First off, on Saturday 2nd July, a news item in Science magazine reported that two papers on XMRV were about to be published, but that the publication of both was "on hold" because they contradicted each other. One paper, from the US federal Centers for Disease Control (CDC), supposedly found no evidence of XMRV infection while the other one, from the National Institutes of Health and Food and Drug Administration (NIH/FDA), did.The papers were only rumored to exist at that stage, and the story behind the NIH/FDA paper was particularly complicated. A Dutch magazine called ORTHO reported (see also) that NIH virologist Harvey Alter had given a presentation in Zagreb, Croatia, in which he reportedly said that the original Lombardi et al 2009 results, which first implicated XMRV in CFS
are extremely strong and likely true, despite the controversy...We (FDA & NIH) have independently confirmed the Lombardi group findings.This was in reference to the still unpublished NIH/FDA paper, which according to Science, has been accepted for publication but currently put "on hold" by the journal PNAS.
However, the Science news was obsolete as soon as it appeared, because the other "on hold" paper, the negative one from the CDC, turned out not to be on hold for very long, if at all. It's now available online at the journal Retrovirology: Switzer et al's Absence of evidence of Xenotropic Murine Leukemia Virus-related virus infection in persons with Chronic Fatigue Syndrome and healthy controls in the United States. It's listed as being published on the 1st July.
The CDC paper Switzer et al, as the rumors predicted, is negative. The authors tested blood plasma from 51 CFS cases and 53 healthy controls and found no evidence of anti-XMRV antibodies; they sent the same samples to a German lab and they confirmed the results. They then tested DNA extracted from blood samples in the same CFS patients and 97 controls, finding no evidence of XMRV DNA using a number of analytical methods; again, a second lab confirmed this. The paper is open access, so you can read it for more details (there are lots).
This is a big deal, because this is the first paper to attempt to replicate Lombardi et al's results in American patients. Several studies have appeared in the months following the original paper, and none of them found XMRV infection in any of their patients or controls. This is mysterious because Lombardi et al found XMRV in 67% of patients, but also in 4% of controls. However, these studies all used European people, raising the possibility that XMRV is just not found in Europe, for whatever reason.
So what exactly is going on here? Maybe only Lombardi et al used the appropriate methods which were able to detect XMRV, and everyone else has been failing to pick it up. However, in my opinion, while this was a reasonable suspicion months ago, it's very unlikely now because (by my count) 6 labs have not found XMRV in CFS patients, using lots of different approaches.
In most cases these labs showed that they were able to detect small quantities of XMRV added into a sample, as a positive control. Switzer et al, for example, say that they were able to detect 10 copies of the virus (not many) mixed into a sample of human DNA; one of the labs they used for a confirmation analysis could detect 4 copies.
There's another possibility - maybe only Lombardi et al were studying the right people. Lombardi et al used a carefully selected subgroup of CFS patients with various neurological and immunological abnormalities suggestive of a "medical" as opposed to a "psychological" disorder. However, the most popular 1994 criteria for CFS are a lot broader than this. Supporters of the XMRV-CFS link say that XMRV is probably associated only with some cases of CFS, and the various failed attempts to confirm XMRV have been looking in the wrong people.
Bearing this in mind, it's notable that the latest Switzer et al paper didn't recruit patients by approaching those who considered themselves to have CFS. Rather they identified cases through population screening: calling random numbers from the telephone directory of Wichita, Kansas, and of sites in Georgia, and asking people whether they were suffering from CFS-like symptoms such as fatigue. People who answered "yes" to enough questions were invited for a medical exam and interview and were diagnosed with CFS if they met the 1994 criteria (though in the abstract these are described as the revised 1994 criteria), as long as their symptoms weren't explained by a known, current medical or psychiatric disorder.
It's fair to say that this will have recruited a very different cross-section of patients than Lombardi et al did. However, in my opinion, while this is important, it doesn't resolve the fundamental mystery of why no-one had XMRV, not even the healthy controls, given that Lombardi et al found XMRV in 4% of healthy people. To my knowledge, this question remains unexplained. Maybe the "on hold" NIH/FDA paper will shed some light...
Finally, those interested in this topic may find my running summary of (I hope) all human XMRV research useful.
Link: virologyblog is also on the case...
