Discussion in 'XMRV Research and Replication Studies' started by pollycbr125, Sep 17, 2012.
Thanks Alex. I'll have a look at it.
haha Currer, I like your partner
really tho, I don't know what to think about mlv's because i dont feel I have the science background to adequately analyze it
but I like Dr Jamie's current blog, my take away wasn't that she emphasizing whether mlv's exist or not, just that whatever the case may be, there are a lot of sketchy circumstances around the whole examination of (retro)viruses in CFS and what went down the last few years is no exception
Polly, Dr Snyderman's blood markers are really intriguing, and he is very well placed to understand their significance.
However it is the case that antiretrovirals also seem to have immunomodulatory properties.
Unless further research goes ahead on ME and retroviruses we cannot know more, and no-one has responded it seems to Dr Snydermans request for research interest.
The antibody results in the Lipkin study do not suggest that PMLV retroviruses are associated with ME.
I dont know why the antibody results in the earlier studies appeared to correlate with ME.
is it just me, or all the years i spent researching first CFS, the on to ME, i never heard a peep that when no answers were found, in the end i will have Multiple Sclerosis. did i somehow miss this info? was it out there to be learned? Did any others of you know about that progression? I must say it is quite nerve-wracking now to consider this grand entry into the next phase. This is very newsworthy information. It's a severe sentence to be imposed.
I'm still reading about the whole XMRV thing; I hadn't heard about it until I joined this site. From scanning some of the comments it looks like the authors of certain papers are making wide, generalized, statements now that XRMV 'wasn't found and now saying no retrovirus is involved. This Lipkin guy is the same guy who said vaccines don't cause autism? So mercury doesn't cause brain damage? No 'evidence'? This is all a high-stakes semantic word game, designed to lull everyone back to sleep.
I guess cigarettes don't cause lung cancer either? This guy looks like an intellectual assassin. He was sent it to sabotage the whole thing.
HIV is a retrovirus. There is a whole slew of controversy on how it came to be. AIDS isn't even defined the same in every country; I'm not sure CFS is either.
'Forced out of her job' code that means 'we had to get rid of the problem'. Then later we accuse her of committing a crime to discredit her in the eyes of the public and press, most who wont bother to do the research to find out the whole story. This is standard operation procedure in a cover up.
Since I'm not totally familiar with this I'm not sure if this fellows comment is accurate but it sounds credible and does help explain what I think this is, a cover up. I decided to post the comment, you can follow the link to the whole thing:
Yes, that's my reading of the situation too. Thanks, Vincent.
I just want to pick up on a specific point about patient selection and blood processing. My understanding was that Judy decided the patient selection criteria. That's definitely why specific criteria for viral-like onset was required, and it maybe why well known ME clinicians were used. The recruitment criteria was specifically tailored to copy Judy's criteria in her own studies. I don't see how it could have been done differently, except to use exactly the same patients. But considering the unpublished UK results, that wasn't necessary. I'm not sure about the processing of the blood, but I would imagine that Judy was quite specific in her requirements for that as well. I can't see that collection or processing were a problem, if Judy gave it the go-ahead, esp because absolutely no XMRV was found. If it was a case of some XMRV being found, in small quantities, then I might have some questions. With no XMRV being found, either it wasn't there, or it was purposely tampered with to destroy it.
One might take note of the speculative language required to make this case. (I’ve emphasized some of it.) Such language is necessary to support the conclusions of the study because, unfortunately, numerous questions remain unanswered and many details remain undisclosed. For example, regarding just the particulars of the collection and processing:
Did Judy have complete control over collection and processing protocols? This study used EDTA tubes, despite the fact that she had previously reported great difficulty with them during the BWG. Even if Judy did have complete control, were there perhaps differences in protocol that affected the results in a manner that was unforeseen by Judy (i.e. unknown unknowns)? Clearly, the use of EDTA does establish the existence of differences in protocol. We are left to speculate about the full spectrum of differences and their possible effects since these differences were subjected only to “prior agreement” instead of actual empirical testing. Even if Judy did have complete control and somehow knew that all the changes in protocol would have no unforeseen effects, how do we know that collection and processing were conducted precisely as “agreed upon”? Beyond the possibility of intentional or unintentional mistakes undermining the process, there could have been issues as innocuous as subtle, unaddressed discrepancies in convention during otherwise routine portions of the protocol.
No one can answer these questions because they were either not disclosed by, not answerable by, or not controlled for by this study. Hence the need for presumptive language in order to gloss over them. Such an exercise in guesswork could be considered acceptable as a provisional step in guiding further research. But in this case we are being told to accept such speculation in place of further inquiry due to the unscientific characterization of this study as “definitive.” At the risk of sounding normatively imposing, I suggest that this state of affairs should be deeply unnerving to anyone who cherishes scientific inquiry, more so if their future is also on the line.
