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The Race to Retract Lombardi 2009...

Discussion in 'XMRV Research and Replication Studies' started by jace, Oct 10, 2011.

  1. Esther12

    Esther12 Senior Member

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    There are always things about any study which we will not know. Mikovits was a co-author on the paper, and if she had information which could be shown to be pertinent to explaining the result, then it's difficult to imagine it not being included in the paper.

    All of us have been making judgements about the likelihood of XMRV/HGRV being related to CFS over the last two years. Hopefully we've all been withholding some judgement, and remembering how uncertain that things were, but I do not believe that you have not being making probabilistic judgements based upon the available evidence. The new evidence from the BWG makes any association seem much less likely, as it showed that the WPI, Ruscetti and Lo/Alter were unable to distinguish between samples from previous positives and previous negatives in a way that would be expected were their testing reliable. The paper they co-authored concluded that the problem lay with the testing, not with the collection methods. Maybe this is wrong, but as yet, we have no particular reason for thinking that it is.

    I'm also genuinely interested to know why you (and a couple of others) think that the BWG was only interested in assays for bulk testing, as I've not seen any reason to think that.

    The BWG did include serology from some labs... not looked in to details - I'm brain fired too. Going off line for a veg out soon!:

  2. citybug

    citybug Senior Member

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    About the Meaning of Slide 2c in Lombardi

  3. Sam Carter

    Sam Carter Guest

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    Hi Bob,

    Singh was unable to find antibodies to XMRV or related MLVs in her study; in the BWG Abbot Diagnostics and the CDC found no serological evidence of infection, while NCI/Ruscetti and the WPI found plenty of "positives" but they were equally distributed between the control group and the patient group -- ie. their tests were no better than a coin toss.
  4. citybug

    citybug Senior Member

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    Some reasons: Dr. Mikovits told patients not to rely on the serology test alone to save money when vipdx serology test came out (I was waiting for serology and contemplating doing that), serology could go up and down and patients might not make antibodies anymore.

    They were not able to complete the culture test.

    And it was a very small sample, was it 15?, which doesn't matter since couldn't complete culture.

    Someone emailed or in a presentation Dr. Mikovits said don't worry about the BWG in response to patient anxieties because it was focused on the testing that could be done for blood banks.

    Science type patients have been saying there was no trizol used in the blood preparation. The online methods and materials for Lombardi in Science say DNA & RNA was isolated with Trizol (page 2). http://www.sciencemag.org/content/suppl/2009/10/08/1179052.DC1/Lombardi.SOM.rev.pdf

    I never thought CDC or anyone else involved had a test (they never said they did), and WPI couldn't complete. I've always thought WPI should have been compensated for participating in all these government comparison tests. They have to spend all their time analyzing samples for other people, who don't have tests ready, instead of doing research for us. I don't know if the panel had all the people doing active research on xmrv like the macaques studies, but they would have looked for XMRV specifically.

    No one has looked in tissue yet. Lipkin said at the AAS talks that he can't analyze blood with his methods, there are too many elements in it.

    Sequencing not done yet to make PCR more possible, but then none of the others do culture to bring up low copy numbers. The studies are all set up and take place before the latest news comes out like Silverman's contamination.
  5. citybug

    citybug Senior Member

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    Taking away the Silverman figure one takes away the misleading single round PCR which most of the negative studies focused on.

    From the Addendum abstract:
    Since our report, controversy arose after the publication of several studies that failed to detect XMRV infection in their CFS patient populations. In this addenda, we further detail the multiple detection methods we used in order to observe XMRV infection in our CFS cohort. Our results indicate that PCR from DNA of unstimulated peripheral blood mononuclear cells is the least sensitive method for detection of XMRV in subjects' blood. We advocate the use of more than one type of assay in order to determine the frequency of XMRV infection in patient cohorts in future studies of the relevance of XMRV to human disease.

    http://www.landesbioscience.com/journals/virulence/article/12486/

    And a necessary sensitivity level for their tests was never established. The 0/0's never saw XMRV to know how many copies there are in blood cells.

    I would like to know more about the numbers and levels needed. Lo said about one of the Retrovirology papers that there was a math error of several magnitudes in his CDC video. (I hate to watch it again, it's after the old guard cdc guy who says there is no POTS).

    Which studies looked at live virus? Most of the clones were injected into water.

    I don't think there is a conspiracy, just premature reliance on PCR technology.
  6. justinreilly

    justinreilly Stop the IoM & P2P! Adopt CCC!

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    Well, thank you Kurt!

    This seems like an awfully low bar for retraction. If this were the case, wouldn't there be a lot more retractions than there are?
  7. JT1024

    JT1024 Senior Member

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    I agree with you Justin...

    If they retract Science... every other XMRV publication would need to be retracted - including the 0/0 studies.

