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Negative XMRV CFS study with Ila Singh's name on it (University of Utah)

Discussion in 'XMRV Research and Replication Studies' started by Jemal, May 4, 2011.

  1. Jemal

    Jemal Senior Member

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    Nice comment by Dr. Snyderman (the oncologist that is taking ARV's and reporting about it) on the latest blog entry from Dr. Deckoff Jones:

     
  2. insearchof

    insearchof Senior Member

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    Hi Jemal

    Thanks so much for this post.

    It is good to put the respective expertise of the research parties into context.

    Thanks again.
     
  3. Bob

    Bob

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    I personally would like to see the XMRV association with ME confirmed, because it would give us an answer to our illness and allow us to start working on treatments. But I always do my best to look at the evidence objectively. The WPI research has not yet been disproven, and in my opinion it gets stronger and stronger the more I hear about their new research developments.

    I'm very pragmatic, and if at the end of the day the WPI are proved wrong, then I'll be disappointed but I'll be grateful for the light that XMRV has shone onto the world of ME, and I'll quickly move on and refocus on all of the other efforts going on in the world of ME, such as Chia's work with enteroviruses, the work with proteins in spinal fluid etc etc. But we haven't got to that point yet. Far from it.

    It seems that we are all in agreement that Singh is a credible and honest scientist.
    I've had some time to read over and think about the Singh study, but I don't yet understand all of the details, and exactly how it differed to the WPI's methodology.

    But it seems to me that in such a difficult to detect, brand new human virus, that if Singh only did one very small thing slightly differently to the WPI in her methodology, then she might not be able to detect any virus at all.

    It has been confirmed by the monkey study, and by the new CDC study that XMRV is exceptionally difficult to detect in the blood because the virus doesn't hang around in the blood. And this may be all that the Singh study has confirmed.

    Singh's main claim against the WPI seems to be that there is contamination. We have heard this many times before.
    My understanding is that the WPI have checked all of their equipment and reagents etc. for contamination, again and again and again, and that they do it continuously. No doubt they will do a fresh round of testing on the back of the Singh study.

    I believe that the WPI regularly put negative controls through their testing procedures, to test for XMRV contamination. To date, no contamination has been found.

    The claim that, because Singh's equipment were contaminated, then the WPI's equipment might be contaminated does not stand up to scrutiny because the WPI's samples have been tested at independent labs. The claim that the WPI's reagents are contaminated also doesn't stand up to scrutiny, because they have been tested.

    But on top of this, the wide variety of strains of virus that the WPI have detected (waiting to be published in genbank) suggest that this is no contaminant that they are finding, but it's a real wild human virus. And on top of this again, the WPI consistently find a major difference in the number of positives between patients and the healthy controls (i.e. 95% vs 4%). I think that all the other studies that were contaminated (i.e. Huber and Singh), found the same number of positives in patients and controls.


    It's interesting to note that all of the other previous claims against the WPI's work have now been rebutted by continuing research developments:

    - First of all, critics of the WPI said that XMRV was not a real virus - that XMRV was just a false positive reading caused by some other product. But that has been disproved. XMRV is a real virus.

    - Then the WPI's critics said that XMRV was purely mouse contamination from mouse DNA. But that has been disproved. XMRV is a real virus.

    - Then the WPI's critics said that the XMRV wasn't a real human virus, but was a mouse virus. But everyone now agrees that XMRV is a real human virus.

    - Then the WPI's critics said that the XMRV that the WPI detected was purely the product of a cell line, and not a wild virus. The WPI has now deposited a wider variety of strains to genbank, awaiting approval. Even the CDC has now confirmed that XMRV is a real wild human virus, and Switzer has detected 3 entirely new strains of XMRV.

    - Then the WPI's critics said that the established testing methodologies, used in the 0/0 studies, were totally adequate to detect XMRV in the blood. But now the CDC says they cannot detect XMRV in the blood of XMRV-positive prostate cancer patients, using established technologies.

    (The latest significant, but widely overlooked, CDC study by Switzer et al., demonstrates that XMRV is a human virus, and that it is not detectable in the blood by established technology or procedures, even in XMRV-positive prostate cancer patients.)

    - Now the only thing left for the WPI's critics to claim seems to be that XMRV is 'definitely' and 'absolutely' not associated with CFS or ME. I'm now waiting for this to be disproved.


