Comments on Lombardi, et al in Science

[rebecca1995]

"Well-Characerized"

When I was reading the comments in Science, I was struck by a term--"well-characterized"--that was used to describe the negative papers' cohorts.

From the comment by van der Meer et al:

Erlwein et al. (6) failed to detect XMRV in any of the patients investigated from a cohort of well-characterized CFS patients from the United Kingdom, thus raising doubt about the role of XMRV in CFS.

From the comment by Lloyd et al:

Similarly, three negative replication studies in well-characterized cases of CFS have now been published (10–12).

I think the reason I noticed this adjective is because it's one that Dr. Vernon applied several times to those cohorts in her February response to the Dutch study. She wrote,

XMRV was not detected in a third follow-up study from a well-characterized cohort of CFS subjects...This study used a well-characterized cohort, well-processed and preserved blood samples and a sensitive technique...The PLoS ONE paper by Erlwein, et al, the Retrovirology paper by Groom, et al, and now the van Kuppeveld, et al, paper in BMJ all studied well-characterized patient cohorts that met accepted and widely used CFS case definition criteria.

What I don't understand is why these authors believe patients diagnosed by the Oxford Criteria or Fukuda alone are better-characterized than those diagnosed by the Canadian Consensus Criteria, as those in the original Science paper were. (Yes, the Science cohort also met Fukuda because the CCC are a subset of Fukuda with PEM, but that's beside the point.)

Leonard Jason has argued that the CCC select patients who are more functionally impaired, probably in part because they require patients to have PEM, which he has found is both sensitive and specific for ME/CFS. In fact, he advised the CAA to require its BioBank donors to have PEM, which is optional for Fukuda. (Oxford, of course, doesn't need it for diagnosis, either.)

Even if Lombardi et al had not laid out additional characteristics of the original 101--which they did, in the Oct. 9 supplement--the Science cohort is by definition a narrower, more select, better-characterized group than the European cohorts because it meets the CCC.

How anyone can argue otherwise is beyond me.

 

[rebecca1995]

From van der Meer et al's comment:

Did the patients fulfill the criteria of the Centers for Disease Control and Prevention?

Questions like these make me wonder if the authors even read the Science paper, which clearly stated which criteria the patients met (Fukuda and CCC).

I have to agree with CBS. If this is the best the critics can do, we're in pretty good shape.

 

[leelaplay]

Yes we are very clear about that!! Sorry that I cut the quote so sloppy!

oh - good leaves leaves - no worries then -

it's my own wee brain at work here. I read it. Some dendrons fired. I mused, did I say that? Then some of the meaning of the quote emerged, I shook said wee brain to clear some of the fog away, and I realized I hadn\t said it.....

 

[leelaplay]

From van der Meer et al's comment:

Did the patients fulfill the criteria of the Centers for Disease Control and Prevention?

Questions like these make me wonder if the authors even read the Science paper, which clearly stated which criteria the patients met (Fukuda and CCC).

I have to agree with CBS. If this is the best the critics can do, we're in pretty good shape.

Rebecca, I hope you and Shane are correct.

My fear is that it's like a shell game. They keep trying to misdirect. To date, it's only been the people who really care - we patients and a few specialists - who realize what nonsense the psych posse is spouting. The horror is that to date, the psych posse have been so successful.

My hope these days hangs on enough new real scientists being interested in a new retrovirus (and the pharma industry having many patents expiring). Hopefully the numbers game will change and these scientists can see in a glance what nonsense the 3 comment papers are. And then their responses or actions will show the babble to be just that.

 

[Cort]

XMRV's fate does not hang on these questions and answers; most of the questions were presumably admitted some time ago - at least a month and a half ago - and the WPI has answered most of them. Science, however, wanted the answers in print. Its not usual to see something like this and Science would not publish questions it did not consider relevant. And several of the questions were relevant at least at one time. I see them as an opportunity for the WPI to buttress its case.

