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XMRV CFS UK study #II

Discussion in 'XMRV Research and Replication Studies' started by Orla, Feb 15, 2010.

  1. usedtobeperkytina

    usedtobeperkytina Senior Member

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    Kurt, do you disregard that NCI and CC were also involved in the WPI study? Does that not seem like validation within the first study?

    I am not remembering things well today, but didn't CC and NCI use other testing methods? I think that was the point that the editors at Science required something more than PCR, so that is how at least one of these other centers became involved. And they found it also.

    Tina
     
  2. Esther12

    Esther12 Senior Member

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    The WPI's lack of concern about replication attempts seems really over-confident to me.

    Maybe they know of a torrent of papers about to be published which back them up, but if not, I wish they took a more cautious approach.
     
  3. usedtobeperkytina

    usedtobeperkytina Senior Member

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    And Kurt, I don't' know a lot about reporting studies in science journals, but seems to me, if there is not enough information in the Science magazine, the WPI study, then doesn't some of the responsibility fall with the reviewers and the editor of the magazine?

    Honestly, from what I have seen, the UK studies were not suffering from a lack of information but a possibly false belief that they could find it using different methods, looking for different gene sequence, etc. The thing is, so much of what they did was obviously different, including cohort criteria, what is the reason to believe that all they needed to know was amplification. If they tried to do the study the same in every other way, then that argument would have some weight. But they chose different methods even of what was clearly outlined in the Science magazine.

    I think normally, you can find viruses using many different methods. But I think this one is unique. Whether you believe that causes illness, it has been proved to be human infectious retrovirus, yet this fact was just discovered this year. I think that speaks volumes as to the unique behavior of this virus. So the old research paradigms that are true for other viruses don't fit with XMRV. This is the flawed thinking. I don't for a minute think either UK study was based on bias. But just too much reliance on past experience, which doesn't fit this new virus.

    I have no problem with what the UK people did. As WPI said, it does prove how not to find the virus. And that is helpful. The problem is the conclusion that since they couldn't find it their way, "XMRV is not in CFS in UK." That is wrong and based on ignorance and arrogance. The thought that their methods are mismatched (especially since they knew they were doing it differently) or that they should have chosen a cohort the same as the WPI study seems to not even enter their mind. (speaking of the first UK study. Second one was more humble.)

    As for WPI, Mikovitz should not have made a comment attributing ulterior motives to the first UK study. No problem with pointing out flaws in study, that is healthy debate and a search for truth, it is science. But attributing motives was out of line.

    I also note that Mikovitz has been very careful to say, "according to the hypothesis." She has avoided saying that XMRV causes CFS. But she is speaking of it as though it does, without saying it does. She said she wanted the Science magazine to have a stronger statement along those lines. Science reviewers did their job and kept in check the overly zealous researcher who jumps ahead of what the actual study showed. It's natural and the system worked. And I have no problems with her explaining how, potentially, XMRV could explain CFS symptoms. But it does come off as though she has already drawn the conclusion, even though she carefully doesn't state it is proven.

    If this acted like other viruses, then it would have been discovered over 20 years ago. And the existence and infectious nature of this virus in humans have now been established. We now know many more cells that it infects and how quickly it gets into immune system cells.

    Tina
     
  4. usedtobeperkytina

    usedtobeperkytina Senior Member

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    oh, and it is now known from independent research that androgens stimulate replication.

    So let's see what has been proven that WPI has stated:
    XMRV is infectious in humans
    XMRV targets immune system cells but may be in other cells (we now know specifically some of the others)
    XMRV replication is stimulated by androgens.

    Tina
     
  5. usedtobeperkytina

    usedtobeperkytina Senior Member

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    Cort, I didn't look closely at Japanese study. But I wonder if they also missed some since they found it only in 1.7% of healthy controls. The other option is that it isn't as prevalent there. And that is entirely possible.