    If anyone can explain to me how the WPI have detected so many different varieties of MRV's in their patients, and reconcile this with the contamination theory, then i'll give them a Phoenix Rising medal! (Actually, I'm not authorised to give them out! But I can give a pretend medal.)

    So far, it is only the WPI who have not changed their position.
    Everyone else has been proved wrong time and time again by the developing research in this fast developing new branch of virology.
     
  4. currer

    currer Senior Member

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    Hi, Bob,
    Excellent summary. Thanks for doing all the work and setting all the details out so clearly. The implications of the CDC paper should not be allowed to fade into obscurity.
     
  5. In Vitro Infidelium

    In Vitro Infidelium Guest

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    Disproving (proving a negative) a 'condition' is only possible if the asserted 'condition' (in this case: "XMRV has been found in the blood of some people with a diagnosis of M.E/CFS") is a logically definable 'condition' - in science this is usally described as being 'falsifiable'. The problem here is that "XMRV has been found in the blood of some people with a diagnosis of M.E/CFS" is not obviously falsifiable, it is of course true that it has been reported as having occured but establishing a 'proof' that 'XMRV' wasn't found' is likely impossible. Singh has shown why WPI probably did not find "XMRV in the blood of some people with a diagnosis of M.E/CFS" but that of itself is not a 'proof'. It is precisely because of this sort of problem with 'proving a negative' that science works in the opposite way - the burden is upon those who hypothesise a (logical) 'condition', to demonstrate the certainty of that 'condition' with repeatable experiment and falsifiability of the hypothesis that supports it. To date WPI have not done that within any standard accepted by their peer group, thus the linkage between XMRV and M.E/CFS is unproved - and that is how it remains until a proof (not a dis-proof) is given. You may not like that circumstance, but that is the scientific position and it is unlikely that any virologist is going to invest resources 'disproving' the WPI work because there is simply nothing to work with.

    The lack of change of position should be of concern - science demands change in the face of evidence, the WPI position looks ever more like dogma than any response to data. And who has been proved wrong ? WPI has 'proved' nothing, all that has happened is that one speculative study has been published, and its results have been questioned by multiple other studies, with the WPI maintaining that 'everyone else' is wrong.

    IVI
     
  6. floydguy

    floydguy Senior Member

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    What about Lo/Alter? Another speculative study where there is nothing to be seen, time to move on?

    What exactly do you advocate anyway? More investment in GET and CBT? Talk about dogmatic speculative studies.

    I am really not thrilled with the whole retrovirus thing and it may not even be relevant to me as I've tested negative but I think it's far too early to dismiss it. And the chances are high that the only ones waiting in the wings of this research are the Psyches and pill pushers.
     
  7. Bob

    Bob

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    If anyone can demonstrate why the WPI has not actually found XMRV in patients then I will accept that.
    But so far, every explanation has been proved incorrect, as I explained in my previous post.
    Singh's suggestion, that the WPI has only found contamination, does not stand up to scrutiny, as I explained.
    I agree that the WPI have got more work to do to prove the XMRV association with ME, and it's a work in progress.
    XMRV research, in general, is a work in progress... There are no definite answer right now... Maybe that's something for us all to remember.

    My point about the WPI not changing their position, is that everyone else has been forced to change their positions, whereas the WPI's position and evidence has remained valid.

    You ask: "Who has been proved wrong?" Please read my previous post, and if you still don't understand the points that I've made then please ask, and I will try to explain the details. The proof is based on various XMRV research, not just the WPI's research.

    One more point that I'd like to make is that 'absence of evidence' is not the same as 'evidence of absence'. Especially in a such a new field as XMRV research, where there are so many unknowns. So a zero/zero study may or may not be helpful, but it doesn't necessarily prove anything. My point being is that, in my opinion, the weight of evidence against the WPI is not as strong as you seem to think it is, taking everything into account.

    Your opinion about the WPI's position does not take into account the wider body of evidence in relation to XMRV.
     
  8. asleep

    asleep Senior Member

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    IVI,

    You appear to be making the (all too common these days) mistake of confusing failure to falsify with unfalsifiability.