Regardless of whoever made them or what their background is - there were relevant questions about the study. For instance this

In their detailed presentation of the immunological abnormalities in the patients, Mikovits also reported a cytokine profile with high interleukin-8 and macrophage inflammatory protein–1{alpha} and a low interferon-{alpha} concentration (3). The authors suggested that the selection of their group of CFS patients was partly based on reproducible immunological abnormalities and presented it as an additional argument for the viral etiology of CFS. Although this cytokine profile may be associated with a possible viral infection (while by no means being necessarily specific), it has not been reported previously as such in patients with CFS. The cytokine abnormalities in CFS patients are notoriously inconsistent (9), with some studies reporting increased (10), not different (11), or even lower (12) cytokine responses. Thus it is not possible to use "immunological abnormalities" as a selection criterion.

WPI admitted they made a mistake by stating the patients had reproducible immune abnormalities, VO2 max problems, etc in the Science paper. That statement lead to statements like this:

First, although the CFS cases studied fulfilled broadly accepted diagnostic criteria, they were selected from regions of CFS "outbreaks" and had specific immunological abnormalities, making them potentially more susceptible to viral infections than most patients with CFS. This could limit the generalizability of the study’s results.

Based on what was reported in the Science paper that's a perfectly legitimate statement. They also made a mistake by stating the patients came from areas where 'outbreaks' had occurred; - both those statements threw alot of people off. They lead some researchers to believe that all the patients came from outbreaks and we know that's not true. That lead to this comment

As a consequence, it is surprising that no independent cohort of patients with sporadic CFS was investigated by Lombardi et al., as these CFS cases represent the majority of patients. Investigation of such an independent cohort is necessary before a claim regarding the presence of the XMRV retrovirus in CFS patients is justified. I

The WPI later cleared up these questions on their website but we don't know when the comments to Science were written and it may have been that Science wanted the answers down in the Journal anyway. No papers are perfect - mistakes can probably be found in most papers and these did create questions in the research community. Dr. Vernon was clearly worried about the cohort as were other researchers; it came up again and again.

Dr. Mikovits recently stated in the IACFS/ME Q&A that the only immune abnormality that correlated iwth XMRV infection was Interferon alpha. The authors are correct that that abnormality is NOT typically associated with CFS. On the other hand none of the immune abnormalities associated with CFS (RNase L, Natural killer cell problems, and some of the cytokines (although watch out for that)) were associated with XMRV infection. Now to be very objective that has really got to give you pause. If XMRV is a major factor in CFS then it's affecting the immune system in a unCFS-like way. Its obviously a complicated situation.

The cytokine abnormalities in CFS patients are notoriously inconsistent (9), with some studies reporting increased (10), not different (11), or even lower (12) cytokine responses.

Based on my reading of the Science this is absolutely true - cytokine profiles in studies are generally all over the map.

 

[Cort]

Fourth, Lombardi et al. do not explain whether identical and contemporaneous laboratory sample storage, handling, and analysis procedures were used for both cases and controls. Differences in these could be another potentially important source of confounding. Fifth, even if identical laboratory procedures for cases and controls were intended, researchers exploring an exciting new hypothesis of a viral cause for CFS in a laboratory established to explore biological causes of CFS will be understandably eager for positive results. This so-called "expectation bias" may lead to completely unconscious and nondeliberate differences in sample handling and data interpretation between cases and controls; it can be avoided only if researchers are blinded to the case-control status of the samples. However, this is not described in (1).

These were legitimate concerns as well. We now know that the WPI looked very hard for the virus in the CFS patients - sometimes looking for it several times in different samples from the same patients. Did they do the same for the health controls? Its not clear from the paper. Nor were the controls handled in the same manner as the patient samples (we know how that can change things by now don't we?)

Nor did the WPI state in the Science paper that they did a 'blinded' study - an important point. They apparently did blinded tests but it wasn't mentioned.

Regarding the concern raised by Sudlow et al. (2) about potential "expectation bias," we point out that the National Cancer Institute (NCI) and the Cleveland Clinic, whose scientists independently performed experiments and coauthored (1), were certainly not "established" as laboratories for the purpose of studying CFS. All samples were blinded, as mandated by the NCI and WPI institutional review board approvals.

They nailed that concern really well and further demonstrated how rigorous the study really was. In the end this comment/answer process works out well for WPI: it helps legitimize them.