Switzer, W., Jia, H., Hohn, O., Zheng, H., Tang, S., Shankar, A., Bannert, N., Simmons, G., Hendry, R., Falkenberg, V., Reeves, W., & Heneine, W. (2010). Absence of evidence of Xenotropic Murine Leukemia Virus-related virus infection in persons with Chronic Fatigue Syndrome and healthy controls in the United States Retrovirology, 7 (1) DOI: 10.1186/1742-4690-7-57Enserink, M. (2010). Conflicting Papers on Hold as XMRV Frenzy Reaches New Heights Science, 329 (5987), 18-19 DOI: 10.1126/science.329.5987.18
25 comments:
"the latest Switzer et al paper didn't actually recruit patients who considered themselves to have CFS"
^^ Science FAIL ^^ haha :)
I wouldn't trust some at the CDC to follow instructions on how to make a piece of toast (after also giving them sliced bread, a working toaster and a power source).
Actually reading it again, that sentence was slightly misleading. They didn't specifically look for people who didn't consider they had CFS, either. They just asked people about symptoms and then diagnosed them, after an exam & interview, if they met criteria.
It's not clear how many of them (if any) thought of themselves as having CFS. They don't seem to have asked them. Or such is my reading of Pages 16 to 18 of the paper. Have edited it to make that clearer.
Hi Neurosceptic
It's still a really vague way of going about things and quite retarded given the amount of previously diagnosed patients out there.
Anyway, if they had used the same patient selection criteria as the Lombardi paper then this could have been seen as a genuine attempt at replication - assuming of course they also used the original methods in the lab!
It seems to me that all the negative studies haven't followed the original papers methods, and therefore shouldn't be considered as replication studies. They are something else (a waste of time springs to mind!).
Have you seen Dr Vernon's comments about the CDC paper?
http://www.cfids.org/xmrv/070110study.asp
The CDC paper was not a replication attempt, it was only a validation study, as were the other negative papers. ( If you looked for HIV with a EBV test, you wont find that either, neither will hundreds of labs looking with the wrong method.) The prostate cancer studies had the same problem, now they are stating to find it.
The German study into transplant patients found XMRV infection in controls in comparable percentages to that of the 'Science' paper.
Samples were exchanged between the WPI & Kuppevald, and 20 were provided to the CDC.
It is not clear how many people with a diagnosis of CFS or ME or CFS/ME will have XMRV, as the definitions that can be used vary considerably. The Oxford, and revised CDC Fukuda definition (Which the CDC XMRV CFS paper used) will include just tired people. This is not speculation, studies have confirmed this. Revising the Fukuda definition increased prevalence by four fold. It would be like trying to pick Tuberculosis out of everyone with a cough, without having a test for Tuberculosis. Furthermore, the revised Fukuda definition is not widely used, whereas Fukuda is, and the revised definition excludes any physical symptom. The CDC is no longer studying those who CFS was intended to represent.
It suggests that the failed studies are not because of geographic distribution or lack of XMRV, but because of methodology. Until a study replicates the 'Science' study, the door of an association between XMRV and CFS will remain very much open. One more point, patients don't want this, they want a cure, it's that simple, but only good science and replication can answer this. Unfortunately when it comes to CFS research, the usual practice of good science and honest replication attempts, are absent.
Anyonymous 15:44 - I hadn't seen that, thanks.
Vernon says that "At the 17th Conference on Retroviruses and Opportunistic Infections in February 2010, Qui, et al., reported that the rate of XMRV in U.S. blood donors was 0.1 percent, or 1 person out of 1000."
That's interesting because it's a lot lower than the rate in the healthy controls in the Lombardi study (3.7%).
In an ORTHO article, Dr Judy Mikovits of the WPI said (this is Google translated from Dutch to English) that "The positive control person [in another study] is no surprise as the family or a caregiver concerned. Control Persons coming along with the patient to donate blood, we call touch controls. Some of these people may be infected."
Now that wasn't said in the context of the Lombardi 3.7%, but that could explain the discrepancy if the Lombardi controls were related to the patients (or to CFS researchers who might also be exposed!) - unfortunately they didn't say anything about where these healthy samples came from.
This is a link to what the Lobardi study said about controls. http://www.sciencemag.org/cgi/content/full/328/5980/825-d
"The great majority, although not all, of the patients analyzed were matched in geographic location with controls. "
They also said that the controls were people visiting a doctors office between 2006 and 2008, if I remember correctly. I cannot find that at this moment, but will post it once I do.
