XMRV Study No. 4

[Frank]

So i'm going to make a prediction.
The next attack from the psych lobby will come from Belgium and the study will be leaded by Prof Van Houdenhove. Let's say they release it in a month or so.

 

[Gerwyn]

The organic illness exclusion to my understanding is that based on problems that show up in standard blood tests -which ME/CFS patients typically pass.

From an NIH website



I don't see any evidence that post-exertional fatigue is excluded. It appears from this that only diseases that can cause similar symptoms (such as untreated thyroid disease, adrenal disease). I'm trying to find the exact definition.

If you read the studies it almost always says that patients with signs of organic disease were excluded which of course is not the same thing You are led to believe that its done by blood tests but that is not the case.It is done subjectively.Post exertional malaise is not a criterea depression is not excluded so how would you tell patients with Me and patients with depression apart.Our own government guiedlines state that post exhertional malaise is the key characteristic that seperates chronic fatigue syndrome from patients with primary depression and before diagnosis is given ALL other causes of fatigue should be excluded >SO the Oxford is against all known official guidelines

 

[Sasha]

Gerwyn's points are very persuasive and I am persuaded when I read them; It would make me feel better, though, if either the ME group with Shephard or Dr. Vernon or some other professional would publicly point them out. I don't understand why, if these tests are so bad, no one has done that.

Cort, I'm also sometimes baffled by why some apparently strong arguments aren't made by the big ME/CFS charities in this context. I wonder whether it's a resource issue (not being geared up to react quickly and with confidence on highly specialised stuff outside their own immediate areas of expertise) or if they're playing a political game for our benefit that we don't understand because we don't know things that they might be party to (e.g. they might be in on upcoming XMRV results and have nothing to lose by a waiting game).

By the way, it's "Dr Shepherd" - the poor man seems to get his name spelled pretty randomly!

 

[Gerwyn]

Here it is from the original paper. . Maybe its applied differently and sure it will throw in more depressed patients but I don't see how it can exclude large numbers of 'ME/CFS' patients. (Altho this is a very strange sentence (b) A syndrome of definite onset that is not life long - but it means nothing regarding diagnosis.

Oxford Definition Chronic fatigue syndrome (CFS)

(a) A syndrome characterized by fatigue as the
principal symptom.
(b) A syndrome of definite onset that is not life long.
(c) The fatigue is severe, disabling, and affects
physical and mental functioning.
(d) The symptom of fatigue should have been present
for a minimum of 6 months during which it was
present for more than 50% of the time.
(e) Other symptoms may be present, particularly
myalgia, mood and sleep disturbance.
(f) Certain patients should be excluded from the
definition.

They include:

(i) Patients with established medical conditions
known to produce chronic fatigue (eg severe
anaemia). Such patients should be excluded
whether the medical condition is diagnosed at
presentation or only subsequently. All patients
should have a history and physical examination
performed by a competent physician.

(ii) Patients with a current diagnosis of schizophrenia,
manic depressive illness, substanceabuse, eating disorder or proven organic brain
disease. Other psychiatric disorders (including
depressive illness, anxiety disorders, and hyperventilation
syndrome) are not necessarily reasons
for exclusion.

It also includes the PIFS subset

Post-infectious fatigue syndrome (PIFS)
This is a subtype of CFS which either follows an
infection or is associated with a current infection
(although whether such associated infection is of
aetiological significance is a topic for research).
To meet research criteria for PIFS patients must

(i) fulfil criteria for CFS as defined above, and
(ii) should also fulfil the following additional
criteria:
(a) There is definite evidence of infection at onset or
presentation (a patient's self-report is unlikely to be
sufficiently reliable).
(b) The syndrome is present for a minimum of 6
months after onset of infection.
(c) The infection has been corroborated by laboratory
evidence.

Here's what they say about fatigue:

Fatigue
(i) When used to describe a symptom this is a
subjective sensation and has a number of synonyms
including, tiredness and weariness. A clear description
of the relationship of fatigue to activity is
preferred to the term fatiguability.

Two aspects of
fatigue are commonly reported: mental and physical.
Mental fatigue is a subjective sensation characterized
by lack of motivation and of alertness. Physical
fatigue is felt as lack of energy or strength and is often
felt in the muscles.