Investigators at NCI received 100 samples from individuals without knowing their health status; furthermore, the samples were sent to NCI directly without passing through the WPI laboratory space. Laboratory workers at the NCI and the WPI who performed the polymerase chain reaction (PCR) and immunological studies used coded, blinded samples that did not reveal the CFS status of the individuals.

I think all these questions have been or are being taken care of...the WPI is currently engaged in a blinded study itself and we haven't found any evidence of a much higher percentage of positives in controls than reported in Science - so these and many of the other questions raised are moot - but that doesn't mean they weren't relevant questions at the time. Prestigious journal don't get to be prestigious by printing stellar material one week and junk the next week.

Finally, the criteria for selecting samples for further analyses (including XMRV protein expression in 30/101 cases and 16/218 controls, infectivity in 12 cases and 12 controls, and immune response in 18 cases and 7 controls) are not described and are another important source of potential bias. Was this selection made at random or without knowledge of case-control status? Were all case and control samples on which testing was performed included in data analyses?

This shows how incredibly rigorous Science is! How did they determine which samples to further test - was it randomly done or ? Tough stuff! I would be surprised if its meaningful but if you're playing at this level - everything gets scrutinized...Its just part of the game.

None of this means that it wasn't a great paper - obviously it was - it made Science, the researchers validated their findings in several ways, its sparked an enormous amount of research - it was a GREAT paper but even at that it had some holes. I don;t have a big problem with that. I imagine most comprehensive papers have them somewhere. It was a first paper as Dr. Mikovits said.

As Dr. Mikovits said

The study was not, nor was it designed to be, a case-control study as Sudlow et al. (2) imply, for it was the first demonstration of the replication and production of infectious XMRV in human blood cells.

 

[biophile]

Re: "well-characterised"

Yes, the term "well-characterised" was obviously meant to be a jab at the original Science study. The next XMRV positive study should use the phrase, "using a well-verified XMRV detection method". :Retro smile:

 

[Cort]

I was surprised the WPI said this:

We further note that no cytokine profiles were presented in (1), nor did we state that abnormal cytokine levels, altered natural killer cell activity, or particular RNase L profiles were a requirement for inclusion in the study.

I guess you can make that make sense because - they said samples were from regions where CFS outbreaks have been documented; they didn't say the patients were from outbreaks - they said the patients were from areas where outbreaks had occurred. I think the WPI would win in a court of law but it was confusing - why mention outbreaks if the patients weren't from outbreaks?

Then they stated the patients diagnosis was based on the presence of reproducible immunological abnormalities.....so if they were diagnosed with CFS you would assume that they had them would you not? They also said they were diagnosed using the CDC/Canadian Criteria neither of which includes those immunological abnormalities in the definition......that's confusing...it doesn't mean their findings are wrong, it doesn't have anything to do with the PCR, etc....its just a confusing point.

SCIENCE PAPER: Samples were selected from several regions of the United States where outbreaks of CFS had been documented (S2). These are patients that have been seen in private medical practices, and their diagnosis of CFS is based upon prolonged disabling fatigue and the presence of cognitive deficits and reproducible immunological abnormalities. These included but were not limited to perturbations of the 2-5A synthetase/RNase L antiviral pathway, low natural killer cell cytotoxicity (as measured by standard diagnostic assays), and elevated cytokines particularly interleukin-6 and interleukin-8. In addition to these immunological abnormalities, the patients characteristically demonstrated impaired exercise performance with extremely low VO2 max measured on stress testing. The patients had been seen over a prolonged period of time and multiple longitudinal observations of the clinical and laboratory abnormalities had been documented.

 

[rebecca1995]

...
Nor did the WPI state in the Science paper that they did a 'blinded' study - an important point. They apparently did blinded tests but it wasn't mentioned....