Here is a link to the German study. http://www.cdc.gov/eid/content/16/6/pdfs/10-0066.pdf
http://www.wpinstitute.org/xmrv/xmrv_qa.html
Who were the patients and healthy controls in the recent XMRV study published in Science?
Every patient sample used in the study (taken from the nationwide WPI repository gathered from several regional physician practices) had a physician's diagnosis of CFS. To further validate the samples, the research team used the well-established CDC and Canadian Consensus Criteria for CFS in every case. The healthy controls were healthy people who came to a doctor's office for a routine sample or from DNA used in routine diagnostics.
In order to meet legal human assurance requirements, identifiers for the control population are not available to the investigators. Nor was additional information on the patient samples used in this study. Age, sex, duration of illness, medical history and medication use have no impact on the identification of a new human retroviral pathogen.
Japan also found a prevalence rate of 1.7% in healthy blood donors. Cannot find the paper right now, but it is cited in the first negative validation study by McClure. http://www.plosone.org/article/info:doi/10.1371/journal.pone.0008519#pone.0008519-Furuta1
"This follows an earlier claim that 1.7% (5/300) of healthy Japanese blood donors carried antibodies to the same virus ."
Here is a link:
THE PREVALENCE OF XMRV IN HEALTHY BLOOD DONORS IN JAPAN
http://www.diagnosesupport.com/health/index.php?option=com_content&view=article&id=305:the-prevalence-of-xenotropic-murine-leukemia-virus-related-virus-in&catid=132:xmrv-research&Itemid=8
In truth, prevalence rates are not yet known, as testing methods have not been standardised.
As XMRV appears to be a hard retrovirus to find, it is very likely the 0.1% figure will go up. It will be interesting to see the rates found in healthy people compared to prostate cancer.
"medical" vs "psychological" disorder: a friend of mine with CFS took ill-health retirement, hoping that his case was psychological and that he would get better in retirement. No such luck.
I think at this point the vastly varying prevalence rates between studies makes the whole enterprise look a bit suspect.
There need to be methodological papers and cross-lab verification before these prevalence studies are repeated.
The CDC study actually didn't use the 1994 Fukuda criteria to select their cohort, they used the 2005 Empirical criteria, which they refer to simply as being 'revised' 1994 criteria.
But if you read the 2005 paper, only 13% of the patients identified as having CFS during the telephone surveillance period between 1997-2001 still had CFS when the study took place in 2003; it was only when the authors added a bunch of SF-36 subscales which identified 'reduced activity'(including the most controversial subscale, the Role Emotional(RE), which specifies a reduction in activity as a result of emotional disturbance that these patients were included in the study, despite previous studies showing the RE subscale had the least correlation with CFS out of any of the SF-36 subscales.
However it is an open question whether 'reduced activity' is a valid equivalent of fatigue, since both patients with depression and anxiety disorders report a reduction in activity without having CFS. Leonard Jason from DePaul has done several studies which showed that something like 30% of patients with depression(but not CFS) qualified as having CFS using the Empirical definition, indicating an extremely large gap in specificity.
After applying the SF-36 subscales, the number jumped from 13% to 40% of the surveillance cohort then qualifying as having the CDC's new definition of CFS. By the authors own admission, which they explicitly state in the paper itself, 2/3 of the patients in the study did not qualify as having CFS according to the 1994 criteria.
This is reinforced by a table in the CDC's XMRV study which showed that at least one patient scored 100 out of 100 on the Physical Functioning subscale, which is higher than found in the general public.
One possible reason that has been suggested as to why the CDC broadened the criteria like they did is because they had spent so much money already during the survellience period with the random dialing, evaluating patients, etc. and when the study took place only a few patients were still able to be diagnosed with CFS, that they had to do something to keep from losing all(or around 90%) of the cohort so that the money which had already been spent(around $2 million if I remember correctly) did not 'go up in smoke' unless they did something drastic, which they did.
As a result of their reformulation, prevalence rates jumped between 6-10x virtually overnight and patients assert that ever since that time the CDC has been throwing good money after bad with their subsequent studies.
(cont.)
All of which is interesting, of course, but the real issue is the goose egg that the negative studies have came up with, with the CDC chosing to refer to an unpublished presentation given at a conference which suggested a prevalence of .1% in place of several published and unpublished studies which have found prevalence rates of between 2-6%.