Furthermore, the appeal to “agreement” by certain “individuals” to justify brushing aside or ignoring unanswered questions and uncontrolled variables is inherently unscientific. Empirical reality has an annoying habit of defying the concords of humanity’s most credentialed investigators. The use of “agreement” in defining truth exists exclusively under the purview of politics and religion. To use a well-worn but germane example, Galileo (ostensibly) “agreed” with the Catholic Church that heliocentrism was unfounded. The Catholic Church made the mistake of not declaring this agreement “definitive” and indefinitely discouraging further exploration.
Lastly, it is somewhat beside the point that Judy has publicly endorsed the study’s conclusions. It’s almost as though no one in the history of the world—especially someone under the trying circumstances that Judy has endured—has said something publicly that they disagree with privately. Or as though no one has ever been falsely convinced that they were previously wrong about something when in fact they were actually correct. There are many open, empirically-supported questions and issues that this study has not addressed, which have been anticipated for quite some time. What I find most peculiar is how people who recognized the importance of these questions up until the release of this study--in defiance of constant accusations of “following scientists instead of science” no less--are suddenly so willing to discount the continued pertinence of these questions simply because Judy publicly agreed with the results. This constitutes the essence of “following scientists instead of science.” Quite strikingly, the same chorus that so fervently voiced this refrain about “following scientists instead of science” in order to discourage interest in RVs prior to the Lipkin study has gone eerily quiet afterwards despite the fact that such admonitions are actually more appropriate now than ever before. I suppose consistency no longer matters once the “correct” outcome is reached.
It’s strange that you say there was no XMRV found because—in addition to the casually discarded serology positives—PCR positives were found and mentioned in the study (discussed below). However, they were reported as "all negative" due to arbitrary, interpretive requirements imposed by this study that effectively hid this data. Each lab had to report both aliquots from a given subject as positive for the subject to be reported as positive by that lab.
Each lab had additional lab-specific requirements for reporting individual aliquots as positive. E.g. the CDC ran three PCR assays on each aliquot (gag, pro, pol) and had to find 2 of the 3 positive in order to report the aliquot as positive.
Taken together, these requirements did result in non-reporting of positives which could very well have obscured important correlations and associations: Were there more unreported PCR positives in patients than controls? Was there a subject-level correlation between unreported PCR positives and reported serology positives (thereby making casual assumptions that serology positives were irrelevant cross-reactions rather cavalier)? Were there any assay-specific associations that were obscured by the data-aggregation rules (e.g. the CDC could theoretically have found strong evidence of gag presence but been forced to report all of it as negative due to difficulty in finding pro and pol sequences)? None of these questions can be answered because the raw data was not reported. Only the high-level, implicitly interpreted results were supplied.
As noted above, the presence of unreported PCR positives is not speculation, as they are mentioned in the paper itself. Consider the following quotes:
Regarding the Mikovits/Ruscetti/Hanson PCR results:
This clearly establishes that there were PCR positive cultures. The paper does not state why these were ultimately reported as negative, but presumably it is either because they were discarded due to inability to run IAP or because their corresponding aliquots were negative. In either case, information was lost.
There are additional, indirect indications that unreported PCR positives were found in all three labs.
Given that the first quote above explicitly establishes the presence of unreported PCR positives and given that these generic references to PCR positive samples do not make explicit reference to them being exclusively positive control samples, it is quite reasonable to interpret these statements as referring to positives found in actual subject samples. Additionally, there is no mention of contamination being found in the labs, thereby making it unlikely that all of these unreported positives were discarded due to indications of contamination.
It is therefore warranted to conclude that PCR positives were found in study subjects in each participating lab. The fact that only the post-aggregation data (which implicitly imposes an interpretation on the raw data), should be seen as suspicious given that it clearly resulted in the hiding of potentially relevant correlations.
I was purposely careful with my wording, to make it clear that I do not know the exact details.
And I was successful in that, because you rightly understood that I was either expressing my opinion or conveying my understanding of the situation.
However, it is clear that Judy had at least some input with the recruitment criteria, and it was my understanding that her needs were accommodated.
So I was adding this to the discussion, for balance, as some people seem to think that she had no influence over some of these details.
I don't know if most of your post was aimed at me, or not, but if you knew my opinions about XMRV research, which I express regularly, then you wouldn't have aimed most of your comments at me.
The serology results were meaningless without further information. Firstly, cross reactivity is possible. Secondly, they were the same percentages in both cohorts. So unless someone is going to investigate them further, then they don't tell us anything at all.
