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The Fight is on...Imperial College XMRV Study

Discussion in 'XMRV Research and Replication Studies' started by George, Jan 5, 2010.

  1. Eric Johnson from I&I

    Eric Johnson from I&I Senior Member

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    YO SPIT,

    Sorry to shout. Just wanted you to see me.

    Check out fig 1 in Wessely -- the positive control. Is that shome faint stuff or what? If the + control is that faint, what would a positive from a human sample look like (if there was one)?

    If anything, the + control should be easier to detect than a patient sample. First of all, XMRV is surely 1000x or so more concentrated in some plasmid, per total amount of DNA, than it is in some human genome, non? Have ye any further thoughts on sensitivity when one is XMRV-spiked water as opposed to human DNA extracted from whole blood?
  2. I tried to message Holmsey directly but interestingly he's not receiving messages. I wanted to take this off this thread but I'll have to say it here. I am not biased mate, I am not scared by you or what you say, just annoyed and irritated. I have met many people in my life who said that they had ME/CFS too. They quite plainly did not. One of them was working and even playing hockey regularly. Yeah right, he must have ME. Not. I'll say it again, there ARE many many misdiagnosed people going round with a wrong diagnosis of ME and that is/has stuffed things up in a major way for those with ME. Why is it wrong to point that out? It's a fact. I'm not saying that you're not ill Holmsey, just that you don't seem to have ME as I understand it. I'd also be happy not to have XMRV to be honest and I'm open minded about whether it really is the big answer. No, what annoys me about you is the fact that you appear to enjoy taking contrary views...

    <snip personal attack>

    Moderator Edit: Fair enough, but taking contrary views (or enjoying it!) is permitted here. We don't check identities or diagnoses, or misdiagnoses. (It's no one's fault that ME/CFS is a subjective clinical diagnosis). Anyone is free to post. And, if someone is not taking your PMs, it's because they have put you on "ignore".

    Let's get this thread back on track, please.
  3. Cort

    Cort Phoenix Rising Founder

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    I think Kurt is right; the retroviral research community would LOVE to find this; my god, thats work for the next decade. They''ve probably been searching for the next big retrovirus for the last 10 years. Of course the provenance of this finding is a bit scary with Dr. Wessely in there but we'll have untainted retroviral labs looking for this.

    the CDC is another matter. Remember its the Retroviral branch thats looking for this bug. They do have WPI samples so they should be able to figure out how to find the bug - using the WPI's techniques or not. That will be one big difference between the two groups; the CDC will presumably be going off the original samples not a standard XMRV test sample. Lets say the WPI found something a bit different from XMRV - the CDC should be able to detect that I would think.

    If its not the standard XMRV then the big question will be what it is, of course.
  4. perovyscus

    perovyscus

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    Per usual, I have nothing earth-shattering to contribute.

    The water for blinding is indeed foolish. I see no embarrassment in the realization that healthy controls have higher XMRV than CFS patients. That phenomenon would be interesting as well, certainly more so than the current results. The paper is short, concise and seems methodologically sound, which is why it was accepted.

    If this study is deemed false, the blame lies on the primary authors, not SW. If the WPI study is true, there would be a 95%+ chance that three British CFS patients would have XMRV, even if they didn't have CFS at all.

    If you had twenty groups of random people

    • 19 out of 20 times you'd get at least three positive results.

    Both WPI and the psychiatric lobbies have vested interests in the outcome of these studies. It will be a relief when a random virology group repeats these tests due to the increased awareness and funding.
  5. perovyscus

    perovyscus

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    Also, if you ask nicely, the PIs of the study may give you the peer review notes given to them by the editors.
  6. Esther12

    Esther12 Senior Member

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    There's no doubt that this paper does not look as thorough as the one in Science.

    That doesn't mean it's wrong though. We'll have more studies coming out soon, and then we'll see.