    You claim that the statement "XMRV has been found in the blood of some people with a diagnosis of M.E/CFS" is "not obviously falsifiable." Do you also claim that the statement "HIV has been found in the blood of some people with a diagnosis of AIDS" is also "not obviously falsifiable"? If so, then the government should be alerted immediately as we've been spending billions of dollars a year pursuing an unscientific premise! It simply cannot be logically true that one of these statements is falsifiable and the other is not. Saying that the latter is "proven" or "consensus" has no bearing on its scientific falsifiability. The falsifiability of a hypothesis is independent of it's current acceptance in society or the scientific community.

    You also seem to be misunderstanding how burden of proof works. Burden of proof generally lies with the person making a positive claim (in the philosophical sense, not the "is something there?" sense). Your claim that "Singh has shown why WPI probably did not find 'XMRV in the blood of some people with a diagnosis of M.E/CFS'" is indeed just such a positive claim. The fact that your claim pertains to the supposed absence of something does not absolve you of the burden to prove your assertion.

    So yes, more evidence is needed to "prove" the WPI's position. But more evidence is needed to support your position as well.
     
  9. Bob

    Bob

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    Indeed. Singh has made a claim about the WPI's XMRV research that is not based on any evidence other than the fact that Singh could not detect any virus in her research study.
    There are so many unknown variables in XMRV research that I think that it was unhelpful, and even dangerous, to express the opinion that there is no association between XMRV and ME.
     
  10. Jemal

    Jemal Senior Member

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    The CDC's HIV department now finding XMRV will be beneficial to us, I am sure. They might not be able (or even want to) link it to CFS, but research will get a boost if an organisation like the CDC asserts that this virus is real and can be found in humans, without it being contamination. It's the first negative study that will probably help us a lot :D

    I have linked the study in discussion with some people that think XMRV is like the Yeti and they totally ignored it. That means that study is gold :D

    That study could be the elephant in the room nobody wants to talk about!
     
  11. toddm1960

    toddm1960 Senior Member

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    The reproducing their results has been done by WPI In Vitro, the problem is it can't be published. That "good science" you're looking for to confirm a new finding is being squashed, and only negative studies are getting airtime.
     
  12. Mya Symons

    Mya Symons Mya Symons

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    Are you saying that you think the WPI has already taken tissue samples and found XMRV in those tissues or are you saying they found XMRV in other areas of the body (besides blood) using some other technique or when you say "in vitro" do you mean something else?
     
  13. toddm1960

    toddm1960 Senior Member

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    The "In Vitro" is a username....In Vitro Infidelium
     
  14. alex3619

    alex3619 Senior Member

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    I cannot agree with the above argument. If philosophy of science is going to be debated, lets debate it - but its a quagmire of complex issues.

    My background is in philosophy of science and systems theory, as part of a degree in artificial intelligence, supplemented by a biochemistry degree. I have not studied philosophy of science for most of two decades now, I have brain fog and poor episodic memory, but I think there is a problem with the quoted argument. This is my opinion, not a fact, but I claim it is logically consistent with what we understand.

    Science is all about falsifiability at its core. I do agree with science must deal with new data as it is produced, but all data has circumstances that help you evaluate that data.

    The Lombardi hypothesis that XMRV is associated with ME/CFS has not been disproved. The quoted argument is correct in saying it cannot be disproved, just as it is correct in saying that the WPI has proved nothing. These "proof" claims are not of any value.

    Any argument based upon use of "proof" like this was falsified by Karl Popper decades ago. Science is not about proof, its about falsification. An argument that cannot be substantially falsified over time is considered tentatively correct. It cannot be proved. It is always possible that someone will come up with a better hypothesis.

    The notion of proof is only unproblematic in mathematical systems. 1 + 1 = 2 is only true in some math systems, sometimes the answer is 11, or even infinity. Indeed, using first order predicate calculus (mathematical logic) you can "prove" anything is equivalent to anything , in the sense you can show it is mathematically true. Math is only a tool, the real world has to be translated to math and back again.

    The Lombardi hypothesis was claimed to be falsified by various studies. The most consistent claim used is that it is contamination. However, the contamination arguments have been falsified (shown to be inconsistent with known data). A falsified counter-argument cannot be used to falsify the original argument.

    The WPI and other labs producing results consistent with the Lombardi hypothesis (which I will abbreviate LH) repeatedly and routinely test for contamination. Their controls show much lower presence of XMRV than ME/CFS patients. The Shin et. al. contamination findings however showed roughly equivalent XMRV rates in controls and patients. This is the expected contamination result.