From the Mikovits/Ruscetti Science comment:

Regarding the concern raised by Sudlow et al. (2) about potential "expectation bias," we point out that the National Cancer Institute (NCI) and the Cleveland Clinic, whose scientists independently performed experiments and coauthored (1), were certainly not "established" as laboratories for the purpose of studying CFS. All samples were blinded, as mandated by the NCI and WPI institutional review board approvals. All experimental procedures were done by the same personnel, in the same physical laboratory space, under identical protocols. Investigators at NCI received 100 samples from individuals without knowing their health status; furthermore, the samples were sent to NCI directly without passing through the WPI laboratory space. Laboratory workers at the NCI and the WPI who performed the polymerase chain reaction (PCR) and immunological studies used coded, blinded samples that did not reveal the CFS status of the individuals.

So did the Science paper meet the criteria for a blinded study? The above sounds pretty good to me, but I'm not exactly sure what has to happen in a blinded study.

 

[Cort]

From the Mikovits/Ruscetti Science comment:


So did the Science paper meet the criteria for a blinded study? The above sounds pretty good to me, but I'm not exactly sure what has to happen in a blinded study.

I agree - I missed that - and later included it in my post. I think that was an area where answering the question allowed the WPI to further strengthen their case. It sounds like both groups had 'blinding procedures' in place. Its unfortunate they didn't spell them out in the paper.

 

[_Kim_]

FYI, I updated the Lombardi et al. thread in the Library to add pdf files of these comments. Lombardi 2009 - Detection of an Infectious Retrovirus, XMRV, in Blood Cells of...

 

[Rrrr]

Judy Mikovits defends original study against the European failure to replicate

FYI...

Judy Mikovits, XMRV researcher, defends the original study against the European failures to replicate.

http://www.sciencemag.org/cgi/content/full/328/5980/825-d

Science 14 May 2010:
Vol. 328. no. 5980, p. 825
DOI: 10.1126/science.1184548

Technical Comments
Response to Comments on "Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome"
Judy A. Mikovits1,* and Francis W. Ruscetti2

We reported the detection of the human gammaretrovirus XMRV in 67% of 101 patients with chronic fatigue syndrome (CFS) and in 3.7% of 218 healthy controls, but we did not claim that XMRV causes CFS. Here, we explain why the criticisms of Sudlow et al., Lloyd et al., and van der Meer et al. regarding the selection of patients and controls in our study are unwarranted.

1 Whittemore Peterson Institute, Reno, NV 89557, USA.
2 Laboratory of Experimental Immunology, National Cancer Institute–Frederick, Frederick, MD 21701, USA.

* To whom correspondence should be addressed. E-mail: judym@wpinstitute.org

Our study (1) documented the presence of a recently discovered human retrovirus, XMRV, in a high proportion of patients with chronic fatigue syndrome (CFS) in comparison with healthy controls. Sudlow et al. (2), Lloyd et al. (3), and van der Meer et al. (4) raise concerns about the cases and controls described in our study and thus the validity of our results. First, we wish to emphasize that our study was not intended to be a detailed clinical description of CFS or an epidemiological study that would relate particular symptoms, demographics, duration, pattern of onset, and the like to the presence or viral load of XMRV. The study was not, nor was it designed to be, a case-control study as Sudlow et al. (2) imply, for it was the first demonstration of the replication and production of infectious XMRV in human blood cells. The fact that a number of the patients tested were from regions of CFS outbreaks does not invalidate the clinical diagnosis. We hope that our report will stimulate the performance of many case-control studies that use appropriate virus detection. We certainly recognize that such studies will be required to determine what role XMRV plays in the pathogenesis of CFS.