    Tina
     
  6. oerganix

    oerganix Senior Member

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    Since the first UK group specifically named Dr Lombardi of WPI in their refutation of the WPI study, I think Dr Mikovits has an equal right to respond to them. And since several of the participants in the first UK study have been paid by the giant UMUM insurance company and by giant pharmaceutical companies for decades and have a long, well documented history of denigrating ME patients, refusing to fund research for organic causes and promoting harmful treatments while refusing to allow ME patients to be tested for organic causes, she did not mistate the facts. What Wessely, psychiatrist, and company hoped to do was muddy the waters enough to discourage any more research in this direction. I have already read seemingly well informed bloggers saying, oh there have been TWO studies disproving WPIs results, so why even look at this anymore? The first UK study should not be counted at all and the second was not an attempt to replicate, so even taken together they do not have the scientific weight of the WPI study, which, by the way, was validated to some degree by NCI and the Cleveland Clinic prior to publication. Anyone knowledgeable beyond the superficial might conclude that the score is now 3 for XMRV vs. 2 for 'no XMRV in UK'.

    I also take issue with your statement that it is the behavior of the retrovirus that accounts for it not being found 20 years ago. It seems to me that the diversion of money, minds and power in the direction of the 'yuppie flu/hysterical women/lazy and or crazy' theories is responsible for not finding this and a lot of other evidence for the organic cause(s) of CFS. For those of us who have been watching this and experiencing its effects on our (disabled) lives, it is plain to see that "Magical Medicine: how to make a disease disappear" by Malcolm Hooper just about sums it up. One of the authors of the first UK study is quoted by Professor Hooper:

    "In 1992, the Wessely School gave directions that in cases of ME/CFS,
    the first duty of the doctor is to avoid legitimisation of symptoms;
    in 1994, ME was described by Professor Simon Wessely as merely 'a
    belief'; in 1996 recommendations were made that no investigations
    should be performed to confirm the diagnosis and in 1999 patients
    with ME/CFS were referred to as 'the undeserving sick'."

    The fact that their 'cohort' was different is no accident. They excluded patients with organic illness because they didn't want to find organic illness in ME/CFS. So even if you don't see any bias, many others do see it. And FWIW, XMRV was discovered in prostate cancer tumors about 6 years ago.
     
  7. usedtobeperkytina

    usedtobeperkytina Senior Member

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    If you and advocacy organizations want to attribute ulterior motives, I have no problem with that. But research scientists should stick to the science and not finger point. Science is supposed to be about search for truth, not blame games. Any scientist that crosses that line loses credibility. Don't get me wrong. I love Mikovitz.

    But even she admitted she released some info on yet unpublished studies, which she said she shouldn't have done. I understand. She is human. She discovered something that is very clear in her WPI labs and confirmed by NCI and CC. I am even amazed she kept it to herself for as long as she did. And they handled the first study beautifully in choosing Science, working with NCI and CC and keeping it quite. That was a PR win.

    But attributing ulterior motives, scientist to scientist, is not in line with professional protocol, therefore it will reflect badly on her. But she was responding to the claim that her study was flawed, possibly, because of contamination. That was a professional insult. But she then went further by saying the first UK study was not sincere.

    The advocacy groups and patients can make such accusations and debate motives.

    I do agree that bias, sexism, arrogance, etc. hindered progress in CFS research.

    But let's remember, some scientists have earnestly looked for viral causes. Some have researched the possible biological causes. Some have looked for retroviruses. All along the way. Did they get enough money? no. And that is a betrayal of public trust that needs to be investigated. But if their first attempts had shown something, anything, then it would have gone that way.

    But this little virus plays hide and seek. And in the game, if you seek for someone for a while, and you don't find it, you give up. We have had many that kept seeking in that direction. Yet, even of these that looked for it, they took 20 years to find it. Why this virus didn't even exist until four years ago - in any illness. Do we really think it just crossed over into humans a year before the prostate cancer study? I bet it has been in humans for over 40 years. So, even in the case or prostate cancer research, without the CFS baggage, why was it not found?

    So, I do believe the nature of this virus has been probably the biggest obstacle to it being found. If it was just out there obviously, it would have been found much earlier. But it plays hide and seek. Harder to find something hiding than something standing in front of you.