Not to mention that several studies in prostate cancer(PC) have reported a significant association between PC and XMRV, while several other studies have all come back finding 0 XMRV in patients or controls. The CDC and it's German collaborators in this XMRV/CFS study are two of the groups which did not find an association between XMRV and prostate cancer. The German study found 0 XMRV in over five hundred prostate cancer patients and CDC reported at the same conference as the prevalence study they referred to that they found 2 positives out of 160-something prostate cancer patients, however when they sequenced the positives, the positives were found to form a distinct branch of MLV from XMRV, so it has not been shown that the CDC can even find XMRV with it's tests. Studies are still coming out showing either a significant association beteen XMRV and PC or not finding any XMRV at all, four years after the initial findings were published, so discrepant studies on XMRV and CFS are absolutely not limited to being a 'CFS controversy'. It's amazing how few of the articles written on the subject(in major science journals no less) point out this absolutely crucial context. "EVERYBODY LOOK AT THE CFS CONTROVERSY! DON'T(or barely) MENTION THE EXACT SAME THING IS HAPPENING IN PROSTATE CANCER STUDIES!"
However, in my opinion, while this was a reasonable suspicion months ago, it's very unlikely now because (by my count) 6 labs have not found XMRV in CFS patients, using lots of different approaches.
Brave words. Reliable detection of XMRV is only in its infancy. There is much more water to flow under this bridge yet before the whole thing is settled.
HarryTheBarmaid: I'm entirely prepared for being wrong on that, but that's the impression I get. In general though I'm agnostic about what's going on here.
I agree with PJ that what we need, before any more of these studies, is to sort out these questions. Because if people are using insensitive assays, these studies are just adding to the confusion. And if they're not, we need to know that for sure.
As far as I see it, different labs sharing samples and using each other's assays on the same samples is the only way forward.
As far as I see it, different labs sharing samples and using each other's assays on the same samples is the only way forward.
Agree. But you might want to ask the CDC and the paper's authors about that. Questions like:
Did they have known positive control samples from external sources?
Did their tests correctly identify those known positive control samples?
Did an external independent third-party lab confirm these control samples were actually positive?
Were their results different from the CDC's test results on those same samples?
Did the CDC or the paper's authors even mention the two sets of test results on the known positive control samples to anybody, let alone properly discuss and account for them in their paper? If not, why not?
I presume that you have inside contacts. Ask around, and see what you can find. Might be interesting.
This is very mysterious, but I agree with Trooper who criticized the CDC. There must be sample criteria differences.
BTW, just a few days ago, I read the June article in Discover Magazine, "The Insanity Virus," about the work of Torrey, Yolken on schiz and Perron on MS----another retrovirus, HERV-W.
What do you think?
Torrey has chased after every infectious agent known to man to try and show an association with schizophrenia - somehow I doubt he's managed to strike lucky this time either.
Your contention that XMRV was not found in UK and Europe is false; I wish blogs such as yours would at least get that right. Several hundred patients from across the pond have been tested by WPI, using the earlier less accurate methods, and at least 50% have tested positive. Also, the original cohort of Lombardi et al DID have patients from Europe as well...patients who, being so disrespected in UK, came to the US clinicians who at least acknowledge ME/CFS is biomedical.
So far there have been NO replication attempts and several Quick and Dirty NONvalidation attempts. None of the European Failure to Find studies even claimed to be replication studies and by their methods and cohorts showed they were not trying to validate the Lombardi findings either.
I have great respect for you, Neuroskeptic, but any scientist who ignores or is not aware of the politics behind the science is not doing science any favors. Simply counting the numbers without acknowledging the lack of quality in those early attempts to disappear the Lombardi findings is regrettable.
The CDC, when it comes to CFS, has the ethics and the ethic of a previous century, similar to those who did the Tuskegee Syphilis experiment until they were dragged into the light of day. CDC has been trying to disappear CFS since 1984. See here for the 1996 Congressional hearing that found CDC misappropriated millions of dollars for CFS research: http://www.oslersweb.com/newsletter.htm (click CDC Scandal) Read the mocking "letter" from a CFS sufferer that they posted on their bulletin board for years, that shows their utter contempt for those who have this disabling illness.
I would like to hear your opinion of the tubes used to collect blood in the CDC's "study". According to virologist Dr Vernon, formerly of the CDC herself, " Further, the samples from these three study cohorts were collected using different types of tubes, each of which has a distinct way of being processed. As if this weren’t bad enough, none of the blood tubes used were of the same type used in the Lombardi study. (They used tubes containing sodium heparin that are intended for use with virus isolation). The blood tubes from the 18 Georgia registry patients are designed to collect whole blood and preserve nucleic acid; it is not clear where the plasma came from for these subjects since plasma cannot be obtained using these blood tube types. So the explanation for not finding XMRV in these samples is simple – this was a study designed to not detect XMRV using a hodge-podge sample set."