    The fact is SOMETHING (or more accurately, a family of MuLV's) has been found. Dr. Coffin did not only anticipate this - it is something he EXPECTED.

    I'm not on this forum much any more for numerous reasons but IMHO, much more will be published in the months/years to come regarding MuLV and perhaps other retroviruses infecting humans.

    Unlike many in online forums, my education is in clinical laboratory science (as well as an MBA) and I continue to work in a lab to this day. I'm well aware of the challenges and what happens in "real life" laboratories.

    The Science paper was based on the test results of over a hundred patients which means that hundreds of test were run. More than one assay type was run which further validated findings

    I look FORWARD to additional research findings despite certain researchers efforts to discredit Dr. Mikovits.

    Sorry... I'm still standing by Dr. Mikovits until proven otherwise. Dr. Coffin and others have not been worthy of my trust to date. The WPI also has to earn my trust back. I've financially supported them in the past but will
    not going forward. Trust is earned... Once lost, it is not easy to regain.
    justinreilly likes this.
  8. kurt

    kurt Senior Member

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    I think Justin hit on something big, we really could and probably should go after some of the worst research, and try for retraction, or at least partial retractions. Why hasn't anyone thought of this before?

    For example, in scientific research, when new information invalidates old studies, there can be retractions, partial retractions, or editorial comments. There have been recent retractions of studies on autism, pregnancy, vaccinations, and even global warming. This happens all around us, but seriously, we often maligned as patients because some really bad research has been allowed to stand.

    Papers that could probably most easily be attacked for invalidity would be all those using the name ME or CFS, but working from a case definition that we now know conclusively did not rule out mental patients, or ordinary fatigue patients. Clearly going after every bad study would be impossible given our low profile, but just one or two wins might do a lot of good. Particularly for the people in the UK and AU who have to work with that crazy out-of-control 'everything is a psych problem' system where they still use electro-shock therapy for bipolar and depression patients (often barbaric and damaging to the patient).

    Wow, that is a really good but very complicated comment, you have shown (probably unintentionally) how the political desperation in ME/CFS has caused people to embrace what appears to be bad science. Here are some thoughts (sorry, I'm not trying to be contrary, you just have illustrated the problem so well it is hard not to be).

    -In Mokovits/Ruscetti we trust? What has personal integrity or trust got to do with research results. If they were the only lab (socialism in science) then maybe trust would really make a difference. But we have a community of researchers and scientific consensus is the standard for determining whether claims are right. They may be trustworthy, and still be totally, completely, 100% wrong. Happens all the time in science, even Einstein was regularly proven wrong about some things.

    -Full retraction is very probable at this point and is important when a study is obviously flawed. Even had there never been a single 0/0 study the paper would need to be retracted after the BWG study. How on earth did WPI get their PCR test results in the Science article when they could not for the BWG study? There is something wrong in their study, even if we can't prove exactly what happened (we will probably never know), we CAN show that the results do not stand up. All the 0/0 studies were NOT horribly flawed as some patient theorists propose, in fact they prove the point conclusively that there is not a single member of the MLV family of viruses in ME/CFS patient blood. That invalidates the WPI study as well. Anyway, data is the issue here, not being nice to researchers we like, or solving ME/CFS political problems (as important as that is)

    -Yes, I believe all HGRV papers related to MuLV will probably end up being retracted eventually, because they are or will be proven wrong. They are based on contamination, cross-reactivity, or mistaken identity with HERVs, or some such problems. Even the Switzer prostate cancer study that found two MLV sequences in two different patients is likely a contamination problem, as they had earlier known contamination issues in their lab. (the CDC used Platinum Taq earlier in their study, don't know if that is published formally but it has been mentioned by researchers and is easy to confirm).

    -Recombination is definitely a valid issue now and I expect most future studies of MLVs in human samples will be related to managing the risk of using lab viruses. But that is a more general issue and is not really an ME/CFS problem.

    -No single virus has yet been proven to cause ME/CFS, of course that is obvious. There are different theories and each needs exploration. What WPI had just proven prior to their Science article was along the lines of multiple co-infections being important in ME/CFS (their virachip study showed this). I really wish they had not abandoned that line of research (I'll bet they wish they hadn't as well at this point). The CFSInitiative is likely to pick up on that thread and perhaps some good will come from that angle. But what proof do we have that ME/CFS is a primary viral infection? We know we have viral triggers some of the time, but not always. And many diseases have viral triggers but are not primarily viral in nature. There is a lot we don't know, but I do think we have to consider ME/CFS a regular disease and not just a syndrome. There will be a way forward for us without HGRV.

    -You are right that XMRV was good for us politically. But that only works if it is true, which apparently it is not, at least not based on the research. So do we really want our advocacy to be based on a virus that nobody can find in our blood? I think not. We are in a deep enough pit already, and don't need to destroy what little credibility we have by insisting we have an infection that nobody can find in us. That would make us look like psych patients for sure.