Samples included in our study (1) were from CFS patients who fulfilled both the Fukuda criteria and the Canadian Consensus Criteria (CCC), regardless of severity. We regret that a sentence in the original supporting online material in (1) implied that immunological abnormalities were part of the CFS diagnosis; indeed, while many such patients do exhibit such abnormalities (5, 6), they were not required for diagnosis. All patients that met Centers for Disease Control and Prevention and CCC criteria were accepted; none were excluded. Patient samples were obtained from 2006 to 2009 and stored in the Whittemore Peterson Institute (WPI) repository. We did not state in Lisbon (7) or elsewhere that the samples analyzed in (1) were only from patients from documented outbreaks of CFS, nor did we state that the 101 patients described in (1) exhibited all the immunological abnormalities described in our Lisbon conference presentation. In fact, only 25 samples in (1) came from patients identified during the 1984 to 1988 CFS outbreak in Incline Village, Nevada. The remaining 76 samples included patients with sporadic cases from 12 U.S. states and Canada, including California, New York, North Carolina, Wisconsin, Michigan, Oregon, New Mexico, New Jersey, North Dakota, Texas, and Florida. Patients in the study were 67% female, reflecting the reported gender incidence of CFS, with an age distribution of 19 to 75 years of age (mean of 55). The healthy control population, which was similar in age and gender to the patients, was composed of healthy people who visited doctors’ offices in the western United States between 2006 and 2008. The great majority, although not all, of the patients analyzed were matched in geographic location with controls. As this was not an epidemiological case-control study, we did not attempt to discern where the patients believed they contracted CFS; at the time of sample collection, some were undoubtedly living in an area different from the location where they first became ill.

The information we provide here and in the accompanying Supporting Online Material (8) should lay to rest any concerns about "bias" or "confounding." Again, the primary aim of the work described in (1) was not to characterize this clinical condition or to prove a cause for CFS but to demonstrate the existence of an infectious gammaretrovirus in patients who had been diagnosed with CFS. We achieved our goal using four different experimental strategies. The original description of HTLV-1 and HIV-1 involved only one or two patients (9–12), whereas we detected XMRV in 75 individuals.

We did not state that our study (1) proves the cause of CFS. A large number of infectious and noninfectious agents have been implicated in CFS, and it is that fact that makes the puzzle of CFS all the more difficult to solve. At no time have we wished to raise false hopes among a group of patients who, in general, have not been treated well by the medical research community. We are aware that many different pathogens have previously been reported to be associated with CFS but have not been proven to be causal.

We further note that no cytokine profiles were presented in (1), nor did we state that abnormal cytokine levels, altered natural killer cell activity, or particular RNase L profiles were a requirement for inclusion in the study. Unpublished comments made during a medical conference (7) exploring hypothetical connections with immune system defects, viral reactivation, and malignancies should not be used to judge the merits of the science in the published paper. Regarding the concern raised by Sudlow et al. (2) about potential "expectation bias," we point out that the National Cancer Institute (NCI) and the Cleveland Clinic, whose scientists independently performed experiments and coauthored (1), were certainly not "established" as laboratories for the purpose of studying CFS. All samples were blinded, as mandated by the NCI and WPI institutional review board approvals. All experimental procedures were done by the same personnel, in the same physical laboratory space, under identical protocols. Investigators at NCI received 100 samples from individuals without knowing their health status; furthermore, the samples were sent to NCI directly without passing through the WPI laboratory space. Laboratory workers at the NCI and the WPI who performed the polymerase chain reaction (PCR) and immunological studies used coded, blinded samples that did not reveal the CFS status of the individuals. The WPI has examined all 218 control and 101 patient samples by both PCR and serological methods for the presence of XMRV nucleic acid and antibodies. In addition, NCI used plasma from all 100 samples they received in infection experiments with LNCaP cells. It was not feasible to examine all 101 patient and 218 control samples with all four XMRV detection methods described in (1), due to time and resource constraints.

Of the technologies used to identify and isolate XMRV in patients with CFS, PCR from DNA or cDNA from unstimulated peripheral blood mononuclear cells is the least sensitive method. We contend that the three recently published negative PCR studies (13–15) do not qualify as being studies that fail to replicate our study, as neither the same PCR methodologies were used nor did these studies draw on the additional cell culture and immunological methods that we employed to observe XMRV nucleic acids and proteins. Although we offer to send samples in which we have detected XMRV, the groups that published these results neither requested nor analyzed any samples we had found positive for XMRV in our laboratories.

Sudlow et al. erroneously state that we did not consider alternative explanations for the findings, namely that patients with poor general health may be more susceptible to viral and other infections. On the contrary, we raised as a question for future study: "Is XMRV infection a causal factor in the pathogenesis of CFS or a passenger virus in the immunosuppressed CFS patient population?" (1). We recognize that the presence of XMRV could be due to enhanced susceptibility to retroviral infection after development of CFS. A causal role of XMRV in CFS is an intriguing possibility, given the known immunosuppressive, neurotropic, and serious consequences of infection with other known retroviruses.