    I suspect it is the cause of many, many illnesses. I think we are seeing an emergence of answers to many diseases, including cancer. Now, with all the research in these other illnesses that have received much more money and respect than CFS, why haven't they seen this virus before.

    It is the unique nature of this virus.

    Tina
     
  8. usedtobeperkytina

    usedtobeperkytina Senior Member

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    Or let me put it this way....

    Is this virus unusual in replication and prevalence after infection?

    Mikovitz says yes.

    Do you have to take unusual steps to find it?

    Mikovitz says yes.

    Does it go dormant, thus hiding?

    Mikovitz says yes.

    Given these facts, does it stand to reason it is harder to find?

    yes

    If it is harder to find than other viruses, then does it stand to reason it will take more research and more years to find it?

    yes.

    Tina
     
  9. Gerwyn

    Gerwyn Guest

    all latent viruses are hard to find .i make no comment re the motives but i do comment that the science was appalling
     
  10. oerganix

    oerganix Senior Member

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    The most pertinent logical fallacy that you have here is this: "does it take more years to find it?"

    When there is a genuine attempt to find it, and if money and desire (political will and direction) are there, it only takes about A YEAR to find it, as demonstrated by WPI. They started with all the problems you've mentioned above yet were able to find it, working under less than perfect conditions, in a year.

    It is well illustrated in "Osler's Web" by Hillary Johnson, that the cause(s) of CFS could have been tackled during the same years that HIV/AIDS was, if the politics had been there for doing it, instead of denying it.

    To put it into another perspective, if Andrea Whittemore were my age and her wealthy parents had put their money into CFS research when I was a young woman, we would have already explored the XMRV possibility and confirmed it or moved on to the other possibilities that are also being researched in 10 other projects at WPI at this moment.

    Instead, our national resources of money, power and minds were squandered on a policy of not finding the organic cause(s) of CFS during all those years, TWENTY EIGHT YEARS, that I have had this illness, despite the very real evidence that has been there from the very beginning, of the very real possibility of viral cause or contribution. The same, or worse, has been done in UK.

    I paid taxes for 20 years before becoming disabled by CFS. I was around (was it 1991?) when the CDC took the tax money we sufferers worked so hard to get out of Congress for CFS research and spent it on polio, measles and equipment for other labs, plus disappearing several millions of dollars they just couldn't account for. Almost NOTHING for the purpose for which the money was appropriated. A friggin' telephone survey in Wichita KS!! And the CDC's good 'ole boys have been doing the same thing, right up to the present year, as has the psych gang in UK.

    So, the fact that a private research lab, operating under less than ideal conditions of funding, was able to find XMRV in association with CFS, in around a year's time put the LIE to the contention that they (the medical establishment) just haven't had time to find out what causes CFS. Now those who having been lying to us for decades are scrambling to counter any real research into the organic causes of CFS, so to question their motives in these rushed studies is appropriate and wise if we want to avoid another 2 or 3 decades of waiting for them to 'have enough time' to find the solutions we need in order to once again have a life. Even if a cause/cure had not been found then, we would have had some treatment of the symptoms that we don't have access to now, because everything is 'experimental' and not covered by insurance. To be aware that the insurance industry drives the anti-organic cause campaign is not unprofessional. To pretend that scientific research is pure and without politics and egos is not helpful and I applaud anyone who will stop pretending and tell it like it is.

    Another 2 or 3 decades is not acceptable to me at age 62. These lies have already wasted what should have been the best years of my life. As it is, any solutions that might come from this research may still be out of reach for me, as I am barely surviving, below poverty level and getting poorer each year, while 'the band plays on'. About the only thing that is different this time around is the internet. Those of us who have no energy for the struggle to be treated fairly can now find solidarity with others and not let them get away with it this time.
     