(ii) Fatigue as a symptom should be distinguished
from low mood and from lack of interest. The symptom
of fatigue should not be confused with impairment
of performance as measured by physiological or
psychological testing. The physiological definition of
fatigue is of a failure to sustain muscle force or power
output.

(iii) To be regarded as a symptom, fatigue must:

(a) be complained of;
(b) significantly affect the person's functioning;
(c) should be disproportionate to exertion;
(d) should represent a clear change from a previous
state; and
(e) be persistent, or if intermittent should be present
more than 50% of the time.

(iv) The symptom should be described as follows:
(a) severity: mild, moderate, or severe;
(b) frequency: continuous or intermittent. If intermittent
the proportion of the time present;
(c) relation to activity: it should be stated whether
the fatigue is greatly increased by minor exertion
and whether it occurs at rest.

Hi Cort no one with an established medical disorder would be sent to a psychiatrist.A person with no presenting diagnosis can subsequently be "diagnosed" with one without recourse to blood tests

.So anyone presenting with unexplained medical symptoms ,which is why they are there in the first place, can be excluded .They can either be"Diagnosed at presentation or subsequently" That is the get out of Jail card "physical examination" is another.

This is how anyone who is given a "subsequent" diagnosis of organic disease can be excluded.

If you have unexplained medical symptoms other than fatigue you will be excluded by "a competent physician"

These guys regard themselves as physicians and attend meetings convened by thre royal college of physicians just to prove their point

.They use words which have a very precise meaning "hidden" in normal prose "Minor depression " is a common phrase--anything other than psychotic depression is the definition but you would not read it as such If you did not know.

These gentlemen invite you to
take what they write at face value It is more in line with"I did not have sexual intercourse with that woman" not lies but---------- IF XMRV is proven causative their losses will be incalculable

These are our national guidelines
The National Institute for Health and Clinical Excellence (NICE) in England and Wales published a multidisciplinary clinical practice guideline in 2007 in which the following criteria are employed:[8]

* fatigue that is new, persistent and/or recurrent, not explained by other conditions and has resulted in a substantial reduction in activity level characterised by post-exertional malaise and/or fatigue (typically delayed, for example by at least 24 hours, with slow recovery over several days) and
* one or more of the following list of symptoms: difficulty with sleeping, muscle and/or joint pain at multiple sites without evidence of inflammation, headaches, painful lymph nodes that are not pathologically enlarged, sore throat, cognitive dysfunction, worsening of symptoms by physical or mental exertion, general malaise, dizziness and/or nausea and palpitations with no identifiable heart problem.

The diagnosis should be reconsidered if none of the following symptoms remain: post-exertional fatigue or malaise, cognitive difficulties, sleep disturbance, chronic pain.[8]

The guideline requires fatigue to have been present for 4 months in an adult or 3 months in a child. It expects a diagnosis in a child to be made by a pediatrician. The guideline states that a referral to a ME/CFS specialist should be offered immediately to the severely ill.[8]

compare the Oxford

The Oxford criteria were published in 1991[5] and include both CFS of unknown etiology and a subtype of CFS called post-infectious fatigue syndrome (PIFS), which "either follows an infection or is associated with a current infection." Important differences are that the presence of mental fatigue is necessary to fulfill the critera and symptoms are accepted that may suggest a PSYCHIATRIC disorder.[1]

 

[Cort]

Hi Cort no one with an established medical disorder would be sent to a psychiatrist.

That's a good point - and for sure they are getting more mood disorder patients in there. And the definition isn't nearly as tight as the definition you mentioned or the Canadian consensus criteria but then again lots of CFS patients don't have any other organic disorders - that's why they end up seeing so many doctors - and the definition states organic disorders known to cause severe fatigue such as anemia. They didn't spell out all these disorders - so in the wrong hands that could be a big problem - it should just refer to things like anemia, thyroid, adrenal etc. disorders but I'm sure some physicians could expand that category greatly. Nevertheless I think, if done properly, a lot of CFS patients would fit in there -- they would just be watered down. That argument is just not resonating with me - I think zero results must still reflect primarily methodological problems on someone's part.