    -Why is it that people act like HGRV is the only possible retrovirus? There are thousands of known viruses and retroviruses, there might be others involved in ME/CFS, Dr Huber proved that HERV K18 is activated by herpes in ME/CFS patients, for example. WPI found HTLV in a subset of patients in their virachip study. There could be others. But to explain ALL of ME/CFS by a blood-borne retrovirus, that seems impossible to me given the epidemiology of ME/CFS. What is more probable is that something is damaging our immune function and therefore we harbor a lot of viruses. In fact that is proven by many studies. But there are many ways the immune function can be damaged, so we have a lot of research still ahead.

    -Sinister? No, absolutely not, I think there is excessive paranoia in the ME/CFS community. Part of that is understandable, given the way we are treated. But this is not one of those situations. All these independent labs are not involved in any conspiracy against us. Insurance companies do not want to cover us, of course, but that is unrelated to HGRV, that is just ordinary life with ME/CFS.
  9. markmc20001

    markmc20001 Guest

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    I think something has been found too. My opinion is it's all smoke and mirrors until the Lombardi study has been replicated. Just ask Dr. Burzynski how many times the government tried to change his cancer treatment protocols to throw off the clinical trials.

    No it's not a conspiracy, just the truth.

    As far as vindictive science precedent against researchers, that horse left the barn years ago in "Chronic fatigue" research.
  10. currer

    currer Senior Member

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    Kurt, just to respond to your suggestion that we ask for the retraction of research we find flawed....how do you propose going about this?

    The editorial board of Science make the decision about retractions.

    It is not done by consensus, even a consensus of scientists.
    Only those with power can make these decisions.

    Are you suggesting we write petitions? And are you sugesting anyone will really listen? And retract research because of patient complaints?

    We do not have any power to enforce this, in fact we would be laughed at by the scientific fraternity.
  11. kurt

    kurt Senior Member

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    I was not referring to Science or anything they have published about ME/CFS. That is already in review, right?

    Rather, think of the long history of flawed ME/CFS studies, particularly those using non-ME/CFS patient cohorts but making claims about ME/CFS. If those studies have resulted in harm to ME/CFS patients (some probably have), or if the studies are based on incorrect samples, or contain other errors we can identify, then we could mount petition drives, things like that. Negative publicity matters to those journals, up to a point anyway. But probably the most important advocates for us would be sympathetic researchers or ME/CFS doctors. If they would write letters, the journals would take that seriously. I believe that is how studies generally get retracted, when other researchers write letters explaining the reasons for retraction.

    So if we could compile a list of candidate studies for retraction requests, that would be a starting point. I'm not the right person for that, have ignored most of the flawed studies since I am only reading research looking for answers and help. But probably there are ME/CFS patients here who are familiar with the problem literature and could name some candidates.

    Papers are retracted regularly, I don't think scientists would laugh at us if we presented a well-documented case. But we would need to make a credible case, and not just write wild letters making accusations of conspiracies, etc. Yes, they would laugh at that approach. But a systematic effort that made claims of harm to patients due to flawed studies that deserved retraction, I think in light of recent events, the tide is right for that type of effort.
  12. JT1024

    JT1024 Senior Member

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    Kurt,

    What you've written above includes insults to patients ("I don't think scientists would laugh at us if we had valid complaints"). I 'm shocked since you claim to be one.

    Glad I only visit this forum once in a while. I had forgotten quite a bit. Thanks for reminding me why I don't come here often.

    I'm not interested in propaganda or perpetuation of crap. I'm much more interested in the truth.
  13. kurt

    kurt Senior Member

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    You're right, that came across poorly, I re-wrote that phrase (see the original post). I certainly did not mean to suggest our complaints are not valid. Thanks for the edit suggestion, although I'm a bit surprised it seemed insulting...Why presume some negative intent?

    Anyway, yes I am an ME/CFS patient, and have brain fog at times just like everyone else. Anyway, I think my meaning was clear from the context, even if not the best choice of words.
    Firestormm and Jenny like this.
  14. markmc20001

    markmc20001 Guest

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    The only way to equitably and fully determine if Mikovitz has found a virus is to replicate her assays. Please consider replicating the rest of her existing study, and we will know if a retraction is in order, OR if some (HGRV) really shows up.

    It's a pretty simple and equitable way of handling the situation where everybody can feel like Mikovitz got a fair shot.

    Using 20 different tests than Mikovitz used, does NOT directly determine if the test Mikovitz used was finding something. Run the replication, and we can all go home or celebrate. Seems simple, and like the least the community can do after all the mud slinging that has gone on here without ever replicating.

    It's a classic problem in science trouble shooting. Somebody changes something, and the test/process no longer works. at this point the only thing to do is go back to a known point where The test has shown to work. I have literally been here hundreds of times.