It's perfectly obvious to those of us who know the history of CDC on CFS that they didn't use blood from people who really have CFS. If they had actually wanted to find the biomedical cause, they wouldn't have restricted their fake study to 51 old, frozen samples, collected originally to "prove" that CFS is all the mind. But that they can't find ANY XMRV, just like their long-time psyche pals in UK couldn't find ANY XMRV, indicates their methods are faulty. Since they surely know about this issue, of what chemicals are in the tubes at collection time, and chose not to follow what Dr. Vernon says is standard practice for finding viruses, what do you say, Neuroskeptic? Don't the tubes tell us that CDC really wasn't going to find XMRV or any other virus, no matter what was there?
Your contention that XMRV was not found in UK and Europe is false; I wish blogs such as yours would at least get that right. Several hundred patients from across the pond have been tested by WPI, using the earlier less accurate methods, and at least 50% have tested positive. Also, the original cohort of Lombardi et al DID have patients from Europe as well...patients who, being so disrespected in UK, came to the US clinicians who at least acknowledge ME/CFS is biomedical.
So far there have been NO replication attempts and several Quick and Dirty NONvalidation attempts. None of the European Failure to Find studies even claimed to be replication studies and by their methods and cohorts showed they were not trying to validate the Lombardi findings either.
I have great respect for you, Neuroskeptic, but any scientist who ignores or is not aware of the politics behind the science is not doing science any favors. Simply counting the numbers without acknowledging the lack of quality in those early attempts to disappear the Lombardi findings is regrettable.
The CDC, when it comes to CFS, has the ethics and the ethic of a previous century, similar to those who did the Tuskegee Syphilis experiment until they were dragged into the light of day. CDC has been trying to disappear CFS since 1984. See here for the 1996 Congressional hearing that found CDC misappropriated millions of dollars for CFS research: http://www.oslersweb.com/newsletter.htm (click CDC Scandal) Read the mocking "letter" from a CFS sufferer that they posted on their bulletin board for years, that shows their utter contempt for those who have this disabling illness.
I would like to hear your opinion of the tubes used to collect blood in the CDC's "study". According to virologist Dr Vernon, formerly of the CDC herself, " Further, the samples from these three study cohorts were collected using different types of tubes, each of which has a distinct way of being processed. As if this weren’t bad enough, none of the blood tubes used were of the same type used in the Lombardi study. (They used tubes containing sodium heparin that are intended for use with virus isolation). The blood tubes from the 18 Georgia registry patients are designed to collect whole blood and preserve nucleic acid; it is not clear where the plasma came from for these subjects since plasma cannot be obtained using these blood tube types. So the explanation for not finding XMRV in these samples is simple – this was a study designed to not detect XMRV using a hodge-podge sample set."
It's perfectly obvious to those of us who know the history of CDC on CFS that they didn't use blood from people who really have CFS. If they had actually wanted to find the biomedical cause, they wouldn't have restricted their fake study to 51 old, frozen samples, collected originally to "prove" that CFS is all the mind. But that they can't find ANY XMRV, just like their long-time psyche pals in UK couldn't find ANY XMRV, indicates their methods are faulty. Since they surely know about this issue, of what chemicals are in the tubes at collection time, and chose not to follow what Dr. Vernon says is standard practice for finding viruses, what do you say, Neuroskeptic? Don't the tubes tell us that CDC really wasn't going to find XMRV or any other virus, no matter what was there?
The WPI did share positive patient samples with the CDC.
The CDC was unable to detect XMRV in the samples yet another lab was.
The CDC folks are either not trying to find XMRV on purpose or bad scientists.
i've had fatigue alot this past week plus where i been the weather has been changing alot plus i heard recent reports that i don't know if it's true but if you have fatigue might be a virues
It would seem obvious that if several studies have found low levels of XMRV in the general population and then other studies come along which cannot seem to find the virus at all in the general population or in patients, then the fault has a higher probability of being with the testing procedures that are finding nothing. Obviously this virus is out in the population some at least SOME patients should test positive for it. If they don't, it's more likely to be a problem with the test (and I'm not saying that this is for sure, but the probabilities are there.) Just a thought.
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