  11. Gerwyn

    Gerwyn Guest

    The limit of detection in the PCR method used in the groom study is 400 DNA copies per ml of serum.There is no way it could detect XMRV even if they had used perpheral blood samples specially prepared for virology.I echo your sentiments completely I missed my Children growing up because of arses like Wessely and Reeves who deliberately diverted funds from scientific research into alice in wonderland "studies"
     
  12. oerganix

    oerganix Senior Member

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    I love the analogy to Alice in Wonderland. Didn't she say "A word means what I want it to mean?" This life with CFS has been such a tumble down the rabbit hole, so surreal at times. Tweedle Dee and Tweedle Dum in control of millions of dollars/pounds and with the accountability of a Mad Hatter. Thanks, Gerwyn, for your wonderful expanations here. I've gained an education just from your posts.
     
  13. kurt

    kurt Senior Member

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    Additive risk due to reagents means that you have a new chance of false results with each re-test as each re-test will use new reagents. That is a different risk than false results due to low viral count. Yes, you would add the risks to calculate the cumulative risk for a number of tests if risk is additive, but it is not a linear function, so no, you do not come up with a probability over unity. I don't know the exact nonlinear function, but you would add less and less for each pass showing the increasing risk for at least one false result in the accumulating tests, for instance, 1x50% is 50%, 2x50% is 75%, 3x50% is 87.5% total risk, something like that.

    OK, you are defining 'flaws' more narrowly than I was, and yes, I certainly agree that if you define 'flaw' as any aspect of the study that did not precisely follow the WPI method then that methodology was full of flaws. But that assumes this was a replication attempt which although they said it was, it clearly was not. They need to go back to a methodology 101 course. They were attempting to validate the XMRV finding, not replicate the WPI study, two different tasks. Also one of the UK studies tried to draw epidemiological conclusions which was ridiculous given that they were not using a standardized test validated by a scientific consensus process. However, for that broader goal of attempt at validation of the general WPI findings, they were free to use any reasonable and customary method, which they did. So in that sense the tests were foolish perhaps but not technically flawed.

    Heavens no!! I am not disregarding anything, challenging a few things maybe but disregarding? No. NCI and the CC both replicated the WPI study. That stands although it was a small replication attempt. The WPI study has therefore been replicated, but that only means that someone else using the precise method as WPI can find what they found. That is not the same as validation of the finding. To validate the finding other researchers unaffiliated with WPI and using different samples and reagents, and also different test designs (hopefully more sensitive) can find the same exact retrovirus in the same patient cohort. Validation and replication are different problems, although some scientific disciplines make more of a deal about that. I come from an area in science where this is critical. There is a HUGE difference between replication and validation. That has bugged me throughout this episode as I see people mixing up the two issues.

    I agree completely, and as I just said above, validation is important and has not happened yet. For either replication or validation efforts to work, WPI must supply a complete factual account of how to run their tests. If they can not explain this to an outside lab sufficient for their test to be replicated and their finding of XMRV to be validated, there is something wrong. Either they are not really as forthcoming as they claim and are trying to control who can replicate and validate their work, or their work is not what it appears to be.

    My point is that the false belief of the labs was partly due to omissions in the Science paper. The reviewers can not evaluate missing steps if they do not know them. For example, WPI has revealed now that banked samples MUST be amplified or tested multiple times and there must even be multiple samples available if someone is to get a positive XMRV hit. I do not believe that was in the Science article, they did mention the amplification but did not clarify that in enough detail that an outside lab would have known that ordinary test designs would be unable to find XMRV. If information is ambigous in a paper like that, the authors have an ethical obligation to state that certain steps or mixes are proprietary, or to state that they are only providing a synopsis of the methods and then explain how to get the full details. There can be many reasons a detail like this is omitted from a paper, I am not making any accusations, WPI was in a rush to get this out, and for a good reason, it is a sensational finding. Maybe some details just got overlooked, but regardless of that, correcting this issue should be a high priority for WPI. By now we should have at least a half dozen reports of replication and several reports of validation of the XMRV finding in CFS. Where are they?
     
