sequence and the phylogenetic analysis that is looking at the sequence of one virus compared to another and the eight samples they have are sequences taken from eight different viruses, taken from eight different patients with prostate cancer. All these are slightly different. Now if it were a lab contaminant you would have expected them all to be the same and they’re not.

And secondly if it were a lab contaminant it would be exactly the same in sequence as all other known murine leukaemia viruses and it’s not – it’s different. So it’s a real new virus.”

This interview can be found here: http://www.abc.net.au/rn/healthreport/stories/2010/2867629.htm#transcript

                                                                                                                                                                                                                                               In the above argument, Professor McClure has proposed that two factors are required for retroviral association to be distinguished from contamination. She states that these two factors are:

  1. The varying retroviral sequences among the set of Z-retrovirus positive patients.
  2. The retroviral sequences distinctiveness when compared to the set of known contaminants (in this case, murine leukemia viruses.)

According to Professor McClure’s argument, these are the two necessary conditions that need fulfilling. If these criteria are fulfilled then “It’s not possible it’s a contaminant.”

                                                                                                                                                                                                                                               In the above argument, Professor McClure is arguing against the prostate cancer XMRV association arising due to contamination. If her argument concerning ruling out contamination is superimposed onto the CFS- XMRV association then she is ruling out an XMRV- CFS contamination. This is due to the XMRV discovered in CFS patients fulfilling both of the criteria that Professor McClure herself has established to rule out contamination. The XMRV found in CFS patients is 1. Different among the CFS patients, determined by sequencing and 2. Is distinct from all known murine leukemia viruses.

                                                                                                                                                                                                                                    Professor McClure now has two options to remain in a consistent position.

  1. She changes her position to state that the XMRV found in prostate cancer may be due to contamination.
  2. She changes her position to rule out the XMRV contamination hypothesis in CFS.

                                                                                                                                                                                                                                                   I can anticipate that Professor McClure would not change her position on these two illness associations with XMRV but rather use a post hoc fallacy. This would entail claiming that more criteria are necessary for contamination to be ruled out such as showing that the retrovirus detected contains human not murine sequences. For Professor McClure to establish this third criterion she would be modifying her original objective stipulations in order to retain a consistent position for an evidence based stance. This is the antithesis of science, which works by evidence based stances becoming theories due to fitting in with already established criteria.

                                                                                                                                                                                                                                     Professor McClure has presented an argument pertaining to necessary conditions to rule out contamination and this argument supports the notion that the CFS-XMRV association has not arisen due to contamination. In essence, Professor McClure’s own argument provides further support for the XMRV association to CFS not being due to contamination.

 

“I would think that the onus is now on the Whittemore Institute (sic) to prove beyond all doubt that they are right when the rest of the world cannot reproduce their findings.”

                                                                                                                                                                                                                                  Professor McClure’s above quote refers to the onus (or burden) of proof as now being on the WPI. Burden of proof challenges and debates concerning who is required to prove the burden of proof are common in academia. These debates often involve a back and forth argument in order to determine which side the burden of proof falls. In many instances no consensus is reached on who holds the burden of proof. Often these burden of proof arguments are laborious and spurious. The burden of proof in most instances falls on the group making the most outrageous claim. In the XMRV-contamination context, determining which group is making the more outrageous claim is not a simple matter. One can argue that by linking XMRV and CFS, one is proposing a paradigm shift which would require a burden of proof. It can be counter argued that many laboratories have sufficiently tested the blood samples for contamination and all tests have been negative. Consequently the burden of proof falls on those contamination proponents to provide a test to detect contamination. The burden of proof argument in this situation is not as black and white as Professor McClure’s claim that “the onus is now on the Whittemore Institute (sic) to prove beyond all doubt that they are right.”

                                                                                                                                                                                                                                                A burden of proof argument isn’t entirely necessary in this situation as the US government’s blood working group are currently working to determine why discrepancies are occurring between different scientist’s XMRV results. By referring to the WPI’s burden of proof, it can be argued that Professor McClure is setting up a spurious argument that will inevitably end in deadlock.

                                                                                                                                                                                                                                    Professor McClure’s statement that the onus is now on the Whittemore Institute (sic)” fails to accurately provide an assessment of the situation. The NIH, FDA, CC and NCI have all detected XMRV/MLV in CFS patients in high percentages. By erroneously singling out the WPI, Professor McClure presents what is a pseudo-enhanced argument. If her statement accurately referred to the totality of the five separate laboratories, the reader may not be as swayed by her argument.

                                                                                                                                                                                                                                    Professor McClure wrote that “The rest of the world cannot reproduce their (the WPI’s) findings.” She uses the phrase “rest of the world” hyperbolically. This phrase is an erroneous way to describe a handful of laboratories. The reader may be influenced by Professor McClure’s use of this dysphemism. It sounds impressive to state “rest of the world” however in this context, this is a synonym for “several laboratories.” It is also erroneous to claim that other laboratories cannot reproduce the Lombardi et al. study and I expand on this point under the subsequent heading titled ‘Confirmation.’

                                                                                                                                                                                                                                    Scientific journals are often an accurate gauge relating to the burden of proof. The Science and PNAS journals both instructed the XMRV/MLV positive laboratories to perform additional tests to rule out contamination. Both Lo et al. and Lombardi et al. performed these additional tests which came back negative for contamination. Science and PNAS both accepted the high XMRV/MLV prevalence in CFS patients study results. It can be argued that this acceptance and consequential publication, a process that lasted many months, was the defining factor that removed the burden of proof from the XMRV/MLV positive study authors. Both journals’ actions of publishing the XMRV/MLV studies indicate that they believe the contamination possibility has been appropriately addressed.

                                                                                                                                                                                                                                                It can be argued that the study authors’ that have found an XMRV/MLV-CFS correlation have performed every possible test to exclude contamination hence how else can they prove the burden of proof? In her first response to my emails, Professor McClure described the reason why she doubted that the prostate cancer-XMRV/MLV connection was spurious. She wrote, “The flanking sequeces to the integration sites for XMRV in prostate cancer cells have been shown to be human sequeces and not murine, suggesting this is not a laboratory contaminant.” The question then arises as to why the CFS- XMRV/MLV positive study authors’ haven’t performed this step on the CFS patient samples. It is not through complacency or avoiding the issue that these scientists have not to date performed this test. It is a very laborious process to identify provirus integration sites. Lo et al. have estimated that there is only a single virus gene copy per 400-4000 nucleated peripheral blood mononuclear cells. Lo et al. highlight a second problem with identifying the provirus integration sites- Previous studies have found that these sites vary significantly. It has been speculated that some scientists are currently working on the laborious process of demonstrating integration of MLV genes into the human genome of CFS patients.

                                                                                                                                                                                                                      Confirmation

During a recent American Society of Microbiology meeting, Professor McClure made several remarks alluding to the Lo et al. study not being confirmatory of the Lombardi et al. study. She said, “It’s important to note that this second paper coming out of the FDA cannot be used at confirmatory evidence of the initial paper that was published in Science and we just have to wait and see whether this paper is confirmed by others.” During the latest ‘This Week in Virology’ podcast, Professor McClure reiterated these sentiments, “It’s important to point out that they (Lo et al.) have not found the same virus either. They have found another member of the family of endogenous retroviruses. Theirs is a polytropic as opposed to a xenotropic virus.”

                                                                                                                                                                                                                                Professor McClure’s comments that the Lo et al. paper was not confirmatory of the Lombardi et al. paper are disputed by the two lead authors of the Lo et al. paper- Dr. Lo and Dr. Alter. Dr Alter has stated that “We think, basically, it confirms the findings of the Whittemore-Peterson Group.” Dr Alter continues on to state that “It does, at least, confirm the findings of Whittemore-Peterson Institute…I think one wants to go back to their studies because they’ve had more time, and they’ve done extensive work…so their study is more advanced than ours, but -with that as…er…with them having done the groundwork I think our study is highly confirmatory of their work…” These comments by Dr Alter emphasise the Lo et al. study authors’ thoughts that their study confirms the Lombardi et al. study.

                                                                                                                                                                                                                                   Professor McClure may argue that Lo et al. detected a different type of Murine Leukemia Virus related virus compared to Lombardi et al. hence the study is not confirmatory. Dr. Lo emphasises that detection of a variety of MLV sequences would be expected in a retroviral infection. Dr. Lo states, “that’s exactly what we anticipate for retrovirus infection…over time you will see the many different sequences there.” Dr. Lo also states that “We can say we found this kind of variability that’s actually more consistent with the natural form of a retrovirus infection in this group of patients.” Dr. Lo’s comments reiterate the point that the diversity of MLV’s being detected in CFS patients makes a stronger case for retroviral involvement in the illness, not a weaker case.