    It could be that this rushed paper with limited peer review and patients selected by Wessely is right, and the paper in Science is wrong. I don't know enough about PCR etc to say how a paper that looked so compelling could be totally wrong, and if this might indicate any other avenue worth investigating, but hopefully we'll find out soon. I'm really interested in those replication studies the WPI has been helping with, and how they're coming along. Maybe the WPI will release some provisional information in reponse to this new study? Yesterday it was mentioned that the WPI was planning a response for today, but I've not seen one yet.
  7. fds66

    fds66 Senior Member

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    WPI official statement in up on their website

    http://www.wpinstitute.org/news/docs/WPI_Erlwein_010610.pdf

    Sorry - pasting it lost all the formatting. Have put in some paragraph breaks now.
  8. Esther12

    Esther12 Senior Member

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    Ouch.

    I really hope the WPI are right about this. That's a lot more aggressive than I expected. Surely they must be hearing positive things about replcation?
  9. Parismountain

    Parismountain Senior Member

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    Well said Cort. I tried to think down that path earlier this morning in a post "How about something really really simple. Our Mikovits study had 101 CFS patients. Have Dr. Mikovits's lab run her tests again on those 101 people blinded then defend the results. If the results are consistent (using the original Science published protocol, not the newer, better finding protocol), IF THE RESULTS ARE CONSISTENT - I don't care what virus they found, they sure did find a screening diagnostic test for CFS or at least a form of CFS. Yeah maybe XMRV virus is slightly different in CFS than the prostate kind, or maybe it's a different virus and they haven't figured that out yet or maybe it's not a virus at all, just a fluke but if they can consistently replicate using blinded then we can at a minimum salvage a diagnostic tool. "

    But your comment on what it is is much more to point
  10. Koan

    Koan Be the change.

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    Well now, that WPI statement seems just about right to me -- itemizing the very real problems with this latest while remaining above the fray.

    :cool:
  11. Jenny

    Jenny Senior Member

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    I Wanna be Well - as someone else said - many people are able to work with ME.

    After 5 years mostly in bed I've worked full time for 21 years. I had a 10 year period with very few relapses, but I rarely felt well and often had to go to bed when getting home from work. More recently I've had more frequent 4 month relapses and seem to be getting worse, but I'm lucky in that even now I can sometimes work from home if I'm feeling up to it.

    You imply that someone can't play hockey and have ME. I played badminton and danced tango when I was in a good patch.

    Many people have mild ME and many people's ME takes a course of relapse and remission.
  12. Cort

    Cort Phoenix Rising Founder

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    I agree. My understanding is that the WPI probably tested and retested and retested their samples until they got consistent results with their test again and again. Only then would they go to publish. The contamination problem doesn't seem signficant. I don't know about the others.

    What if it was an endogenous retrovirus? Well thats not necessarily so bad. Yes we do carry loads of endogenous retroviruses but we don't have many, I don't think, that are active and can go on to infect other cells. Basically what we carry are bits of broken down retroviruses. Even if Imperial is right they still grew something in that culture....something living.....something that their immune system was apparently responding to.

    All speculation from someone who knows very little.

    I wish we had a retrovirologist on board!
  13. Eric Johnson from I&I

    Eric Johnson from I&I Senior Member

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    SPIT, yo again --

    Whats with the dimness in fig 1?

    Worse, why did the + control amplicon get *smaller* in the second round of nested PCR, in fig 2? There is some mislabeling on that fig, but you can see by the electrophoretic migration lengths of the amplicons that round one and round two are labeled in the correct order at least.

    Man, the round 2 amplicon is DIM. I'm sure you dont use the entire amplicon from round one as template for round two. But still, the DNA is at a decent concentration in the round one amplicon. And after 30 cycles, the thing gets *dimmer*, and indeed quite dim? Looks like hell!
  14. Cort

    Cort Phoenix Rising Founder

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    Dr. McClure's Response To Questions

    I emailed Dr. McClure some questions and she responded.

    (1) You (apparently) looked at different gene sequences than in the original report. Why look at different sequences.

    We chose sequences we considered to be specific for XMRV and generic to MLV for the reasons given in the paper.

    (2) You stated that you felt Lombardi et. al. should held off a bit with their findings. What do you they should have done differently?