Supporting Online Material

www.sciencemag.org/cgi/content/full/328/5980/825-d/DC1

SOM Text

References

References and Notes

* 1. V. C. Lombardi et al., Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science 326, 585 (2009). [Abstract/Free Full Text]
* 2. C. Sudlow, M. Macleod, R. Al-Shahi Salman, J. Stone, Science 328, 825 (2010); www.sciencemag.org/cgi/content/full/328/5980/825-a.[Abstract/Free Full Text]
* 3. A. Lloyd, P. White, S. Wessely, M. Sharpe, D. Buchwald, Science 328, 825 (2010); www.sciencemag.org/cgi/content/full/328/5980/825-b.[Abstract/Free Full Text]
* 4. J. W. M. van der Meer, M. G. Netea, J. M. D. Galama, F. J. M. van Kuppeveld, . Science 328, 825 (2010); www.sciencemag.org/cgi/content/full/328/5980/825-c.[Abstract/Free Full Text]
* 5. N. G. Klimas, F. R. Salvato, R. Morgan, M. A. Fletcher, Immunologic abnormalities in chronic fatigue syndrome. J. Clin. Microbiol. 28, 1403 (1990).[Abstract/Free Full Text]
* 6. K. J. Maher, N. G. Klimas, M. A. Fletcher, Chronic fatigue syndrome is associated with diminished intracellular perforin. Clin. Exp. Immunol. 142, 505 (2005). [Web of Science] [Medline]
* 7. J. A. Mikovits, presentation at Conference on Cellular and Cytokine Interactions in Health and Disease, Lisbon, Portugal, 17 to 21 October 2009).
* 8. Additional patient information is provided as Supporting Online Material.
* 9. F. Barr-Sinoussi et al., Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 220, 868 (1983). [Abstract/Free Full Text]
* 10. R. C. Gallo et al., Isolation of human T-cell leukemia virus in acquired immune deficiency syndrome (AIDS). Science 220, 865 (1983). [Abstract/Free Full Text]
* 11. B. J. Poiesz et al., Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc. Natl. Acad. Sci. U.S.A. 77, 7415 (1980). [Abstract/Free Full Text]
* 12. B. J. Poiesz, F. W. Ruscetti, M. S. Reitz, V. S. Kalyanaraman, R. C. Gallo, Isolation of a new type C retrovirus (HTLV) in primary uncultured cells of a patient with Szary T-cell leukaemia. Nature 294, 268 (1981). [CrossRef] [Medline]
* 13. O. Erlwein et al., Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome. PLoS ONE 5, e8519 (2010). [CrossRef] [Medline]
* 14. H. C. Groom et al., Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome. Retrovirology 7, 10 (2010). [CrossRef] [Medline]
* 15. F. J. M. van Kuppeveld et al., Prevalence of xenotropic murine leukaemia virus-related virus in patients with chronic fatigue syndrome in the Netherlands: retrospective analysis of samples from an established cohort. BMJ 340, c1018 (2010). [Abstract/Free Full Text]
* 16. Patent applications were submitted for XMRV detection methods in CFS by the WPI, a not-for-profit 501c3. J.A.M. has signed over any personal rights she may have on royalties from these patents to the WPI.

Received for publication 10 November 2009. Accepted for publication 19 April 2010.

 

[Andrew]

Thanks for posting this. This is a very important clarification.

 

[natasa778]

Don't forget that one can send in e-letters in reply to each letter published (one can't with lots of journals but one can hear). The psychiatrists, etc. I imagine won't like to be criticised in academic circles which should be possible.

Ideally, make it look like a journal letter so if one can put [1] after the first reference, [2] after the second reference, it'd be ood. One and certainly two references makes a little letter look very scientific. There are "easy" ones to use e.g. the letter you are replying to will give you one; if you quote the Lombardi study, it'd be a second. Or if you quote the Fukuda criteria or any other criteria, they can be references and you're probably free then to stop having to give references. These are e-letters so don't have to be tight like letters for publication. Websites can also be given as references esp. if you're struggling to get a reference or two.