Do you happen to have a quote for that? I'd be interested to see it. I haven't studied the paper in fine detail yet.
I thought that Judy was using her own methodology, and could determine the positives in any way she saw fit, as long as it was determined before the study began. But I wasn't clear about the details of that particular aspect of the study.
I think my post was fair, except you do make a very good point about the possibility of XMRV being found in some samples, so I'll have to wait until I read the paper more closely before I form an opinion about that.
Bob, my intention was not to single you out. I was using your post as more of a launching point to address a number of items I've seen expressed rather frequently. I tried to make my response as generic as possible but I apologize if it seemed like I was aiming it directly at you.
This is problematic for two reasons: 1) It is disingenuous (not of you but of the study itself) to not conduct follow-up work to check for specificity and then turn around and claim that the results can be dismissed out of hand because no evidence for specificity exists. There are other methods that can be used to pinpoint specificity of a serological reaction. 2) Because some PCR positives went unreported, it's possible that these PCR positives could have correlated with the same subjects that showed serological activity, thereby adding support for the specificity of the serology. The fact that percentages were equal between cohorts would not alone be sufficient grounds to reflexively dismiss serology positives that correlate with PCR positives on a subject level, as this would be strong evidence of genuine infectivity regardless of disease association (which itself could be affected by issue like cohort selection).
The last four quotes from my previous post are all directly from the paper.
Oh, OK, thanks for clarifying. I'm always using posts as launching points.
I meant, do you have a quote about how they determined if a sample was positive or not?
It would be handy, otherwise I'd have to read through the whole paper looking for it.
I don't understand why some people think they can have it both ways.
For whatever reason some people have elevated judy m up to be more trustworthy than other scientists. I don't get that reasoning but ok. But when she then says "actually, I was wrong. This has been proven to my satisfaction" some of you still don't believe it. Now, either you trust her or you don't. If she is the only totally trustable one there is then you should trust her, after all one of the reasons she has so much trust with the ME community is that she has shown that she will speak out if she has even the smallest doubt, even if this means making personal sacrifice.
So it seems crazy to me that this reasoning does not result in acceptance that XMRV and the other MLV are not the cause. They were an accidental red herring. You can't both trust the judy that found XMRV and not trust the same judy that said it was amistake.
Personally I trust judy. The one who found XMRV and the judy who then said it was a mistake.
For every sample, each lab was sent two independently coded aliquots. This quote pertains to all labs and explains that both aliquots sent to a given lab had to be "positive" for the sample to be considered positive by that lab:
As the above quote notes, each lab had individual criteria for calling a single aliquot positive.
As I mentioned earlier, the CDC ran 3 PCR assays on each aliquot. The rules for the CDC calling the aliquot positive were:
The rules for the Alter/Lo lab are difficult to decipher from the text.
The rules for the Mikovits/Ruscetti/Hanson labs were:
This last quote sounds identical to the general requirement (both aliquots must be positive for a sample to be positive), but it could possibly mean that both aliquots had to be positive with the same assay for the sample to be positive...it's a bit vague.
I realize that these criteria were "agreed upon," but placing a concordance (i.e. interpretive) criteria on how the data itself gets reported is problematic. The raw data could contain relevant correlations that are obscured by this criteria. Additionally, these criteria could have compounded any other possible issues that affected the reliability of assays (EDTA, viral transience, etc) by obscuring transient and/or weak signals. Interestingly, these "positivity criteria" and the fact that they resulted in unreported PCR positives seem completely at odds with Lipkin's claims prior to the study that he would be looking "any signal" (paraphrased).
I don't feel I know what the answers are with all of this. I really don't. sort of like "does god exist?" dunno.
but snowathlete, for me its not really about "trust"...I don't know Judy, so can't judge her honesty,but high profile public situations like this I don't think can be judged on "trust" same way you might with your friends or family. an analogy....did people trust Colin Powell when he said there were weapons of mass destruction? he had pretty good credibility with the people.....but he was given bad information. Or if a robber has a hidden gun trained on a bank clerk and clerk tells a cop peaking in that everything is cool, is she a liar?.....might be honest under normal circumstances. I just have impression a lot of money and ego and history is weighing down on this thing......just lots of sketchy circumstances around it all, doesnt make me assume xmrv the answer for us, but it does seem like some powers that be are trying to obfuscate some thing.
just seems, as far as honesty goes, they may have offered judy a better alternative (as far as survival physically and as a scientist) than they did elaine defreitas. maybe i seem like I have read too many Grisham novels but Osler's Web reads like one but its true.
Thanku for that, asleep. Much appreciated.
It's not what I thought the situation was.