Sasha- I can't imagine that Shepherd doesn't have his retroviral contacts. I know over here the CFIDS Association has its scientific advisory Board - I would think that any organization that sponsors research would have a similar setup, and as I mentioned, they must be talking to people in the field.

I'm really surprised that MERUK has basically been silent since the initial finding. I believe they've been pretty outspoken about the direction of research in the UK. if they felt there are major problems with these studies I can't imagine why they're not saying that. They have excellent researchers there; I don't think they have retrovirologists on board but even so I feel that as an important patients supported research group they have an obligation to comment more fully on the studies. They must the doing the same thing we're doing just at a more advanced level; going over the studies picking them apart, talking to people.... I don't get it. If

My fear is that they don't want to be perceived as stepping on XMRV and so they're standing back and letting other organizations Such As Shepherds organization and the CFIDS Association to take the brunt. Maybe they just feel that outside of their core competency.

 

[Cort]

One would think the quickie studies would be the most impaired - if for anything was going to go wrong in XMRV studies it would go wrong in the early studies. Dr. Mikovits did note that she expects Some National Cancer Institute studies to be out shortly. She sounded positive about them...its really time for a win isn't it?

I would think that a positive NCI study from a top researcher in a top lab would trump any three UK or Dutch studies. I would think it would realign how the field views XMRV overnight.

 

[Sasha]

I would think that a positive NCI study from a top researcher in a top lab would trump any three UK or Dutch studies. I would think it would realign how the field views XMRV overnight.

I agree - I think any positive study would trump a load of negative ones at this point! A +ve one would show that the virus can be found by other researchers outside the original group and could only be positive through having nailed the methodological issues, which would throw light on the failures. Also, presumably a +ve study would once again detect a certain level of XMRV in the healthy controls, underlining the failure to detect any XMRV at all in the studies so far.

Roll on, any +ve study! Fast!

 

[oerganix]

Wake me up when someone finally does a decent replication study. This one looks like another waste of resources.

Also, this statement--attributed to van Kuppeveld et al in the editorial--is patently false:



Dr. Mikovits said in the ProHealth talk that the cohort of 101 in the Science article came from at least a dozen US states and several foreign countries.

I second that YAWN. That the UK ME denialists thought it important to come out fast with an editorial on a Dutch study tells me that this is more about the politics and manipulation of public opinion than it is about the science. The editorial is full of falsehoods, misrepresentations and smoke. Like a chant, McClure, who does not reveal that she was a part of negative study #1, repeats 'three studies, three studies' over and over again. This is a masterful piece of disinformation. Here is my take on her editorial:



Published 25 February 2010, doi:10.1136/bmj.c1099
Cite this as: BMJ 2010;340:c1099

Editorials
Chronic fatigue syndrome and human retrovirus XMRV

Three studies now refute the original study reporting the link.
(Unsupported conclusion, but useful technique in oratory, if not in scientific research.)

In the linked case-control study (doi:10.1136/bmj.c1018), van Kuppeveld and colleagues describe their failure to find evidence of a new human retrovirus in Dutch patients with chronic fatigue syndrome.1 The study is the latest contribution to a controversy that has surrounded two conflicting publications (where she doesnt reveal that she is a major author of one of them) on the retroviral aetiology of this syndrome.2 3

The saga (injects inappropriate emotional drama) started, not with chronic fatigue syndrome or a virus, but with an enzyme (RNaseL) that plays a pivotal role in antiviral defences when activated by the interferon released in response to infection. Variants of the gene encoding this enzyme have been linked to an increased susceptibility to prostate cancer, and this led to the identification of a new virus in prostate tissue that was related to, but different from, known xenotropic murine leukaemia viruses4; hence the designation xenotropic murine leukaemia virus-related virus (XMRV). Sequence analyses showed that it is not an endogenous human virus, and the fact that eight clones derived from eight different patients are slightly different from one another confirms it as a new virus that has found its way into a human population.