                                                                                                                                                                                                                                               Dr. Lo has also commented that “They are in the same family but…they are compatible with the earlier finding of the XMRV, however they are not identical and they are more diverse.” This quote highlights the Lo et al. studies extension of the Lombardi et al. study through the means of detecting a variety of MLV in CFS patients. Dr. Alter clarifies that the WPI have also detected a range of MLV in CFS patients since the publication of the Lombardi et al. study, “Since the original publication, the WPI and NCI groups have found that they too are finding greater variability in their patients so it is not just XMRV as in the original cohort of patients.” As both the Lo et al. group and the Lombardi et al. group are finding a range of MLV’s in CFS patients and both study’s authors believe that the Lo et al. group have confirmed the Lombardi et al. result, Professor McClure’s statements are quite contentious.

                                                                                                                                                                                                                                          During the recent American Society of Microbiology meeting, Professor McClure stated “So my position would be that in the absence of confirmatory evidence, there is at the minute no confirmatory link of CFS and either of these Murine Leukemia Viruses. But of course, life changes and if there is evidence to the contrary then of course we would happily embrace it.” This quote by Professor McClure seems to indicate that if a positive MLV-CFS study is confirmed, then she will believe in the CFS-MLV link. As I have documented above, the Lo et al. study can be considered as a confirmation study. Also the three autonomous laboratories that produced the Lombardi et al. paper can be considered as two confirmations of the first laboratories results. Also the Lo et al. paper was performed by two laboratories hence it can be argued that the second laboratory confirmed the first laboratories result. This is due to Professor McClure’s logic that In fact, if you read the Bill Switzer paper from CDC, you will see that this paper actually describes, not just one study from CDC, but 3 since they had the samples independently tested in 3 laboratories (and blinded the samples). This effectively means that there were 3 studies described in this paper, all giving the same negative result . Hence, although I say 4 papers, the total number of investigations is actually 6.”

                                                                                                                                                                                                                                                If one ignores the five separate laboratories finding MLV in a significant number of CFS patients and the Lo et al. study being confirmatory of the Lombardi et al. study, another confirmation study has emerged. This study was revealed at the recent XMRV International Conference. This study by Hanson et al. was performed at Cornell University and concluded that “Our results corroborate those of Lombardi et al.” This Hanson et al. study also went to great lengths to avoid contamination. The study abstract states that “PCR with mouse COX2 primers was performed on all cDNA preparations to rule out mouse cell contamination.” The laboratory in which this study was performed had never worked with or housed mice.

                                                                                                                                                                                                                                              Let us assume that Professor McClure is given the benefit of the doubt and contrary to the study’s authors, the Lo et al. study is not considered confirmatory of the Lombardi et al. study. Also if Professor McClure’s logic concerning umbrella studies counting as several studies is only applied to the Switzer et al. study and not the Lombardi et al. or Lo et al. studies then the Hanson et al. study is still confirmatory of the Lombardi et al. study. Professor McClure’s has made an admission that “In the absence of confirmatory evidence, there is at the minute no confirmatory link of CFS and either of these Murine Leukemia Viruses. But of course, life changes and if there is evidence to the contrary then of course we would happily embrace it.” Professor McClure should therefore “happily embrace” the CFS- XMRV/MLV connection.

                                                                                                                                                                                                                                Professor McClure made the comment in her response to my second email that “I would think that the onus is now on the Whittemore Institute (sic) to prove beyond all doubt that they are right when the rest of the world cannot reproduce their findings.” She seems content to segregate the WPI from the other laboratories finding XMRV as her quote indicates that no portion of the Lombardi et al. study has been reproduced. In her email to me, Professor McClure also made comments indicating a definitive line creating a dichotomy between the studies finding no XMRV in controls or CFS patients and the studies finding XMRV in CFS patients, “There have now been 4 major papers published in reputable journals from highly reputable laboratories who have been unable to confirm the Lombardi findings…. I would think that the onus is now on the Whittemore Institute to prove beyond all doubt that they are right when the rest of the world cannot reproduce their findings.” Professor McClure has committed the fallacy of creating a false-dichotomy. This fallacy is defined as “A situation in which two alternative points of views are presented as the only options, whereas others are available.” Professor McClure’s false-dichotomy has excluded those studies which have found a comparable percentage of XMRV in healthy controls or controls to the Lombardi et al. study. These studies did not test for XMRV in CFS patients however they are in contradiction to the studies finding no XMRV in CFS patients or controls.

 

The first of these studies is a German study (Fisher et al.) which detected XMRV in respiratory secretions. XMRV was detected in 2.3% of people with respiratory infections. Also XMRV was detected in 3.2% of people with chronic obstructive pulmonary disease. Japanese scientists detected XMRV in 1.8% of healthy blood donor’s blood. XMRV was also found by Chinese scientists at a prevalence of 3.4% in Chinese blood donors. These percentages are comparable to Lombardi et al. group which detected XMRV in 3.8% of healthy controls. The single figure detection of XMRV in controls of several studies is a partial confirmation of the Lombardi et al. study. This single figure positive percentage confirms an aspect of the Lombardi et al. study. Professor McClure may argue that there is still a range of percentages being found in these studies hence it is erroneous to deem this aspect of the study as confirmatory. Retroviruses are not distributed homogenously worldwide and retrovirus prevalence fluctuates depending on the area. Also a non-standardised XMRV test may cause a small discrepancy in results due to some false negatives being detected. A third factor explaining the small discrepancy in results is the small number of controls being used on some of the studies which may influence the actual XMRV positive percentage of a larger group or country. When Professor McClure portrays the situation as the WPI versus “the rest of the world” she is creating a false-dichotomy and as I have demonstrated the situation resembles more of a nuanced trichotomy than the dichotomy Professor McClure suggests.

 

 

“I do believe that part of the problem for the misleading results in both the Science paper and the PNAS paper by Lo et al is the fact that CFS samples and control samples have not been blinded, randomised and treated in exactly the same way at the same time. Lo et al say their samples were “coded”, but that might just mean that the patient identity was removed, it doesn’t say that the samples and controls were simultaneously subjected to the same  procedures and that the person doing the experiments was blinded as to which were CFS samples and which were controls. In fact, if you look at Fig 1 and Fig 2 in this paper, you can see that a different primer set was used on the CFS patient samples and the control samples. This suggests that the study was not blinded.”  

                                                                                                                                                                                                                                Professor McClure has stated that the Science and PNAS papers had “CFS samples and control samples (that) have not been blinded, randomised and treated in exactly the same way at the same time.” This argument is used by Professor McClure as a potential mechanism to explain how the CFS samples were contaminated while the control samples were largely unaffected. Professor McClure has falsely associated these non-procedures with the Lombardi et al. paper as explained by Mikovits et al. in a ‘technical comments’ addendum to the Science paper. Mikovits et al. state that “All samples were blinded, as mandated by the NCI and WPI institutional review board approvals. All experimental procedures were done by the same personnel, in the same physical laboratory space, under identical protocols. Investigators at NCI received 100 samples from individuals without knowing their health status; furthermore, the samples were sent to NCI directly without passing through the WPI laboratory space. Laboratory workers at the NCI and the WPI who performed the polymerase chain reaction (PCR) and immunological studies used coded, blinded samples that did not reveal the CFS status of the individuals.” These technical comments can be found here http://www.sciencemag.org/cgi/content/full/328/5980/825-d

                                                                                                                                                                                                                                 Professor McClure has erroneous information concerning this crucial aspect of the Lombardi et al. study. Contrary to Professor McClure’s assertion, the CFS samples and control samples in the Lombardi et al. study were in fact “blinded, randomised and treated in exactly the same way at the same time.” McClure’s contamination argument seems largely contingent on her erroneous piece of information. With this new information, Professor McClure’s conclusion that the “weight of evidence indicates laboratory contamination” is further jeopardised. If Professor McClure is to maintain her contamination hypothesis, she must now provide a mechanism explaining how contamination occurred in only the CFS sample subset that was part of the larger set of blinded and coded samples that were treated in an identical manner.    

                                                                                                                                                                                                                                Professor McClure is correct in that the Lo et al. study was not blinded or randomized. Dr. Alter has explained that “We did not specifically blind and mix the two sample groups (CFS and blood donors.) However, they were studied in parallel by polymerase chain reaction (PCR).” Dr. Alter’s assertion that the samples were “studied in parallel” is reiterated by the Lo et al. paper itself which states “PBMC DNA (30–40 ng) from the CFS patients and the healthy blood donors, as well as serial dilutions from 50 to 1 fg of mouse DNA mixed with 35 ng of human DNA as the positive templates, were tested in parallel.”Another section of the Lo et al paper says, “All patient and control samples were coded and tested in parallel.” If both the CFS group and control group samples were tested as part of a continuum in a random sample order then the contamination likelihood is very small.

                                                                                                                                                                                                                        Explanatory Power and Mechanisms

I will now examine the evidence for the contamination hypothesis and the rival CFS- XMRV/MLV high correlation hypothesis. The evidence I will present is entirely empirical.

This is the empirical evidence supporting a CFS-XMRV/MLV link:

1. XMRV from patient samples has been seen from a transmission electron microscope.

2. XMRV has been grown from CFS patient’s blood in culture and uninfected cells have been infected with XMRV via CFS patient’s serum.