  14. Gerwyn

    Gerwyn Guest

    The" foolish" tests were indeed idiotic. If you say that you are trying to replicate a proceedure then try a completely different untried protocol in scientific terms that is incompetence.When you misapply the proceedure you do decide on then flawed is the mildest of descriptions .A F grade would normally apply if a Grad student did this
     
  15. ukxmrv

    ukxmrv Senior Member

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    I guess that because XMRV is so new and so much was/is unknown then any attempt to "validate" (rather than replicate) the results was a very risky undertaking.
     
  16. Gerwyn

    Gerwyn Guest

    that is putting it mildly
     
  17. ukxmrv

    ukxmrv Senior Member

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    Hindsight is a fabulous thing.

    Looking back - what "flaws" were in the two UK studies that the researchers should have known about at the time. Or it is that anything else other than a total replication effort was just too risky?

    Should they have know not to use frozen samples?
    Should they have known to grow the virus in LaCAP culture?
    Should they have known that the virus replicates slowly?
    Should they have known that patient selection was important?

    Anyone else - what would the UK researchers have done differently at the start and what would have told them this.

    (I'm gutted, so please don't read me wrong. We know about Wessely etc but lets assume that the other collaborators were naive here)
     
  18. julius

    julius Watchoo lookin' at?

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    I agree that besides wrongly calling a replication, the studies weren't fatally flawed. And they did help advance our knowledge a bit in that now we know that you can't just do any old PCR anywhere in the world and find it.

    To try to answer your question ukxmrv, one thing the UK folks could have done differently is contact WPI before doing their studies. The WPI has been very clear that they will share openly with anyone who wants to talk to them. That could resolve some of the problems with the unpublished information as well.
     
  19. usedtobeperkytina

    usedtobeperkytina Senior Member

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    Ok, Kurt, I understand a little bit more what point you are making.

    But while I do think there was a "rush" on the part of WPI, the process was not rushed. It took them many months and responding to additional requirements by Science Journal reviewers. Again, seems to me that if the end study publication left out something pertinent, maybe the editor shares some blame.

    Oerganics, you do make a point about the timing. If it took a long time to find, why was WPI able to find it so quickly?

    Answer is they were looking for it....

    But, from my reading of Osler's Web, Defrietas and many others with honest intentions looked for it. Folks, I believe, made an honest attempt. Although some ego came into the picture in that no one, him included, was willing to follow DeFrietas' methods to the letter.

    While I do believe that they gave up early, partly due to ego, early set bias, sexism and more, and once decided, refused to look at the evidence that came in with a fresh eye. And misspending funds is criminal.

    But, I do believe that if this virus was like HIV and replicates and fills the blood, or if it was like the flu, or if it cause imminent death, it would have been different. I do believe, in reading Osler's Web and reports from others, that an honest search for viral cause has been going on by individuals for years, WPI an example of that. There was a study of higher endogenous viruses. Klimas has been looking into immune system abnormalities. Yet Mikovitz looked at same abnormalities and her light went off... retrovirus. Again, even in association with prostate cancer, this virus was just discovered four years ago, no politics or bias included. It is just a particularly hard virus to find, according to WPI.

    One factor may be building knowledge on top of knowledge of testing methods or viruses. Maybe we just needed to get Mikovitz, or someone with her experience to know the particular nature or to detect the clear indications of retrovirus.

    Also technology increase might have helped too. I remember in Osler's Web that the UBOs were seen because more sensitive MRIs became available.


    Tina
     
  20. Gerwyn

    Gerwyn Guest

    They would have known to use healthy controls and use permissive cells They would have tested their assay protocols to make sure they worked The time between transfection and the production of viable virus was in the public domain.you dont keep the same primers for the second round of PCR.You dont neglect to use amplification protocols if looking for a mostly latent virus all this is in the public domain.We still dont know whether those samples contained XMRV or not but they concluded that the results were negative if this isn,t a fatal flaw i dont know what is.The controls were so laced that interpretation of the results would have been impossible because we would never have known what the xmrv levels were compared to healthy controls.it takes some doing to design a study where the outcome and conclusions are unfalsifyable-that is the antithesis of the scientific method and makes any progress impossible
     

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