Abnormalities in the RNaseL gene of patients with chronic fatigue syndrome had been reported in some studies,5 but not in others.6 Nevertheless, this prompted the search for evidence of XMRV in patients with chronic fatigue syndrome. The resulting study claimed (claimed for WPI, but shows ,indicates etc. in denialist papers)
that 67% of patients with chronic fatigue syndrome were XMRV carriers, compared with 3.7% of healthy controls.2

(Begin SPIN: actually this news was received excitedly (ie John Coffin), not philosophically by those scientists who are looking for the truth; and with panic and anxiety by those who are determined to divert attention away from the organic causes of ME)
The news was received philosophically by most retrovirologists, who are used to claims of associations between retroviruses and diseases that fail to withstand the test of time. Most researchers into chronic fatigue syndrome were also sceptical, (as opposed to open minded?) mindful of the problems of defining the syndrome, (to which problems the ME denialists contribute as often as possible) its imprecise boundaries, and almost certain heterogeneity. It was not that they doubted a viral cause in some patients because this had already been shown,7 8 but the possibility that any single agent or risk factor could account for more than two thirds of cases seemed implausible (Only to those who have not been taking patients seriously. Clinicians who have the power to actually observe the facts already thought there was a virus or retrovirus implicated and that it would be a matter of time before it was found.) on the basis of what has already been established.9 (Now we get to the heart of this whole editorial. Wessely/McClure hope to regain control of what has already been established by quickly negating anything that doesnt support their career objectives of proving ME patients to be mentally ill.)

But if the research community was underwhelmed, (More subtle disdain for those researchers and patients who havent gotten onboard the ME denialist train. In fact, much of the research community was very excited.) people with the syndrome were not. If true, these findings would have transformed the understanding of the illness and opened up new avenues of treatment. (Yes, and that is exactly what Wessely/McClure and van der Meer, their Dutch counterpart in promoting the idea that ME is not an organic disease, are terrified of. New avenues of treatment that do not focus on talk therapy and forced exercise are the stuff of nightmares for them. To have all their phony studies claiming that these psychological therapies are all that are needed to treat ME wiped out in one stroke has thrown them into a panic of smoke screening, muddying the waters and diversion of attention away from the real search for answers.)
Some saw this as a definitive response not only to those few professionals who, they claim, continue to doubt the reality of the syndrome, but also to the larger number of professionals (Professional what? Psychiatrists in search of business? who believe that, irrespective of causation, (Oh yes, lets skip finding causation and jump right to the kinds of treatments that are offered to those with cancer, diabetes, MS, polio etc. AFTER the organic causation of those illnesses has been treated. Lets ignore the physical cause of ME and jump right to talk therapy and useless exercise programs and call them rehabilitative despite plenty of proof that these treatments do not rehabilitate and sometimes harm Me patients. rehabilitative treatments can reduce symptoms and disability. It is depressing (Wessely/McClures favorite word - are they depressed that the world may find out that their whole agenda has been a fraud?) that the first, untenable, view is too often confused with the second, a perspective that offers hope to patients and is backed by evidence. (PATIENTS have been telling them for decades that their agenda does NOT offer hope and professionals like Prof. Malcolm Hooper have shown that their claims are NOT backed by evidence, but like this editorial, ME denialists believe that if they say it often enough, and lazy journalists copy cat their speeches often enough, they can bombard the public with their propaganda to the point that they have forced a consensus that their agenda represents the truth.)

First and foremost, however, as with any discovery, the data must be unequivocal, and the finding has to be confirmed by others. In January 2010, our own group found no evidence of XMRV in a well characterised cohort of 186 patients with chronic fatigue syndrome in the United Kingdom.3 Van Kuppeveld and colleagues study adds to this negative evidence. Although the study is small, the patients are well defined and matched in age, sex, and geographical location. The polymerase chain reaction used to amplify XMRV gene sequences has been well controlled and its sensitivity is sufficient to detect low virus copy numbers. XMRV was not detected in this Dutch cohort, a result that comes in the wake of a third study published this month,10 which also failed to identify XMRV in 170 patients with chronic fatigue syndrome. (These claims have been well refuted by WPI and others, so simply repeating how great the McClure study was is just another attempt to repeat the disinformation often enough that it is taken to be true.)