    I gave my opinion in response to a question at a press conference, but it is not for me to advise or lecture Lombardi et al

    (3) Some questions have been raised by Dr. Vernon regarding techniques that were slightly different from the original paper. Could those effected your results?

    No. Provided controls have been included to a) confirm the integrity of the DNA b) ensure that human DNA is being amplified c) to ensure that no inhibition of the PCR is taking place and d) the assay is sufficiently sensitive to detect the virus, then a diifference in protocol does not matter. We controlled for all of this. The one major difference we could not control for, of course, was that the patient cohort is different.

    (4) You noted your rigorous attempts to preclude contamination. Does this suggest that contamination from a murine leukemia virus could have effected Lomdardi’s results?

    It is far from clear that this was a problem in the Lombardi paper. Indeed, their sequencing data (given in the supplementary data to the Science paper) would argue against it. We highlighted our own conditions because it was right to give a clear insight into how the experiments were carried out.

    (5) If the Lombardi et. al. are not finding XMRV what might they finding and culturing in their lab?


    They would argue that they are detecting XMRV in their patients. We have not tested those patients, so we cannot dispute this point. Our data simply says that we cannot find this virus in a UK cohort.
  15. spit

    spit Senior Member

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    Very, very interesting find. I hadn't looked at the figures, but damn, that is pretty faint. I mean, faint bands happen, but the positive control -- here, straight-up plasmid -- is the best amplification you're going to get. I sure wouldn't be confident in my assay if that was the best amplification I could get from my only known positive.

    I'm not sure what concentration they used for running the + control, I'll have to read more carefully than I had.

    I was looking at that other figure, too, though I'd only just begun getting over being annoyed by the mislabel. The 2nd run signal on that is really weak, weaker than the figure 1 weak. I'm going to have to think on that some. A lot of things don't make much sense to me.
  16. Eric Johnson from I&I

    Eric Johnson from I&I Senior Member

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    SPit, see also my prior message to you 20 min ago, a page back or so
  17. flex

    flex *****

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    Campaign to bring Wessley to justice

    I suggest that we play Wessley at his own game and set up a foudation to take direct legal action against him to bring him to justice and hopefully jail. This will play right into his tactic of headlining and PR. The difference is we know that we are in the right.Evidence and science is on our side. Worldwide we are 17 million strong and if we go for him all his cronies around him may abandon ship or try to pass the blame onto him.

    There is no shortage of people around the world that would give evidence against him, especially people whom have been thrown into swimming pools!!!! We could highlight his deliberately flawed "studies" and the repremands he has had from the WHO. The evidence could be endless.

    If we set up a trust fund to be held by a legally appointed group and each donated a minimum of 10 the amount we could raise may be phenominal.

    The evidence could be submitted on line and assessed for its legal credibity by our appointed legal team.
    With good PR large organisations sympathetic to our cause may put in large donations. Any funds raised could be used in the continued battle to bring out the clear scientific truth.

    Wessley keeps dumping untruths into the public domain we need to put the truth into the public domain. We we are never in the same ring fighting. We just keep telling each other the truths that we already know and leave the media and the general public open to his nonsense. We need to be on the radio, tv and in the courts rather than being underground momements on internet forums.

    I am looking for positive feedback on this from lots of different internet sites and am willing to set up the campaign.
  18. Eric Johnson from I&I

    Eric Johnson from I&I Senior Member

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    > I think Kurt is right; the retroviral research community would LOVE to find this

    Undoubtably true.
  19. Funkster

    Funkster

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    Hi Cort,

    Good of her to answer you promptly.

    WPI (Anette Whittemore and Dan Peterson) both asked the scientific community to cooperate at the CFSAC in late October.

    Is it confirmed that McClure et al has not been in contact with the researchers at WPI/NCI/Cleveland Clinic before or during their study?

    Do you consider the answers from McClure to be a positive confirmation that this is not an attempt to conduct a replication study?

    In light of the official statement from WPI, do you consider the answers inconsistant?
  20. kurt

    kurt Senior Member

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    I don't really want to get in the middle of this venting thread, but have to comment, but not because I want to defend the IC study, rather just to clear up some misconceptions about this type of research that are running rampant on this thread.