3. The Lo et al. paper saw the MLV related virus mutate over a 15 year period in seven individuals.

4. XMRV has produced antibodies in CFS patients.

5. XMRV from CFS patient samples has been sequenced and it has been deemed to be distinct from every known murine ERV.

6. The XMRV found in a high percentage of CFS patients is almost identical to the XMRV found in prostate cancer patients.

7. A diversity of MLV’s have been detected in CFS patients. This is consistent with a retroviral infection.

8. Five laboratories have published data showing a high prevalence of XMRV in CFS patients as opposed to controls.

9. These laboratories have found non-ubiquitous and comparable levels of MLV related virus in CFS patients and controls from several studies.

10. Three further studies have found comparable levels (to the other five laboratories) of XMRV in controls. All of these laboratories have found XMRV in a noticeable percentage of controls.

11. Countless contamination tests have come back negative for all studies detecting XMRV in both CFS patients and controls. Some of these tests have even been created by authors of XMRV negative studies. These tests have still failed to detect any traces of contamination in the XMRV positive samples.

12. Hanson et al. have independently confirmed the Lombardi et al. study.

 

The following is the empirical evidence in favour of the contamination hypothesis:

  1. Four studies have failed to find XMRV in CFS patients or controls.

 

Based on the above empirical evidence, I will present a hypothesis explaining the “CFS-XMRV/MLV link: hypothesis.” This hypothesis must be consistent with all of the above 13 empirical points of evidence. The cohorts, testing mechanisms (all which were not replications of the Lombardi et al. study) and the blood collection process including type of collection types used were the reason for the “Four studies that have failed to find XMRV in CFS patients or controls.”

 

 Based on the above empirical evidence, I will present a hypothesis explaining the “contamination hypothesis.” I am not a retrovirologist however I cannot conceive of any contamination mechanism that can adequately explain all of the above 13 factors. Each individual point from 1-12 provides an argument against contamination and in order to sufficiently explain all 12 points, multiple contamination sources that have gone undetected by the tests and have coincidentally found comparable XMRV/MLV levels in CFS patients and comparable XMRV/MLV in controls (by 8 laboratories) is required. Also, unique to most contamination occurrences, non ubiquitous levels of XMRV would require an atypical contamination scenario. The antibodies to XMRV in CFS patients would need to indicate that CFS patients have a similar virus to XMRV, but not XMRV. The large diversity of XMRV/MLV detected would require multiple undetected contamination sources. These would be new and distinct sources, unique from every currently known murine ERV. The likelihood of all of these factors occurring simultaneously in multiple laboratories is extremely low and very close to zero. Professor McClure’s comment that “I believe the weight of evidence indicates laboratory contamination” is therefore erroneous. Occam’s razor suggests that “the weight of evidence” significantly supports the CFS-XMRV/MLV connection.

 

Conclusion

Professor McClure has used numerous fallacies, logical inconsistencies, explicit contradictions and flawed arguments to support her conclusion that contamination is the most likely explanation for the CFS-XMRV/MLV results. I have demonstrated that some of these arguments that Professor McClure has presented to support the contamination conclusion, inadvertently provide more weight against the contamination hypothesis. Contrary to Professor McClure’s claims, I have demonstrated that the weight of evidence strongly supports the XMRV/MLV- CFS link arising due to a pure retroviral-illness correlation as opposed to contamination.  

 

 

 

 

 

 

 

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FDA/NIH Study Released

The long awaited Food and Drug Administration (FDA) and National Institute of Health (NIH) paper has finally been published. The paper was published today in one of the world’s most eminent scientific journals, the Proceedings of the National Academy of Sciences (PNAS.) The abstract of the FDA/NIH study can be found here: http://www.pnas.org/content/early/2010/08/16/1006901107.abstract?sid=0caef811-3af1-40e8-80db-269182b6307c

The entire 6 page FDA/NIH study in PDF form can be found here: http://www.pnas.org/content/early/2010/08/16/1006901107.full.pdf

                                                                                                                                                                                                                                          The Results

The FDA/NIH study authors found a Murine Leukemia Virus-like Virus in the blood of 32 out of 37 (86.5%) CFS patients. This contrasted the Murine Leukemia Virus-like Virus being found in the blood of 3 out of 44 (6.8%) of healthy controls.

Eight CFS patients who were gag-positive in this study (based on blood that was banked 15 years ago) were retested  with blood drawn from 15 years later (drawn in 2010.) Seven out of the eight CFS patients remained gag-positive. The one patient who had now returned a negative gag result still hadn’t recovered from their CFS.

The FDA/NIH study results have not only confirmed but extended the results of the Lombardi-Mikovits paper published in October 2009. This 2009 paper found XMRV in the blood of 68 out of 101 (67%) CFS patients. This was in comparison to just 8 out of 218 (3.7%) healthy controls being XMRV positive.

                                                                                                                                                                                                                                     XMRV vs MLV

The Lombardi-Mikovits paper in 2009 detected XMRV while the FDA/NIH paper detected MLV. XMRV is the initialism for Xenotropic Murine Leukemia Virus- related Virus. MLV is the initialism for Murine Leukemia Virus. Mikovits, Lo and Alter seem to have unanimously confirmed that both studies found the same retrovirus (Alter and Lo are two of the FDA/NIH study authors.) This retrovirus is a human retrovirus that is a member of the Gammaretrovirus family. There are a family of these Gammaretroviruses that are Murine Leukemia Virus-related Viruses and this is what both studies have detected.

The FDA/NIH study detected four slightly different types of these MLVs. This is similar to the other infectious retroviruses, HIV and HTLV which have several variants. The FDA/NIH study shows that there is a genetic diversity among MLVs infecting humans. Seven out of eight gag-positive CFS patients tested in the FDA/NIH study had their MLV mutate during the 15 year period in which their blood was drawn on the separate occasions. Since the WPI’s October 2009 study, the WPI have found more than one strain of MLV and this supports the FDA/NIH study results.

The FDA/NIH study authors wrote that “In contrast to the reported findings of near-genetic identity of all XMRVs, we identified a genetically diverse group of MLV-related viruses. The gag and env sequences from CFS patients were more closely related to those of polytropic mouse endogenous retroviruses than to those of XMRVs and were even less closely related to those of ecotropic MLVs.” ‘Polytropic’ forms of MLV can infect mice cells and non-mice species cells. ‘Xenotropic’ forms of MLV can’t infect mice cells anymore but can infect non-mice species cells. This supports the notion that the Lombardi-Mikovits paper and the FDA/NIH paper found the same retrovirus. The FDA/NIH study not just confirmed but also improved upon the Lombardi-Mikovits study by determining that the retrovirus studied can infect mice cells. The XMRV versus MLV confusion in this situation only centres around the semantics and nomenclature of retroviruses, not the science.

Prior to the FDA/NIH study being released, there was a lack of clarity concerning the nomenclature of the retrovirus the Lombardi-Mikovits and FDA/NIH studies found. This suggests that the proposed renaming of XMRV to HGRV may have stemmed from the FDA/NIH study result. Dr Alter has commented that a superior name (to XMRV) for the retrovirus is Murine Leukemia Virus- related Virus.

                                                                                                                                                                                                                                          CFS Cohort Used

The majority of the CFS patients used in the FDA/NIH study were from the New England area. None of these CFS patients were related and almost none had regular social contact. Dr. Anthony Komaroff (a CFS physician) supplied the CFS patients. The patients were deemed to be CFS patients based on many laboratory tests, a patient questionnaire, a physical examination and the patients fulfilling specific CFS criteria. This specific CFS criteria was the 1988 CDC criteria for CFS. There was a lack of diversity of CFS criteria in the mid 1990s (when the patients were diagnosed as CFS patients.) The 1988 CDC criteria, also known as the Holmes criteria, differed majorly from the current CDC CFS criteria. The 1988 CDC criteria excluded psychiatric diagnoses and required the presence of eight secondary symptoms for the patient to be diagnosed with CFS. This contrasts the current CDC criteria which does not exclude psychiatric diagnoses and requires just four secondary symptoms for the patient to be classified as having CFS.        

                                                                                                                                                                                                                              Criticisms of the FDA/NIH Study

The FDA/NIH study only tested a small number of CFS patients and healthy controls and hence the exact MLV positive percentages may not be entirely accurate. The study found 3 out of 44 healthy controls to have a MLV which equates to 6.8%. If one of the healthy controls that was MLV positive was not included in the study by chance, the MLV positive percentage would be reduced to 4.5%. If one of the healthy controls that was MLV negative was by chance replaced with a MLV positive healthy control, the MLV positive percentage would change to 11.4%. This variation of between 4.5%-11.4% MLV positive based on just one person in the study having a different result highlights the lack of precision that underscores the 6.8% healthy control MLV positive figure.