Great idea, anyone up to it? Gerwyn? Parvofighter?? Wouldn't it be great if Science published your details on the "well defined cohort" of the Dutch group?

 

[Gerwyn]

Great idea, anyone up to it? Gerwyn? Parvofighter?? Wouldn't it be great if Science published your details on the "well defined cohort" of the Dutch group?

If someone lets me know how to do it in idiot proof language that my legendary computer skills can cope with i will try when I have led the oppositions drivel in more detail.

 

[Gerwyn]

Great idea, anyone up to it? Gerwyn? Parvofighter?? Wouldn't it be great if Science published your details on the "well defined cohort" of the Dutch group?

If someone lets me know how to do it in idiot proof language that my legendary computer skills can cope with i will try when I have led the oppositions drivel in more detail.

 

[Mithriel]

The negative comments give the impression that cytokine abnormalities etc are not usual in CFS so a cohort which has them is not typical, but these are not tested for in the UK. Everyone with a CFS diagnosis could have them.

It is the usual practise in science journals to show differing views. The New Scientist will talk about a new finding or theory and then the last paragraph will be a quote form Professor so and so saying that the claim is rubbish because.... (Of course even thye did not follow this practise with Wessley (He Whose Word Must Not Be Questionedt) When the BMJ did its editorial I was shocked that they did not include a rebuttal by the WPI. I felt it was very unprofessional.

"Science" has shown its calibre by giving space to the critics and then answering them.

The continual harping on about "well characterised" groups is the usual weasel words. They keep repeating something so it is taken as true, yet their patients were less well characterised than the WPI ones.

The honours are all with the WPI.

Mithriel

 

[citybug]

If these all the critical comments from Science, then there were no questions from the CDC or uninvolved virologists from other universities. (Unless they left out duplicate questions). And no questions of the nitty gritty technical procedures. The only questions were from the European psych lobby.
And the CDC and FDA are working on testing. No one sees any big holes.

 

[Mithriel]

I think it was done because these three groups have been spreading their disinformation widely.

Pinning them down in print and showing they were wrong has been a good move.

Mithriel

 

[Gerwyn]

The negative comments give the impression that cytokine abnormalities etc are not usual in CFS so a cohort which has them is not typical, but these are not tested for in the UK. Everyone with a CFS diagnosis could have them.

It is the usual practise in science journals to show differing views. The New Scientist will talk about a new finding or theory and then the last paragraph will be a quote form Professor so and so saying that the claim is rubbish because.... (Of course even thye did not follow this practise with Wessley (He Whose Word Must Not Be Questionedt) When the BMJ did its editorial I was shocked that they did not include a rebuttal by the WPI. I felt it was very unprofessional.

"Science" has shown its calibre by giving space to the critics and then answering them.

The continual harping on about "well characterised" groups is the usual weasel words. They keep repeating something so it is taken as true, yet their patients were less well characterised than the WPI ones.

The honours are all with the WPI.

Mithriel

can someone have a look at this please before i add references etc


Aside from these crucial methodological issues, other plausible alternative explanations for the findings are not explicitly discussed. Foremost among these is reverse causality: Patients with poor general health because of CFS may be more susceptible to viral and other infections.Well-conducted case-control studies provide important insights into disease pathogenesis. Lombardi et al. (1) demonstrated an apparent association between chronic fatigue syndrome (CFS) and the presence, infectivity of, and immune response to the human gammaretrovirus, xenotropic murine leukemia virus–related virus (XMRV).

I am surprised that Sudlow begins with such loose terminology.Lobardi et al reported a statistically significant correlation beween patients who fulfilled the Canadian Consensus criteria for diagnosing a person as suffering from ME,cfs defined as a neurological disorder by the world health authority and the presence of XMRV.