    This information is not consistent with the view that the claimed XMRV association is due to contamination. Furthermore, the viral diversity that has been found is not consistent with the view that XMRV was due to an accidental lab creation in the early 90s. The XMRV crossover accident is also not consistent with the control results.

    The contamination arguments are often portrayed as what I call "nudge, nudge, wink, wink" arguments, after Monty Python if I recall correctly. They are something like this: "It might be true, we found some evidence, therefore we are implying it is absolutely true." (Nudge, nudge, wink, wink, say no more, said with a sly grin.) A logically defensible claim from these studies is that contamination is a concern and needs to be controlled - which it has been.

    The thing that is of critical importance is that the LH has not been falsified. The falsification arguments against it have been falsified.

    The contamination arguments and others are not anti-scientific. They are the other side of science - if they can convince enough scientists that the LH is probably wrong, we can't have confidence in the LH. On the other hand, because the contamination arguments have been shown to be probably false for the LH specifically, they are not convincing. If the falsification arguments continue to be falsified, and the LH is pragmatically useful, we can have confidence in the LH.

    It has been portrayed on some sources that proponents of the LH cannot be swayed by evidence. I cannot speak for everyone, but here are two ways I can be convinced the LH is wrong, presuming these cannot be falsified:

    1. A large blinded controlled experiment (eg BWG, Lipkin) that shows that WPI and others cannot isolate claimed XMRV positive patients would be falsification. Some controls will of course be found XMRV positive if the hypotheses about XMRV background rates is correct, but not many.
    2. The specific identification of contamination sources, together with a defensible reason they did not contaminate controls equally, with such sources matching the genetic sequence of the XMRV positives, would be falsification.

    Both proponents and antagonists of the LH are part of the scientific process. It the Socratic method, deeply disguised. Some argue for, some against. In the end the argument that survives is considered correct, at least until somebody shows otherwise with some great new experiment.

    There is a serious dearth of good research, due to lack of interest and funding over many decades. We, as patients, want results. We don't care who is "right", only who can cure us. We are not stuck in dogma, we look at all the science, although individually we have limitations in understanding it. This is why forums like PR are so important, we can discuss the research. When we object to poorly conducted science, it is pragmatic and often reasonable, in the sense it is subject to reasoned debate. When we support well conducted science, it is pragmatic and often reasonable. That does not mean we don't get it wrong frequently, but over time the debate improves. Those who want all of us to agree miss the point - it is disagreement that continually tests our claims, and only by testing them can we have confidence in them.

    The ultimate value of any hypothesis is about pragmatism, not proof. If using XMRV to identify and cure patients is the long term outcome, it does not matter if the LH is right as we currently understand it. What matters is that we are cured (or adequately treated in the absence of a cure). This is pragmatism, not proof. Proof is for mathematicians, and denizens of Flatland.

    I did not address the issue of the zero zero studies here. Maybe I will write another post.

    Bye,
    Alex
     
  15. Cort

    Cort Phoenix Rising Founder

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    From Bob

    I think everybody grants this - the question is what is the definition of 'very small'; my guess is that while there are small differences between the two studies - that they are simply too small for many researchers to believe that they are significant. Note that the Singh study was developed in close collaboration with Dr. Mikovits and Dr. Mikovits was, as she put it, 'astounded' that Dr. Singh didn't find XMRV. This indicated that she thought the two studies were close enough to work. We'll see how this all turns out with the BWG.

    Until the WPI starts saying you have to look in the tissues I think we should take them at their word and accept that it should be findable in the blood on CFS patients; that, after all, is what the WPI found. If Singh got 5 or 10% positives - then I think tissue exploration should be an would be explored...but zero percent - in a population that should be showing 50 or 60 or 70% is another matter.

    I agree that they appear to be alot of work on avoiding contamination but I don't think we know exactly which parts they are testing....Could they be missing something?
    We don't really know this either. We think it must be happening and there are references that it has happened but has it? That would require finding healthy controls an getting their blood. So while it may very well be happening I don't know that we know to what extent it is happening.

    If XMRV got into the WPI's samples at the WPI then anything sent out of the WPI would be 'contaminated' with XMRV. If they added healthy controls to the mix - and the labs were able to differentiate between the two - that would be a good test...

    The prostate cancer paper was interesting in this regard...but again until those samples are deposited in GenBank we don't know.