The FDA/NIH study utilised blood from CFS patients that was drawn 15 years ago. A greater number of CFS patients in may 2010 be MLV positive due to the infectious nature of MLVs. This means that more CFS patients are likely to be MLV positive now due to catching a MLV after already having CFS. For instance if I already have CFS (from a non-MLV source) and am MLV negative, then I have 15 years to be infected with MLV to change the MLV CFS prevalence. In other words, a small minority of CFS patients will be MLV positive but not have MLV as a cause of their CFS. This figure will most likely be very small if not negligible.

The FDA/NIH study used blood from healthy controls that was from blood donors. This blood was collected between the years 2003 and 2006. If MLVs are infecting the population at a rapid rate then the true prevalence of MLV in the healthy population may differ from 6.8% in the year 2010. The 6.8% figure may have been more accurate between the years 2003 and 2006.

The FDA/NIH paper mentions that “Future studies should adhere to consensus case definitions such as that developed by the Centers for Disease Control and Prevention (CDC.)” This is a very careless comment by the FDA/NIH study authors. The current CDC CFS criteria are much less restrictive in diagnosing CFS than the criteria used in the FDA/NIH study. The CDC is notorious for using flawed CFS definitions as well as controversial and heterogeneous CFS criteria. Leonard Jason has published a study showing that 38% of those with a major depressive disorder were misclassified as having CFS based on the new CDC CFS criteria. Jason’s study concludes that, “This study suggests that the Reeves et al. (2005) empirical case definition has broadened the criteria such that some individuals with a purely psychiatric illness will be inappropriately diagnosed as having CFS.” Jason’s study can be found here: http://www.co-cure.org/Jason-7.pdf

                                                                                                                                                                                                                              Negative Studies

Several studies that have aimed to detect XMRV have failed to do so. The question now arises as to what retrovirological techniques are required to detect MLVs. I have written in detail elsewhere on this blog about some of the flawed techniques and non-representative cohorts the XMRV negative studies have used. I mentioned some of the flawed techniques here: https://livingwithchronicfatiguesyndrome.wordpress.com/2010/06/30/xmrv-publications-by-fdanih-and-cdc-both-on-hold/

The negative studies have used the molecular synthetic clone of XMRV, which is VP62. VP62 is a very specific sequence that fails to detect XMRV or MLV variants. The FDA/NIH paper has emphasized that MLVs are genetically variant. This means that a natural isolate is required to detect MLVs as this accommodates detecting the variants of MLVs.

Prior to the release of the FDA/NIH study, Dr Katz claimed that the Lombardi- Mikovits study was evenly poised on a pair of scales with the negative XMRV studies. He then stipulated that if the FDA/NIH study confirmed the Lombardi- Mikovits paper, it would be analogous to placing an elephant on the Lombardi-Mikovits side of the scales. As the FDA/NIH study has now confirmed the Lombardi-Mikovits study, the scientific paradigm scales are now heavily favouring a high MLV- CFS correlation.

                                                                                                                                                                                                                                        How Does This Relate to the Future of CFS?

Despite a correlation between CFS and MLVs, causation has yet to be proven. It is currently premature to claim the scientific paradigm that MLVs cause CFS. Fulfilling Koch’s Postulate and determining if MLVs are causative of CFS is the next step scientifically. At the very least, it looks as if MLVs are a biomarker of CFS. The MLV-CFS studies also support the 2500 plus published journal articles that show that CFS is purely an organic disease. The psychosomatic proponents of CFS have had the last nail inserted into their psychological model of CFS. From “negative illness beliefs” alone it is impossible to be infected with an infectious human retrovirus that is not ubiquitous.  

                                                                                                                                                                                                                                        More Information

Dr Mikovits gives her thoughts on the FDA/NIH paper in a video found here: http://www.youtube.com/watch?v=9ZEwQUg7o6I&feature=channel&forumid=331851

Annette Whittemore congratulates the FDA/NIH study authors here: http://www.youtube.com/watch?v=ne7if7FKJFg&feature=channel

CFS Central has an excellent article about the FDA/NIH study including quotes from the study authors. This article can be found here: http://www.cfscentral.com/2010/08/fdanihharvard-xmrv-study-same-thing.html

The Wall Street Journal provides an overview of the situation here: http://online.wsj.com/article/SB10001424052748703846604575447744076968322.html

                                                                                                                                                                                                                        Conclusion

Today not only marks an historic day for the CFS community but also a victorious day for the scientific process. After being held back by government officials, the FDA/NIH paper has been published. The scientific paper has shown that the large majority of CFS patients have an infectious retrovirus that belongs to the Murine Leukemia Virus class. I’d like to finish with a quote from One Flew Over the Cuckoo’s Nest, “I mean—hell, I been surprised how sane you guys all are. As near as I can tell you’re not any crazier than the average asshole on the street.”

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                                                                                                                                                                                                                                     HGRV

It has been proposed that XMRV, the initialism for Xenotropic Murine Leukemia Virus-Related Virus be changed to HGRV. HGRV stands for Human Gamma Retro Virus. If one is currently XMRV positive, their disease is known as XAND which stands for XMRV Associated Neuroimmune Disease. If one is HGRV positive, their disease may be known as HGRAD. This is the initialism for Human Gamma Retrovirus Associated Disease.

                                                                                                                                                                                                                                   Source

Rich Van Konynenburg recently received a message from Dr. Joe Burrascano, a leading authority on tick-borne diseases. The message Dr Burrascano wrote to Rich was as follows:

“Hello all from Dr. B.
I just returned from the first official scientific symposium of the Whittemore-Peterson Institute on the topic of XMRV. We formed a working group to be in constant touch and we plan to meet regularly because advances are coming so rapidly.

Big news that everyone should know and adopt is that we have proposed a name change for the virus.

This virus is a human, not mouse virus, and it is the first and so far only gamma-retrovirus known to infect people. Also, it is clearly not an “endogenous” retrovirus (one that is present in all genomes due to ancient infection). Because of all of this, and because of the desire to begin on the right track:

• The new name of the virus is HGRV – Human Gamma Retro Virus.

• The illness caused by this infection is named HGRAD – Human Gamma Retrovirus Associated Disease.

We plan to announce this at the upcoming NIH retroviral conference this September.

Definitely stay tuned – the volume of new and important information about this virus and its disease associations is increasing rapidly and in my opinion should be a concern to every patient with chronic neuro-immune diseases, including those with chronic Lyme.

Joseph J. Burrascano Jr. M.D.
Water Mill, NY, USA”

The above article can be found here: http://www.prohealth.com/library/showarticle.cfm?libid=15543&utm_source=SiteTracking&utm_medium=SiteTracking&utm_campaign=home_LatestNews

                                                                                                                                                                                                                              Negative Consequences of Calling XMRV, HGRV

If HGRV does replace XMRV and HGRAD does replace XAND, there are some potentially negative consequences. The term HGRAD is a mixture of both an initialism (HG) and an acronym (RAD.) This means one likely pronunciation of HGRAD will be HG RAD (H and G pronounced as letters and the word “rad” following the H and G. Calling a disease “rad” a colloquial term and synonym for awesome or cool seems inappropriate. Another possible pronunciation of HGRAD is “H- GRAD.”

If HGRAD is pronounced as only an acronym then it will be called “Hagrid.” Hagrid is the half-giant gamekeeper from the popular Harry Potter empire.  If HGRAD is pronounced as an acronym, it may also be called “Haggard.” Haggard has several definitions, one of which is “tiredness.” Millions of CFS patients around the world have suffered due to naming the illness the misnomer: “Chronic Fatigue Syndrome.” The layman translates “Chronic Fatigue Syndrome” literally to “always tired” which completely undermines the severity of the illness. A study showed that if patients present to a physician with the illness named “Chronic Fatigue Syndrome,” the physician didn’t believe their illness was very severe. If the patients presented to the same physician and just presented their symptoms (not revealing the name CFS) the physician deemed their illness more severe. Also a survey of medical trainees showed that they considered “Chronic Fatigue Syndrome” to be less severe than “myalgic encephalopathy.” These are not isolated example of the harm that the name CFS has brought to patients.

The term XMRV encompasses the word “Leukemia” which to the layman highlights the severity of the illness.  The term XAND contains the word “Neuroimmune” which emphasises the seriousness of the disease. The term “Human Gamma Retro Virus” does not contain any words that can be interpreted as showing the layman the true disabling nature of the illness.

The initialism HGRV uses the term retrovirus as two distinct words: Retro Virus. This contrasts the disease name HGRAD which initialises retrovirus as a single word. My understanding is that retrovirus is a single word hence fragmenting the term into Retro Virus may be erroneous.

                                                                                                                                                                                                                              Positives Consequences of calling XMRV, HGRV

XMRV is the third known infectious human retrovirus after HTLV and HIV. The nomenclature of infectious human retroviruses to date have the term “human” as a prefix.  It therefore seems appropriate to have the term “human” as a prefix for this retrovirus, which the name HGRV accommodates. Also the disease name XMRV contains the word Murine, which means “mouse.”  This does not adequately explain the infectious transmission of this retrovirus to humans.