    You can't just drag people through the mud without ever trying their original test, and claim the test didn't work. You never replicated the test. It is that simple.

    If the test gets replicated by two or three different labs, and no retrovirus turns up. We all move on and you can get a retraction! I'll be happy to change my mind at that point you weren't a bunch of scientists who didn't fully explore Lombardi et al studies fully. That what science is about right? Being absolutely sure?
  15. Esther12

    Esther12 Senior Member

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    So this rumour about 'bulk testing methods only' is just from that? Even though the BWG has repeatedly said that researchers could use whatever assay they wanted?

    I don't think that anyone else has posted this yet:

    http://www.research1st.com/2011/10/14/xmrv-updates/
  16. JT1024

    JT1024 Senior Member

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    IMHO, the BWG appears to have been poorly designed and poorly run. There were way too many variables allowed so essentially it proved nothing.

    The wording of the answers to questions posted (provided by Esther12) is not only sad but misleading given the significance of infectious retroviruses and the reputations of the scientists in involved.

    I have worked in clinical labs for many years where laboratory procedures and testing methodologies have been approved by the FDA. Test manufacturers determine a test's performance capabilities, procedural steps that MUST be followed as well as substances and testing conditions that interfere with the assay. Quality Control, Specificity, Sensitivity, Accuracy, and Precision, are provided with every testing
    methodology used by clinical labs unless it is clearly stated that the test is for research purposes only.

    At this point in time, very few labs have the ability to consistently run an assay for the accurate detection of human gamma retroviruses. If researchers don't have the specifics of what they are looking for and they don't even have an accurate positive control, they cannot state that something does not exist.

    Dr. Mikovits, Dr. Ruscetti, Dr. Lo, and Dr. Alter are seasoned researchers and this is not some minor discovery. The discovery certainly scares the $#it out of researchers because it has the potential of shutting down research labs due to actual contamination (previously unknown) and the risk of transmission of "new" retroviruses to lab staff and the general public.
    markmc20001, ukxmrv and currer like this.
  17. currer

    currer Senior Member

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    Hi JT1024,

    Couldnt agree more.

    I am not competent to discuss the details of the BWG protocol, but even to me, it seems they introduced far too many variables.

    I've just watched Judy Mikovits talk on the Invest in ME DVD and I am amazed by her expertise and knowledge of her subject. This discovery is so much more that it is portrayed as being to the public.

    She has gone way beyond just finding the virus, but is analysing in depth interactions between the virus and the immune reaction and finding parallels with the way other retroviral infections distort biological processes.

    I remember Frank Ruscetti said last year that he was going to move on from just isolating the virus to studying pathogenesis. There is lots in this talk to suggest they have made great progress in doing just that.

    Fascinating and humbling to watch.

    I believe a retraction of the Lombardi paper would be a disaster.

    I really would advise everyone to get themselves a copy. Inform yourselves so that you can make your own judgements and are not reliant on spin.

    www.investinme.org
    6th International ME/CFS Conference 2011

    Would you believe I was actually present at this talk. I was so brain dead and tired at the time, (it was afternoon before JM's talk,) I couldn't take it in.
    ukxmrv likes this.
  18. Esther12

    Esther12 Senior Member

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    Surely any threat to research staff would mean that they would be extra careful about this? This issue was taken very seriously, but now it seems likely that the initial findings were the result of poor blinding, contamination, and unreliable tests, there is much less concern.

    Mikovits, Ruscetti and Lo/Alter were all able to run whatever assays they wanted. They were not told the specifics of what to look for because they're the ones who said that they had found something - the BWG was set up to see if this could be done consistently under independently blinded conditions. It could not.

    I don't think that anyone from the BWG has said that anything does not exist, they've just said that the current tests for XMRV/HGRV/whatever do not seem to be able to distinguish samples from previously positive and previously negative individuals - that the Mikovits and Ruscetti got 'positive' results scattered across both, that their positives did not correlate with one another, and did not seem repeatable.

    It may be that something went wrong with the BWG, or it could be that there is an undetectable virus there, however it seems likely that the WPI's claim that they had found a virus which was significantly more common in CFS patients than healthy controls was based upon an unreliable test.
    Firestormm and Sam Carter like this.
  19. Sam Carter

    Sam Carter Guest

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    Is it possible to name even one lab that has the ability to consistently run an assay for the accurate detection of human gamma retroviruses?

    And if not, on what basis is the claim that HGRVs exist being made?
    Firestormm and Nielk like this.
  20. JT1024

    JT1024 Senior Member

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    Over time, testing will improve. However, while many researchers want to be the next winner of a Nobel, the risks associated with all the genetic manipulation that has occurred in the last 30+ years has
    become more apparent. Sad to say but money seems to be more important than risks to the general population and to even the researchers themselves.

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