    That was the first paper - so I don't think you can say consistently until we have evidence that this is so....Huber found that her healthy controls were positive but her CFS samples were not. Still this is the KEY area; if the WPI can demonstrate their ability to differentiate between healthy controls and patients - then they win the day :cool:. They will have the opportunity to do that iwth the BWG and Lipkin studies.

    ???? they were the first to grow XMRV I belive

    I think this referred to other labs that mistook mouse DNA for XMRV and went back and looked and found it was mouse DNA. I don't think this refers to the WPI. There is no doubt that they did find XMRV because they were able to culture it.
     
  16. Cort

    Cort Phoenix Rising Founder

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    From Bob

    Not sure how important this is....At first they were unable to tell if XMRV jumped from mice to humans. Since they have never been able to find it in mice they now believe it is either a lab produced virus and/or a human virus. The only other place they've been able to find it ironically is the 22RV1 prostate cell line, which suggests it is a lab creation.

    These two are not mutually exclusive at all. XMRV could be produced in a laboratory and then escape and become a wild virus. Singhs study is a case in point. She patched two plasmids from VP62 together to make a clone; when she dropped that clone into culture - it produces XMRV! and not only does it produce XMRV but it produces virtually the same type of XMRV the WPI reported they found. That was a lab creation.
    Actually all the published evidence to date suggests that this is correct! All the XMRV samples provided from the WPI to GenBank to date suggest that their version of XMRV was derived from the 22RV1 cell line. Their XMRV is almost identical to the 22RV1 XMRV.

    The CDC like all the other major labs must show they can find XMRV in spiked samples before they do their test. Coop Diagnositics is a case in point; they can put XMRV from prostate cancer samples into their samples at very, very low amounts and detect. For them to miss XMRV from CFS patients - the version of XMRV in them must be VERY different from the type of XMRV the WPI reported in the Science paper.
     
  17. Cort

    Cort Phoenix Rising Founder

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    :D:D:D - the problem is obviously with the lack of published data as they have stated this but not published it. They may be in a bind because they're having trouble publishing - but I suppose they could drop them in GenBank.
    I'm going to have to disagree with this.....and I don't think its necessarily bad that someone changes their position - as science progresses - but they have changed their positions over time. They backtracked on the type of patients in the original study, changed their testing methodologies and we were told the discrepancies in the studies were due to storage/sampling/freezing/lack of antibody tests/not doing culturing/patient cohorts/ variable testing results, etc.

    I vividly remember Dr. Mikovits emphatically stating that the storage results from the BWG would be THE reason for the discrepancies....There was the freezing idea at the Scandanavian conference.....They are trying to figure out what's going on - that's understandable - but except for the fact that they are confident in their results - things have changed over time.
     
  18. Cort

    Cort Phoenix Rising Founder

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    If we're being really rigorous here we cannot say that contamination in CFS is disproved by the CDC prostate study. All we can say is the that might be true (needs validation) in prostate cancer. Until the WPI can show gene variability results that suggest that XMRV did not come from the prostate cancer cell line - the contamination theory is certainly not disproved. THe big puzzle is why the WPI's gene variability results have not, over the past year, been deposited in GenBank - since if they are a variable as they say that would have taken a question mark off their back. Perhaps there's more to getting results into GenBank than we know (since we know very little :))

    The initial control study results CAN be explained - it's later control/patient tests that cannot be - if both were treated in the same manner. The upcoming studies will provide plenty of controls to test this theory out...:)
     
  19. Mya Symons

    Mya Symons Mya Symons

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    LOL, sorry. I was hoping you had some information we didn't have.
     
  20. Angela Kennedy

    Angela Kennedy *****

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    But NONE of this means the Lombardi findings have been disproved, as Alex has tried to explain. But what we see happening are attempts to insinuate or even downright claim that the Lombardi paper has, in some way, been found 'wrong' (insinuating disproving has happened), which is, currently and possibly for always, untrue!

    Thank you Alex for that extremely useful post. I wish more of the 'scientists' out there understood this complex, yet basic issue. I have squirmed every time I've seen people, especially those invoking scientific authority, use the words 'prove' and 'proof'.

    Of course what we are seeing in this whole arena is an awful lot of rhetoric and even bad faith, and THAT is obfuscating the science, even, possible especially, for those claiming scientific expertise and authority.
     

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