The disease XMRV contains the words “virus-related virus.” This is not a very scientific term and more of a general term. Science likes to be precise in classifications and calling something “related” is not precise. It seems more appropriate to determine if a distinctive new classification branch is required or whether it can definitely be contained within the existing classification branch. A further reason that HGRV is preferable to XMRV involves the term retrovirus as opposed to virus. Although virus is the general classification term, retrovirus is a more accurate classification term. Several laymen have commented on XMRV being a run-of-the-mill standard virus like a cold. This misconception has arisen partly due to the word “virus” in the name of XMRV. Calling the disease retrovirus in the name, like HGRV does, shows to the layman that the disease is distinctive from a standard virus like a cold.

The term XAND, has potentially negative connotations, depending on how the term in pronounced. If it is pronounced as an acronym it sounds like “sand.” If it pronounced as a mixture of initialism (X) and anagram (AND) it sounds like “X” the letter following by “and” the word. Telling someone you have “X and” may results in confusion, finishing the sentence with a conjunction. There may be further reasons for the name change to HGRV that are unbeknownst to me. I speculate that these may involve the signalling of a fresh slate for research into the disease and funding for the disease.

                                                                                                                                                                                                                               Counter Arguments to the Positives and Negatives

I will now present some counter arguments to the positive and negative reasons I have mentioned above. Many of the arguments that I have presented are contingent upon an appeal to the layman’s interpretation of the disease name. The layman’s literal interpretation of the disease name may be superseded by the seriousness of the illness that the media and government may present. It is also questionable as to whether XMRV/HGRV positive patients want their disease to be known as serious. A positive to the disease being considered serious may be the more appropriate and caring treatment from friends, family and physicians alike. This would be a stark contrast to the current paradigm in which CFS is not widely considered serious. A negative to the disease being considered serious involve the infectious nature of the illness. This may entail a general public fear of catching the illness and hence an isolation of disease positive patients.

The term HGRAD overcomes some of the etymological issues of similarly sounding terms if it is pronounced as an entire initialism, H-G-R-A-D.

                                                                                                                                                                                                                                 History of Naming HIV and AIDS

AIDS was originally named GRID, Gay Related Immune Deficiency. Once it was realized that the disease did not only affect homosexual men, the CDC changed the name to AIDS, Acquired Immune Deficiency Syndrome.

Robert Gallo, one of the co-discoverers of the fact that HIV infects AIDS patients, claimed that the virus (HIV) was similar in shape to other HTLVs. He called HIV, HTLV- III. Luc Montagnier, the other co-discoverer of the fact that HIV infects AIDS patients, determined that HIV was different, immunologically to HTLV and called the retrovirus LAV, Lymphadenopathy-Associated Virus. The International Committee of Taxonomy of Viruses replaced HTLV-III and LAV with the name HIV, Human Immunodeficiency Virus. This is relevant to XMRV/HGRV as it possible a group with higher nomenclature authority may change the name of the retrovirus again.

                                                                                                                                                                                                                                     HGRV Already Taken?

The initialism HGRV is already in use medically. HGRV stands for Human Gastric Residual Volume. This is not a common medical expression as this term is mentioned less than 4000 times on the internet according to a Google search.

The initialism HGRV is also already used to name a separate virus. This virus is a botanical virus called Hibiscus Green Ringspot Virus. This is a rarely documented virus that is mentioned less than 30 times on the internet according to Google. Both of these uses of HGRV are uncommon meaning that there will most likely not be any confusion with HGRV the retrovirus if is enters the medical lexicon

                                                                                                                                                                                                                        Conclusion

Dr. Burrascano’s comments are ambiguous regarding whether XMRV will definitely be changed to HGRV or if this is only a proposal. The name HGRAD may potentially lead to a misconception about the disease depending on how the term is pronounced.  Almost any name is better than Chronic Fatigue Syndrome and I am personally not too worried about the name HGRV as it is not a misnomer.  I am more concerned about the disease name HGRAD. Ultimately the name is not that important as long as the researchers are studying the same retrovirus.

I’d like to finish with a quote by Gilbert Newton Lewis, “There is always the danger in scientific work that some word or phrase will be used by different authors to express so many ideas and surmises that, unless redefined, it loses all real significance.” This is what happened with the term ‘Chronic Fatigue Syndrome’ but will not happen again with this retrovirus.

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An XMRV Update

                                                                                                                                                                                                                                                     Over the past two days, myriads of snippets of information regarding XMRV have been partially revealed. I will examine this XMRV related information.

                                                                                                                                                                                                                                             Dr Katz’s Webinar

Yesterday, Dr Katz presented a webinar on XMRV and blood safety.  A YouTube video of his webinar (lasting over 74minutes) can be found here: http://www.youtube.com/watch?v=ex6iS_2RqiY

Dr Katz described the current scientific paradigm regarding XMRV and CFS as evenly poised. He made the analogy of the set of negative XMRV studies weighing the same on a set of scales as the original WPI study. He then alluded to the FDA/NIH XMRV study which is expected to show XMRV in a high percentage of CFS patients. He said that if this study is released linking CFS to XMRV then it will tip the scales heavily in the favour of the XMRV and CFS link. He said the FDA/NIH study would be comparable to placing an elephant on the currently evenly balanced scales. Dr Katz predicted that it would take a year for a clinical XMRV assay to be available for diagnostics.

                                                                                                                                                                                                                                   Annette and Andrea on Nevada Newsmakers

Yesterday, Annette Whittemore and Andrea Whittemore-Goad appeared on Nevada Newsmakers. They discussed XMRV and the opening of the WPI.

The interview is available for viewing on YouTube in two parts.

Part 1 is here: http://www.youtube.com/watch?v=GQJ60UdWz0c

Part 2 is here: http://www.youtube.com/watch?annotation_id=annotation_119896&v=4qLrFxxEf6w&feature=iv

Both Annette and Andrea sounded very optimistic about the link between XMRV and CFS and referred to XMRV as a “biomarker.” Andrea mentioned that she has recently been seeing an infectious disease specialist and her condition has correspondingly improved. Annette and Andrea also mentioned having the results of a small trial. Some people on various forums have speculated that they were referring to a treatment trial.

                                                                                                                                                                                                                                             Dr Mikovits and a Newspaper Article

Perhaps the most exciting news of the past few days was the information that Dr Mikovits revealed in an interview with the Reno Gazette-Journal (RGJ). The article can be found here: http://www.rgj.com/article/20100816/NEWS/100816069/1321

The article mentions that “Dr. Judy Mikovits, one of the lead researchers with the Whittemore Peterson Institute for Neuro-Immune Disease in Reno, said the FDA’s review of their findings is scheduled to be published in September.” There has been some speculation online regarding the release date of the long awaited FDA/NIH study. There has also been speculation about whether the FDA/NIH studies will be released separately or together. Some media sources have reported that the FDA and NIH studies are distinct while other media sources have classified them as the same study. The majority of online material mentioning the FDA and NIH studies refers to them as being part of the same study. I believe the most likely scenario involves the FDA/NIH being a single study that will be released during September.

During her interview with the RGJ, Dr Mikovits mentions “There has been an issue over whether anybody could replicate our study, and it will not only confirm our findings but extend our findings, which is really exciting for us.” Dr Mikovits is reiterating what has already been widely reported- The FDA/NIH study confirms the original WPI study. 

The RGJ article continues, “Mikovits said they also have new, unpublished data concerning the retrovirus, XMRV, that could lead to treatment of Chronic Fatigue Syndrome.”

Dr Mikovits mentions “We have immune system profiles and we can tell by the immune system how the XMRV is doing the damage,” she said. “So we could have a diagnostic test to follow clinical treatment and show that people’s immune systems go back to normal. That’s the latest data that’s really amazing. That’s what we’re after.” This study hasn’t been released however what Dr Mikovits mentions is some of the most hopeful information regarding treating XMRV. This statement by Dr Mikovits also supports the hypothesis that XMRV does cause symptoms and possibly disease. The data detailed above will most likely be published before the end of the year in a clinical immunology journal.

Dr Mikovits also says “We totally expect at least one clinical treatment trial before the end of the year,” she said. “That is our goal and that’s what this new facility is for.” This is an encouraging statement for CFS patients as clinical treatment trials can often be a long and drawn out process.

Overall, the enthusiasm of Dr Mikovits is apparent throughout the RGJ article. This enthusiasm supports the notion that the WPI is still confident of the XMRV-CFS link.

                                                                                                                                                                                                                                    XMRV conference

The first international XMRV conference will be held on the 8th of September 2010. The conference program can be found here: http://www.virology-education.com/html/virology/document_download.cfm?doc=7B8A4161-945A-B176-59E650D0423712C5.PDF&doc_name=Program_XMRV_final

 Originally Dr Mikovits wasn’t invited to speak at this conference however her name has recently been added to the program.  Dr Mikovits will be discussing the “Detection of infectious XMRV in the peripheral blood of chronic fatigue syndrome patients in the United Kingdom.” Dr Lo will also be presenting the results of the FDA/NIH study at this conference. The results of the Swedish study looking for XMRV in the blood of CFS patients will also be revealed at this conference.