First, although the CFS cases studied fulfilled broadly accepted diagnostic criteria,

Again I am surprised by this comment. The CCC diagnostic criteria are the only clinical diagnostic guidelines in the world.All others are research guidelines.The FUKUDA guidelines are internationally agreed and recognised.The research guidelines(The Oxford criteria) used to diagnose people in the European studies are not. The Oxford criteria has fatigue as the only mandatory diagnostic criteria(sharpe et al 1991).This a strange way of diagnosing a neurological disorder.The CCC guidelines on the other hand have neuroimmunoendocrine symptoms as mandatory.

Sudlow also seems to be unaware of the fact that CFS is not an objective diagnosis.

It is a socially constructed label driven by the diagnostic criteria applied by the diagnoser.Different doctors apply different diagnostic criteria and thus produce objectively different patient cohorts which are unfortunately given the same label.
I am astonished that someone who purports to be an epidemiologist does not seem to realise this.

Second, to avoid selection bias, the CFS-free controls should have been drawn from the same background population as the cases and selected independent of the exposure (in this case, a viral infection) under study (2, 3). Put simply, the controls should ideally have been people who would have been cases in the study if they had CFS.

Sudlow is assuming that XMRV is not causative.Put simply if XMRV is causative then Sudlows design would leave us with no way of telling XMRV levels in patients with CFS compared to controls.They would all have equal levels of the virus .Selection bias is all to obvious in the Imperial college study because all the patients were supplied by one psychiatrist using diagnostic critera constructed by himself and his colleagues which are not internationally recognised.Sudlow is completely silent on this subject.

However, the control subjects are not described in (1) beyond a mention that they were healthy donors. Third, the lack of clinical data for cases and controls makes it impossible to assess the potential for confounding by numerous other characteristics that may independently influence XMRV status, including age, sex, social deprivation status, medical history (e.g., of prostate cancer), and area of residence.

None of these parameters are described in the European studies.She seems to be accepting,albeit tacitly, that there is a link between XMRV and prostate cancer while questioning the link between XMRV and ME/cfs which is in statistical terms about a hundred times stronger.There is no clinical data supplied in the European studies for any of the patients control groups or otherwise.

Fourth, Lombardi et al. do not explain whether identical and contemporaneous laboratory sample storage, handling, and analysis procedures were used for both cases and controls. Differences in these could be another potentially important source of confounding. Fifth, even if identical laboratory procedures for cases and controls were intended, researchers exploring an exciting new hypothesis of a viral cause for CFS in a laboratory established to explore biological causes of CFS will be understandably eager for positive results. This so-called "expectation bias" may lead to completely unconscious and nondeliberate differences in sample handling and data interpretation between cases and controls; it can be avoided only if researchers are blinded to the case-control status of the samples. However, this is not described in (1).

Expectation bias arises as a result of the self biasing nature of mental representations.This leads us to interpret things according to the nature of our beliefs world views and expectations.In neurocognitive terms it is called top down processing. This is one of the main reasons why the scientific method is constructed in such a way that to test a hypothesis is to actively try to disprove it. Lombardi et al far from displaying expectation bias challenged their hypothesis by attempting to find XMRV using 4 different methods.Had any one of their approaches failed then their hypothesis would have been invalidated.That is robust science.Contrast that to the approach used in the imperial; college study when the author of the study on the basis of one study claimed that”there is no XMRV in the UK.That in objective terms corresponds to the scientific definition of expectation bias.By not extending the scope of her analysis to the other studies in this area Sudlow appears to be displaying cognitive biases of her own.

Aside from these crucial methodological issues, other plausible alternative explanations for the findings are not explicitly discussed. Foremost among these is reverse causality: Patients with poor general health because of CFS may be more susceptible to viral and other infections.

The conclusion in the study by Lombardi et al was that there was a statistically significant correlation between the presence of XMRV and peopled diagnosed with ME,cfs according to the CCC criteria. There were a myriad of counfounding vatiables in the design of the European studies which made the results impossible to interpret and the conclusions reached unfalsifyable. Surely an epidemiologist would note that point.

Finally it is extremely common that people in very poor health because of a retroviral infection fall prey to secondary pathogens.This is what happens in patients suffering from Aids.So it is far more likely that a retroviral infection accounts for the poor health seen in patients with ME,cfs.I feel that a scientist should offer that as an alternative explanation especially as she is so keen on plausible alternative explanations been put forward