I agree with you that Lipkin suggested that any signal could be considered a 'positive', and I assumed that Judy would use just a single positive sample from a patient, as an overall positive result, as the signals are so difficult to detect.
But we don't know if she happily agreed to this methodology or not, so we can't discuss it without speculating.
In any case, this study has put a lid on further XMRV research, and I personally have to move on, for my personal sanity.
No one is going to do any further XMRV research, now, in relation to specific illnesses.
And if Mikovits and Alter say it doesn't exist, then there is no scientist left to continue the fight.
Lipkin has said that any retroviruses should show up in his pathogen studies, if present. But I suppose that doesn't mean much if you don't trust him.
I had already been thinking that XMRV was probably a contaminant, for a while, for various reasons, so the results of this study don't bother me. I'll be looking out for further retroviral research, with interest.
The group was instructed to comply with the interpretation several months before commencement of the research. This included Dr Coffin's design and the case definition devised by the physicians and Suzanne Vernon. No other options were given. Dr Mikovits would never be allowed any influence over selection criteria given her qualifications as laboratory investigator, and her continued response to cohort issues that she is not a clinician.
This will surprise you, but this infection cohort would not be recognizable to a retrovirologist, who would know that such retrovirus infections are silent. A prolonged infection is then characteristic of a herpes virus like Epstein Barr. So this cohort was wildly speculative for harboring a retrovirus.
Here is a proposal to consider regarding the PCR data. If all patients were positive 100% of the time in 1 out of 3 of their aliquots and the controls were negative 100% of the time in all 3, then the study would still be reported as it has been. Yet an infection from such a virus cannot produce enough virus to fill more than 1 out of 3 aliquots, so this interpretation is mistaken and there is the small issue of sequencing the complete virus from each aliquot to determine its taxonomy, and difference to the mouse host retroviruses. There is also a missing contaminant in all the ME studies which have sequenced viral DNA/RNA of whatever virus.
There is now a need to view Dr Lipkin's research as helpful in deciding some more what the truth could be, but Dr Lipkin has embarked on a hunt for known pathogens using specific primers that would not pull out novel retroviral sequences, making it impossible to disregard the involvement of other retroviruses or even other MLV-related viruses. A program directed to use high throughput methods is what I would now prefer to see.
Yes, Lipkin said, in the TWIV interview, that the interpretation was agreed before commencement of the study.
He said it was necessary to agree this beforehand, so the targets were not moving after the study commenced. (I think that his implication was that this was to avoid confusion and arguments at a later date.)
I was under the impression that she had influence over the selection criteria.
I thought that I had heard this stated in the past, but maybe my memory is false.
Maybe I have not seen or heard any evidence either way.
I think it's impossible to pick a perfect CFS/ME cohort.
In the TWIV interview, he described a comprehensive search for known and unknown pathogens, also looking at proteins and genes, using NGS/high throughput techniques, using faecal swabs, tears, saliva, blood. And there has been a suggestion that he is using spinal fluid as well.
He specifically said that if retroviruses are present, then he would 'hope' that they would show up.
But that all depends on whether people trust him or not.
I'm giving him the benefit of the doubt, because I've got no evidence to cause me not to trust him.
Plus, I would go insane if I harboured thoughts that there was a government conspiracy to hide a virus that caused my illness, that I had no power to change.
Even if the "cohorts" weren't perfect and not all the patients had CFS/ME then I would speculate that there would be more positives in the population, other than the ones they found and were discounted.
The fact that there will be continuing research, as well as his professional history, does make me feel that Lipkin knows what he is talking about. This is not "blind faith" but based on looking at many factors about Lipkin, what other scientist are saying, the fact that judy is on board, etc. etc. etc.
It could be because this is not about trusting Dr Mikovits and has never been about her.
You could also consider that if Dr Mikovits was wrong about the original findings she could be wrong about these as well - but that's not how I see it.
It's about the science and if the findings over the past years have been right or wrong. How do we explain them and is there a retrovirus associated with ME and CFS?
I never stopped asking questions and examining each finding as it comes up. I've never "trusted" a scientist or researcher in a blind trust, nothing to see, move on sort of way.
For some of us we are doing what we have always done. Keep examining the science, keep asking questions, keep evaluating evidence as it comes up.
Whether Dr. Mikovits is being truthful or not, we really don't know. All the speculation above could just be the opposite or somewhere in between, eh?
You are absolutely right about scientist, not so much about trusting them as using critical thinking about science. Question, question and think critically which might include knowing which scientest are up to speed which is very different than blind trust. This could also apply to other people/situations in our everyday life.
This is why I am a strong advocate for Science Based Medicine vs. Evidence Based Medicine/ alternative medicine in the true sense of their definitions.
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