    1. Using a different cohort is a validation tactic, and very useful to help clarify who does and who does not have a given illness. All I really care about, all any of us should care about, is whether WE are included in the test cohort definition. There may be many definitions of ME/CFS but in my experience we nearly all have the same basic illness, we are just at different stages. If WPI says XMRV is found in 98% of PWC, almost any definition should turn up something. And if they found XMRV in 20 year old samples, so should other labs. So the cohort is almost a non-issue in this case. Cohort would be a major issue if we were dealing with a small subset of PWC, certainly, but the claim being tested here is that XMRV is a superset issue for CFS.

    2. There is a difference between pure replication and validation. Regardless of what people call the IC study it was clearly an attempt to validate the general thesis of the WPI study, and not a pure replication. They even took some extra steps to avoid problems they thought might have been present in the WPI study. Not many labs like pure replication studies, they want to 'do their own thing' use their own tests, cohorts, etc. When someone makes a bold claim, such as a retrovirus causing CFS, we need to see many different types of validation and replication attempts, coming from all angles. That is how we determine what is really happening. This IC study is useful, even if it is not a true replication effort.

    3. Using different methods, different primers, different types of PCR tests, that is all GOOD in attempts to validate a new finding. We want to see many different test designs all find the same thing. This is not rocket science, it is a basic antigen supposedly ubiquitous in the ME/CFS population, and it should be relatively easy to find many different ways. Based on the tolerances published in the Science article, other labs should easily find the antigen, one lab I know was able to increase sensitivity at least 10x over the WPI study, certainly IC could do that as well. Most important in fact is to target all areas of the genome, we should see tests for gag, env and pol sequences. You have to find the WHOLE bug and not just one part of it. If WPI only found part of a bug in their PCR test, it might not actually be XMRV.

    4. No control was really necessary since they found nothing, most labs would stop worrying about controls once they saw the pattern of zero findings. Unless you suspect a reverse finding, that controls will have the bug and PWC will not, forget about controls.

    5. If a test hits on a known positive control it works. That pretty much ends debate about reagents, which probes used, etc.

    6. Some people seem to think that 'peer review' is a big deal. In reality, peer review is simply an informed review and edit of an article by an expert. The peers do not go to your lab, or in any way verify that you did the experiment properly. All they have is your words on the page. So there is no 'gold standard' for peer review and the reputation of the journal has little to do with the whether a given study can be verified or not. In particular, journals like 'Science' and 'Nature' have their reputation in part because they are the top forums for DEBATE about difficult topics. Outside scientists can submit comments and rebuttals, and are probably encouraged to submit articles with conflicting viewpoints. Then the original authors answer, although they can also sit on the questions for a time (which I wonder about in this case since we have not seen any rebuttals yet and should have by now). I have been a peer reviewer, and really, it is not very glamorous. Glorified editing, simple fact checking, making a few recommendations. Something you have to find time for because it is not paid. Researchers put their reputations on the line no matter how or where they publish their results, so I think we owe the same respect to the many authors of the IC study as to those of the WPI study, and debate their data on its own merits, rather than by disrespecting people involved.

    7. Some people seem to have forgotten the many warning statements made by WPI. Such as, XMRV could be a passenger virus. This research is early stage, things like that.

    8. Many respectable academic journals are only editorially reviewed, and not peer reviewed. Peer review is slow, and sometimes inhibits sharing of new ideas that the gatekeeper reviewers do not agree with. Perhaps they should be called magazines though, I agree that they have qualitative differences from the peer reviewed journals. But certainly they can be much better than blogs.

    9. In my experience peer reviews are mostly editorial. Some peer reviewers have a hobby horse and they want you to include extra references, or adress some pet issue of theirs. That gets annoying. Then others want you to cut out vital parts to tone things down. Peer reviewers do improve the article text, but can not really pass judgment on whether a study was valid. As I mentioned above, they do not go to your lab and see if you did things properly. Peer review is useful but also oversold. So I agree with Eric.

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