                                                                                                                                                                                                                                    XMRV Antibody Study

A study has been published today titled “Characterization of antibodies elicited by XMRV infection and development of immunoassays useful for epidemiologic studies.” The abstract of this study is available here: http://www.retrovirology.com/content/7/1/68

The complete paper can be found here: http://www.retrovirology.com/content/pdf/1742-4690-7-68.pdf

This is an exciting result as it supports the notion that XMRV does cause an immune system response. This increases the likelihood that XMRV does cause human disease. It also supports the Lombardi et al. study which found an XMRV antibody response in a high percentage of CFS patients.

                                                                                                                                                                                                                                             Dr David Bell’s Newsletter

Dr Bell’s latest Lyndonville newsletter is available here: http://www.davidsbell.com/LynNewsV7N2.htm

Dr Bell writes that “It is my educated guess that XMRV can be found and that it will turn out to be the cause of this disease (CFS.)”

Dr Bell also speculates that if XMRV does cause CFS it does so by knocking out enzymes which causes “massive oxidative stress.” Dr Bell speculates further that these enzymes may be makers to gauge the success of treating XMRV. Dr Bell’s newsletter is worth reading as he discusses more about XMRV and speculates about its role in CFS including further mechanisms of action.

                                                                                                                                                                                                                                          The WPI Opening

On Saturday the 21st of August, the Whittemore Peterson Institute (WPI) will be officially opened. A flyer with details about the opening can be found here: http://wpinstitute.org/news/docs/cmm_opening.pdf

The WPI is an institute dedicated to unravelling the mysteries behind neuro-immune disease. The WPI opening is part of the opening of the Center for Molecular Medicine at the University of Nevada, Reno. The Patient Advocate has written a wonderful article detailing the different aspects of the WPI building and what the WPI will use the building for. The Patient Advocate’s article can be found here: http://cfspatientadvocate.blogspot.com/2010/08/rainmakers-wpi-makes-things-happen.html

                                                                                                                                                                                                                                          The WPI Symposium

The WPI held an “invitation-only scientific symposium” today. The WPI brought together “leading researchers, clinicians and key collaborators from the medical and research community to discuss the latest XMRV research findings, medical research data and evaluate treatment outcomes since the publication of their 2009 XMRV study.” The symposium was titled ‘XMRV in Human Disease’ and was organised by the WPI. More information about the symposium and some details of the WPI opening can be found in this media release: http://www.wpinstitute.org/news/docs/WPI_pressrel_081610.pf

                                                                                                                                                                                                                        Conclusion

The past two days have been filled with a foreshadowing of what is to come regarding XMRV research. Most of the evidence of the past two days will be published over the coming months. The FDA/NIH study should be published imminently and should signify a paradigm shift in the CFS and XMRV worlds. Each piece of information that I have mentioned in this article symbolises a puzzle piece. Some pieces are larger than other however all the pieces seem to be fitting together nicely.  The jigsaw that is XMRV is coming together.

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XMRV Advocacy

I originally intended to write this ‘XMRV Advocacy’ post with information aimed at emailing specific government, CDC and Health Department officials demanding action on XMRV and a release of the FDA/NIH paper. The latest rumour is that the FDA/NIH study will be released within 3 weeks. If the FDA/NIH study is not released or if the government is indecisive in action towards XMRV after the paper is released, I will write another ‘XMRV Advocacy’ post. 

This ‘XMRV Advocacy’ post is aimed at emailing media with the hope that the media cover the XMRV story in coming weeks. If the media do catch onto the XMRV story in coming weeks they will then most likely report the positive FDA/NIH study. This will put more pressure on the government to act on XMRV. 

  

Letter 

This is a short letter that anyone can copy and paste and then email. Feel free to modify the letter if you wish. I believe there are 4 important aspects to increasing the chances of the media covering XMRV. These are 

  1. A short letter that summarises the main points. This is to encourage the person receiving the email to read it. If the letter is too long or detailed there is a chance it won’t be read.
  2. Many letters must be sent. If the media see great interest or passion in a potential story they are more likely to cover it.
  3. Emails must be sent to as many media outlets as possible. This increases the chances of one of the outlets covering the XMRV story.
  4. The media outlets must be assured that the public will find the news story interesting. On a fundamental level the media works by covering stories that the public want to hear. The two main factors the media look for are:

1. Great interest in a story 

2. The story affects many of the readers/viewers 

If these two points are fulfilled then there is a greater chance that the story will be produced. It is important to emphasise these two points when writing to the media. 

Once again feel free to email the letter below. 

                                                                                                                                                                                                                                                 To whom it may concern, 

I encourage your media outlet to do a story on XMRV. 

XMRV (Xenotropic Murine Leukemia Virus-Related Virus) is a retrovirus similar to HIV. During October 2009, the Whittemore Peterson Institute, the Cleveland Clinic and the National Cancer Institute published a study on XMRV, in the eminent journal Science. These groups found XMRV in 3.7% of the general population and 67% of Chronic Fatigue Syndrome patients. Later studies have shown that greater than 95% of Chronic Fatigue Syndrome patients are infected with XMRV. XMRV is a newly discovered retrovirus and has been recently linked with causing human disease. XMRV has also been associated with prostate cancer, atypical MS, fibromyalgia and autism. If 3.7% of people are infected with XMRV, this translates to approximately 12 million Americans. These 12 million Americans may be at risk of the above mentioned diseases or may have had their disease caused by XMRV. 

The National Institute of Health (NIH) and the Food and Drug Administration (FDA) have recently finished a study that allegedly confirms the original Science published study. For the alleged confirmation, see this press release: http://www.mmdnewswire.com/xmrv-9040.html. The NIH/FDA study was approved for publication by the journal ‘The Proceeding of the National Academy of Sciences.’ Government officials at the 11th hour decided to stop this study being published (this occurred within the past 2 weeks.) 

The UK’s Independent newspaper recently covered this story here: http://www.independent.co.uk/news/science/study-that-solves-chronic-fatigue-syndrome-blocked-2022195.html 

Despite the XMRV studies being American-centric, this story was the most popularly read and emailed story for several days in the Independent Newspaper. The New York Times also covered this story on the 14th of July 2010: http://www.nytimes.com/2010/07/14/health/14fatigue.html?_r=1&ref=health 

I believe that your media outlet doing an XMRV retrovirus story would be of great interest to the public. Many people are currently infected with XMRV and countless people will be infected. Everyone will know at least one person who is infected with this newly discovered retrovirus that may cause serious human disease.
Thankyou for taking the time to read this and I hope you consider doing a story on the XMRV epidemic. 

Kind Regards, 

   

Email Addresses 

 Below are some media sources that may cover XMRV. 

60 Minutes: 60m@cbsnews.com 

Washington Post (Health News): health-science@washpost.com 

Washington Post (National News):  national@washpost.com 

USA Today: Editor@usatoday.com 

USA Today (health care reporter):ssternberg@usatoday.com 

USA Today (health and science reporter): mhealy@usatoday.com 

Los Angeles Times (health care editor): pat.mcmahon@latimes.com 

Los Angeles Times (Health and Science editor): tami.dennis@latimes.com 

                                                                                                                                                                                                                                     America Live w/ Megyn Kelly: kelly@foxnews.com 

America’s Newsroom w/ Bill and Martha: americasnewsroom@foxnews.com 

Bulls and Bears: bullsandbears@foxnews.com 

Cashin’ In: cash@foxnews.com 

Cavuto on Business: cavuto@foxnews.com 

Forbes on FOX: forbes@foxnews.com 

FOX & Friends: friends@foxnews.com 

FOX News Specials: fncspecials@foxnews.com            

FOX News Sunday: fns@foxnews.com 

FOX News Watch: newswatch@foxnews.com 

FOX Report Weekend: foxreport@foxnews.com 

Geraldo at Large: atlarge@foxnews.com 

Hannity: hannity@foxnews.com 

Happening Now w/ Jon Scott & Jane Skinner: happeningnow@foxnews.com 

Huckabee: huckmail@foxnews.com 

Glenn Beck: glennbeck@foxnews.com 

The Journal Editorial Report: jer@foxnews.com 

On the Record w/ Greta Van Susteren: ontherecord@foxnews.com 

Red Eye w/ Greg Gutfeld: redeye@foxnews.com 

Special Report w/ Bret Baier: special@foxnews.com 

Studio B w/ Shepard Smith: studiob@foxnews.com 

The O’Reilly Factor: oreilly@foxnews.com 

International viewers can email Fox here: FOXaroundtheworld@foxnews.com 

                                                                                                                                                                                                                                             Sky News(UK): for the same day news: news@sky.com 

Sky News (UK): for a future event: news.plan@bskyb.com  

Sky News online (UK): newsonline@bskyb.com  

   

Further XMRV/CFS Advocacy 

Currently the UK press all go to the notorious Simon Wessely for all matter CFS. The Science Media Centre is responsible for this. To try and change the go-to man for CFS matters in the UK Tom Sheldon from the Science Media Centre should be emailed: tsheldon@ri.ac.uk
XMRV petition: 

Petition on XMRV: http://healthcare.change.org/petitions/view/xmrv_allow_science_to_progress 

Obama’s Science advisor is John Holdren. He can be contacted at AskDrH@ostp.gov 

   

Conclusion 

Once again I emphasise that if the FDA/NIH paper isn’t released for whatever reason, then I will write another ‘XMRV Advocacy’ post with another letter and government, CDC and health official’s emails. Ideally the FDA/NIH study will be released within 3 weeks and hopefully emailing the media will result in some media doing stories on XMRV. If the media make the public more aware of XMRV then it hopefully forces the government into action. 

As Samuel Adams said, “It does not require a majority to prevail, but rather an irate, tireless minority keen to set brush fires in people’s minds.”

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CDC XMRV study released

The CDC’s long awaited XMRV study has finally be released. The abstract of the study can be found here: http://www.retrovirology.com/content/7/1/57 and the full 41 page study can be found here: http://www.retrovirology.com/content/pdf/1742-4690-7-57.pdf

The CDC study was started not long after the 9th of October 2009 when the Lombardi-Mikovits study was released. The CDC study was completed before February the 1st 2010.

 

The results
As the Wall Street Journal (WSJ) and CFS Central (http://www.cfscentral.com) reported correctly (several days ago), the CDC failed to find XMRV in the blood of the CFS cohort or the healthy control group. I have only had a chance to skim read the CDC study but already I can say that they used very dubious techniques with a dubious cohort leading to their flawed study. Some of the methodological flaws of the CDC study include the ones I  anticipated they would make and I wrote about in this article: https://livingwithchronicfatiguesyndrome.wordpress.com/2010/06/30/xmrv-publications-by-fdanih-and-cdc-both-on-hold/

Essentially the CDC study involved looking for XMRV without using the techniques needed to find XMRV. They searched for XMRV in a cohort that didn’t consist of CFS patients yet they labelled the cohort ‘CFS patients.’ If the CDC used a similar study methodology to look for ‘lung cancer in smokers,’ it would look like this. 1. Gather a group of non-smokers than have never smoked in their life and call them smokers. 2. Following this, look at their feet for lung cancer. If an identical methodology to the CDC’s XMRV study was applied to this hypothetical ‘lung cancer-smoking study,’ the conclusion would be that smoking doesn’t cause lung cancer, in fact nothing causes lung cancer.

 

The FDA/NIH XMRV Study

According to the CFIDS Association of America’s Facebook page, found here: http://www.facebook.com/CFIDSAssn Dr Harvey Alter, the lead author of the FDA/NIH study said “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”

If this statement is correct and indeed referring to the NIH/FDA XMRV study that found XMRV, then several questions are raised. The WSJ reported that the government had put BOTH the CDC and FDA/NIH study on hold from being published. The WSJ were correct in their details of the contents of the CDC study and saw an email between insider scientists. The WSJ article also quotes prominent figures that have an insider’s view on the situation. These comments by ‘prominent figures’ supported the WSJ article’s conclusion that both the FDA/NIH and CDC studies would be put on hold.

According to a press release by ORTHO (found here: http://www.mmdnewswire.com/xmrv-9040.html) Dr Alter confirmed that an NIH/FDA XMRV paper was to be published. It is reasonable to assume that for Dr Alter to confirm this, the paper would have been accepted for publication. This directly contradicts his statement from the CFIDS Facebook page that “Our paper has not yet been accepted for publication.”

 

Sorting Out the Contradictions

The CDC paper was completed by February 2010 and not published for 5months (until today.) It was released 2 days after the WSJ exposed the CDC study vs FDA/NIH study contradictory results. The CDC study was released 2 days after the WSJ reported on both studies being held back. This backpedal on publishing the CDC paper and then release of the CDC paper doesn’t seem like a temporal coincidence.

The government most likely originally planned on delaying both papers. When this information leaked into the public domain through the means of the WSJ, the government most likely rethought this strategy. The question then arises as to why did the government approve the CDC study being published and ask the FDA/NIH study authors to conduct additional experiments to confirm their results? To answer this question it is necessary to examine the situation from the government’s point-of-view.

 

The Options the Government Had

The government had several options once the information of them delaying both papers reached the public domain.

Option 1: The government could have let things be (persisted with not releasing either paper) and let the scientists sort things out behind closed doors to determine the correct study

Negatives to option 1: The government would have been (and indeed was) accused of biasing science and letting politics potentially dictate scientific results. The government would have also been accused of being unscientific by deciding science in the private domain, behind closed doors. This would have caused an outrage (and in fact did) among the scientific community. These reasons seem sufficient for the government to abort this option once it became public knowledge, thanks to the WSJ article.

 

Option 2: The government could have released the FDA/NIH study and held the CDC study up.

Negatives to option 2: The government probably still isn’t 100% sure what role XMRV plays in human disease nor the prevalence rate of XMRV infection. If it released the positive FDA/NIH study now it would need measures in place to test the public with a reliable XMRV test. It would also need knowledge on XMRV such as mode of transmission, which it currently doesn’t have. These reasons seem sufficient reasons from the government’s point of view to abandon this option.

 

Option 3: The government could have released both the FDA/NIH and CDC studies.

Negatives to option 3: After already ruling this option out according to the WSJ, it would seem unlikely for the government to backpedal and release both studies. The government would be sending a weak message out to the public in finding contradictory scientific results. The government would also not be sure where to stand on XMRV issues officially.

 

Option 4: The government could have released the CDC study but held back the FDA/NIH study.

Consequences to option 4: Through this option, the government would have bought more time to fully explore the XMRV threat. They could work out any ambiguities regarding all aspects of XMRV and could determine an official government stance on XMRV. They couldn’t be accused of doing science in the private arena as they released the CDC study. Their official stance would be that ‘the evidence suggests that XMRV doesn’t cause disease.’ This official stance could always change in the future months if the additional experiments performed by Alter et al determined their FDA/NIH study to be correct.  

From the government’s point-of-view, it is easy to see why they chose ‘option 4.’ If XMRV does turn out to be disease causing, they would have bought more time to develop measures to prepare for the threat. If XMRV doesn’t turn out to be disease causing, they would have released the “right” study that didn’t find XMRV.

The above options and consequences are all hypothetical and what I imagine the government’s thought process would be like concerning XMRV. The thought process is in no way what I think the government should have done.

 

Conclusion

As I write this there is a level of confusion among the CFS patient community, as the CDC study was only released an hour ago. Hopefully comments will be made by some organisation to clarify the seemingly contradictory state-of-affairs at present. At the moment it seems the FDA/NIH study is still on hold and Dr. Alter has been told to conduct further experiments to support the FDA/NIH study. The fundamentally flawed CDC study should be the study having additional experiments performed to prove its validity. For CFS patients this is déjà vu of 20 years ago- dealing with the Centre for Disease Control that is not concerned with ‘disease control.’ This time however, the globalisation of the world through mediums such as the internet mean we are not individual CFS patients but a group united. Individually we are just timid souls searching for truth yet standing together we are a force to be reckoned with that will expose the truth.

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The XMRV study conducted by the NIH and the FDA has been delayed for publication by its authors. The CDC XMRV study publication has also been put on hold for publication by its authors at the 11th hour. The Wall Street Journal (WSJ) picked up on this information and wrote an article about it here: http://online.wsj.com/article/SB10001424052748703374104575337160225739290.html?mod=googlenews_wsj#articleTabs%3Darticle

It has been reported that the CDC failed to find XMRV in the blood of CFS patients. This contrasts the FDA/NIH confirming the original Lombardi- Mikovits study in finding XMRV in the blood of a significant number of CFS patients.

After devoting many months to a scientific paper, scientists tend to be confident of their results and the icing on the cake for them comes when their study is published in a scientific journal. It is therefore rather suspicious that both study groups’ authors, the FDA/NIH and the CDC asked for their papers to be put on hold for publication. The WSJ article reports that “senior public-health officials” were the reason that both papers were thwarted from an imminent publication.

 

Possible Reasons for the Delay

I will explore the possible different reasons for the delay of publication of these two studies. I am assuming that the WSJ is correct in that “senior public-health officials” were the reason that the papers were put on hold.

1. The government may now know that XMRV causes disease and between 3% and 7% of the population are infected with XMRV. If both studies were released, the government may have felt unprepared for the consequences of a Lombardi-Mikovits confirmation study. In order to “regain control” of the situation, the government may have delayed both studies to give itself extra time to be fully prepared for the XMRV threat. Very little is known about XMRV and the government may have wanted a 100% reliable XMRV test to be available to the public before revealing the XMRV threat. The government may have also wanted to gain more knowledge regarding the ease of transmissibility of XMRV to avoid further public fear. It may also have wanted a definitive list of illnesses XMRV can be responsible for.

                                                                                                                                                                                                                                               2. Another possible reason for the delay concerns the different conclusions on XMRV by different government departments. For the government to release two conflicting studies (1 of which has to be flawed) may be seen as failing to be an appropriate medical authority. The government may also feel a level of embarrassment at presenting contradictory findings. This situation would be problematic for the government regarding its recommendations on XMRV and an official XMRV stance.

                                                                                                                                                                                                                                         Why They Should Release the Studies

1. Scientific progress is a collaborative, world-wide effort. Scientists around the entire world contribute to scientific knowledge. The US government not releasing the XMRV studies results in the consequence of all scientists outside of the US government not being able to build upon, replicate, improve and critique the US government scientists work. One of the attractive aspects of a scientific journal is that the readership is generally an expert in the specific field. The government preventing these experts from analysing the studies,thwarts or at least delays scientific progress.

                                                                                                                                                                                                                                               2. Science is known for is objectivity and separation from political agendas. The act of the US government not releasing the XMRV studies is a slap in the face to science. Science is played out in the public yet professional arena (as opposed to the private arena.) To solve scientific issues behind closed doors leads to the possibility of government agendas dictating the scientific results to suit themselves. This is as opposed to the way science should work in scientific results dictating government agendas.

                                                                                                                                                                                                                                                 3. By not releasing the studies into the public arena, the government is directly delaying the scientific process. If only a few scientists (as opposed to scientists around the world)are to decide if the FDA/NIH or CDC study is correct then a longer time will lapse before a conclusion by the wider scientific community on XMRV is settled upon.

                                                                                                                                                                                                                                                4. The delay mentioned in (3) means a delay of treatment for CFS patients and those patients infected with XMRV. The delay also means that more people will become infected with XMRV while the government decides on this issue within their own time frame.

                                                                                                                                                                                                                                                5. If the government released the FDA/NIH study, a numerable amount of scientists and institutions would put a large amount of money towards XMRV research. At the moment the Lombardi-Mikovits study remains officially unconfirmed. If the FDA/NIH study was released, the Lombardi-Mikovits study would become officially confirmed resulting in a wave of immediate worldwide research towards XMRV.

                                                                                                                                                                                                                                                    6. The question now arises on the timeframe until the government reaches an internal consensus on XMRV. There is little external pressure on the government to hurry along with its XMRV research and consensus. If the Lombardi-Mikovits confirmation study was released by the government, they would have to work swiftly on XMRV as the public would demand this. If the general population is not aware of an XMRV threat (as the situation is like at the moment) then the government can do things at a leisurely pace.

                                                                                                                                                                                                                                               The delay may be good for the superficial government image but is bad for the people the government agencies are meant to be helping- the CFS patients and potentially the XMRV positive patients. The misperception of the misnomer that is CFS means the wider public probably wouldn’t be too worried about catching CFS, although they should be.

                                                                                                                                                                                                                                       What May Have Been Wrong With the CDC Study

I am assuming the CDC study is flawed in its conclusions and will examine where they may have went wrong. This is all speculation as I haven’t read the CDC XMRV paper. I am hypothesising on where the CDC may have gone wrong in not finding XMRV in CFS patients.

 

Cohorts

The CDC are notorious for using flawed CFS definitions as well as controversial methods of finding patients for their CFS studies. Let’s assume the CDC used their normal cohorts for this XMRV study.

They find their cohorts by phoning up a cross section of the population and asking them questions such as whether they are fatigued. (From http://www.cdc.gov/cfs/cfsgastudy.htm) They then give the positive respondents medical examinations that are intended to determine if their apparent “fatigue” is from an obvious organic source, to exclude a CFS diagnosis. The medical examination DOESN’T involve doing any specific testing for things considered to be potential CFS biomarkers such as NK cell function or SPECT scan tests.  After their medical examination, if the subjects fit into the CDC criteria for CFS, they are included in a study. The CDC criteria for CFS is highly controversial and a world apart from the Canadian Criteria that has almost ubiquitously been recognised by CFS specialists as sufficient to diagnose CFS.

The former head of the CFS department of the CDC said 84% of the people they found through random phone interviews and the CDC diagnosed as having CFS didn’t know themselves they had CFS. (From http://www.cfidsreport.com/News/06-CDC_CFS_Reeves.htm)

Also the CDC researchers determined that the average workload of its CFS cohort was 48 hours per week. (http://www.cfidsreport.com/News/06-CDC-CFS-Controversy.htm)

If the CDC did use their traditional cohorts and techniques of diagnosing CFS patients, then their failure to find XMRV in their cohort isn’t surprising. If their XMRV retrovirus finding techniques were correct they would have by their own study shown their cohort to NOT represent CFS patients.

 

Did the CDC Find it in Anyone?

The CDC study according to the WSJ failed to find XMRV in their CFS patients. They may have failed to find it in their healthy controls. If this was the case, they would have used very dubious techniques similar to the European failed XMRV attempts that didn’t find XMRV in anyone. If the CDC didn’t find XMRV in anyone, it contradicts the findings of many groups such as: The Whittemore Peterson Institute, The National Cancer Institute, The Cleveland Clinic, the Japanese Study, The University Medical Centre-Hamburg, The Drug and Food Administration and The National Institute of Health. All of these groups found XMRV in a similar, comparable percentage of the healthy population.

 

Hindsight

When the CDC started their XMRV study, (not long after the 9th of October 2009) it wasn’t widely known how difficult it was to detect XMRV. Since the WPI study, the failure of many groups to detect XMRV in prostate cancer and CFS has highlighted the need for specific techniques. The CDC didn’t have this hindsight and may have overconfidently completed their study. The CDC study was completed before the start of February- a much shorter timeframe than the Lombardi-Mikovits study.

 

Techniques Used

Without having read the CDC XMRV study, I can only guess what mistake they made in managing not to find XMRV in CFS patients. The other studies that failed to find XMRV may have had comparably flawed methods to the CDC. The CDC may have messed up like these studies in areas such as:

  • Using the wrong cohort (i.e. not true CFS patients)
  • Failing to amplify, culture or activate their samples
  • Using old blood
  • Looking in non-replicating cells for XMRV
  • Using a PCR technique designed at detecting a lenti-retrovirus such as HIV as opposed to a gamma-retrovirus such as XMRV.
  • Using a PCR test not capable of detecting the low tire levels of XMRV
  • Looking for the primer pairs for ENV as opposed to a different primer pair
  • Looking for the primer pairs for ENV which may not have been sufficient to find XMRV due to diversity of that area

 

It becomes evident that finding XMRV requires a very specific technique and changing one variable even slightly from the original Lombardi-Mikovits paper may be sufficient to not find XMRV. Dr Suzanne Vernon highlighted this point when she talked about the differences between the Imperial College London XMRV study and the Lombardi-Mikovits XMRV study. She writes:

  • The blood was collected from CFS patients in different types of blood collection tubes. 
  • The genomic DNA was extracted and purified using different techniques. 
  • The amount of genomic DNA included in the amplification assay was different. 
  • Different primer sequences were used that amplified different regions of the XMRV proviral DNA. 
  • The conditions of the PCR amplification assay were different – from the numbers of cycles, to the type of polymerase used.”

Dr Vernon’s full article can be found here: http://www.cfids.org/cfidslink/2010/010603.asp

                                                                                                                                                                                                                                        Lead Author

According the WSJ, the lead author of the CDC XMRV paper was the microbiologist, William Switzer. He was also involved in the study titled, “Prevalence of Xenotropic Murine Leukemia Virus in Prostate Cancer.” The abstract of the paper can be found here: http://www.retroconference.org/2010/Abstracts/37160.htm

In his prostate cancer study, Switzer found 1.2% of prostate cancer patients to be positive by ENV and POL PCR, which means they probably had XMRV. This number is distinctly different from other prostate cancer-XMRV studies which have found XMRV in as high as 40% of those suffering from prostate cancer.

 

Conclusion

Given the CDC’s history of treating and viewing CFS, their negative XMRV-CFS study is a further sign of their failure to understand the complexities of CFS. If the government had a scientific viewpoint they would let the scientific process take its natural course (releasing both papers) which would involve embarrassing the CDC. Instead the CFS patients must wait on bureaucracy rather than a global scientific effort.

                                                                                                                                                                                                                                    

UPDATE: Since writing this article, some new information has emerged. This new information is definitely worth reading and can be found on the CFS Central website http://www.cfscentral.com/2010/06/embargoed-studies-redux.html

This new information (although only a rumour at the moment) reveals the details of the FDA/NIH study and CDC study, including XMRV positive percentages.    

                                                                                                                                                                                                                                     UPDATE: If you’re interested in signing a petition urging the DHHS to allow both papers to be published, click here: http://healthcare.change.org/petitions/view/xmrv_allow_science_to_progress

This petition is only for U.S. residents only.

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