There has been much talk of different protocols being used in the four studies. These technical differences are irrelevant (Repeat the lie, repeat the lie, repeat the lie - the advertising industry has found that people begin to remember and believe to be true anything that has been repeated three times.) provided amplification is controlled by inclusion of a "housekeeping gene"to show that a known human gene can be amplified under the conditions usedand the sensitivity of the assay is known, as was the case in all three European studies. (This is non-scientific blather, designed to razzle and dazzle without actually saying anything. Notice how she keeps mentioning THREE studies, THREE studies, THREE studies.)

Meanwhile, a different strategy is also being considered to reconcile these different findings: that new blood samples should be taken from patients with diagnosed chronic fatigue syndrome and sent to laboratories capable of carrying out the analysis. This is unlikely to be soon. (WHY? They only HOPE it is unlikely to be soon, and have done their part to make sure it isnt done at all. They hope to destroy interest in further research by putting out rushed and biased studies such as their own.)

Three (The magic number. So, now all you retrovirologists who were excited about studying XMRV can now go back to whatever you were doing before.) studies have now generated data that are in stark contrast to those of the original study. (Stark but failures all, nonetheless.) However, at least two explanations for this are still possible. (Lets ignore the third explanation: that unbiased studies, using the methodology used by WPI have not yet reported their finding, so no one really knows at this point whether XMRV is causative.) The first, and more unlikely, (Cover your arse because you know it isnt true. Retain deniability.) explanation is that XMRV infection is geographically confined to the United States. (This is disingenuous as she certainly knows by now that UK patients have had their blood tested in the US and about 50% have tested positive, using the less precise earlier testing methods. But she throws it out there, more smoke screen, more mud in the water, more diversion from the facts.) The second is that the virus is infecting an atypical cohort. (This is masterful diversion. Their own cohorts excluded patients known to have organic illness and included those with major depression. Their cohort composition has been shown to be seriously flawed since a conclave of psychiatrists came up with it.)This may well be so. Although the patients were not well described in the original study, (But no more poorly described than these 3 quick and dirty studies designed to eliminate interest in pursuing an organic cause discovery.) van Kuppeveld and colleagues provide the additional information reported at a conference last year (what conference was that and why not report Dr Mikovits public statements contradicting this?) that the patients in question came from an outbreak of chronic fatigue syndrome at Incline village on the northern border of Lake Tahoe in the mid-1980s. (This is probably the most masterful disinformation in this whole editorial. If any of the European studies were really interested in exploring the possibilities of different cohorts, they would know, and I think they DO know, that this statement is false. The WPI/Science paper stated that the cohort came from various clinics from around the US, that is, many states, AND it was publicly stated later that, upon unblinding the cohort, it included patients from UK, Ireland, Germany and Australia who had gone to the US for treatment. Whether or not this was a genuine cluster was never established,11 (According to who? The CDC?) but an association with viruses, such as Epstein-Barr virus and human herpesvirus 6, has already been suggested.12 (Suggested? Double standard here, where she can repeat suggestions but patients, doctors and researchers may not even suggest that Wessely/McClure/Reeves/van der Meer have an agenda biased toward proving ME/CFS has no organic cause.) It is possible that XMRV is implicated in the Lake Tahoe episode but does not play a substantial role in most cases of chronic fatigue syndrome elsewhere. (Another attempt at damage control and muddying the water.)

The results from other US laboratories investigating XMRV and chronic fatigue syndrome are eagerly awaited. If the link fails to hold up, it will be another bitter disappointment (She used the word bitter in her first study. Very scientific.) to affected patients. Nonetheless, the current debate will still bring critical attention to the causes of chronic fatigue syndrome, and XMRV may turn out to be important in the pathogenesis of other diseases. (They are finding it impossible to refute the evidence of XMRV in cancer and other research, so are attempting to divert attention away from ME/CFS while not going against the strong associations with prostate cancer.)
This whole editorial is a masterful Public Relations effort. McClure should be designated the new spokesperson for the ME-is-all-in-your-head-and-youre-crazy-if-you-think-well-let-anyone-prove-otherwise-conclave.

Cite this as: BMJ 2010;340:c1099

Myra McClure, professor of retrovirology and honorary consultant in genitourinary medicine1, Simon Wessely, professor of psychological medicine2

1 Jefferiss Research Trust Laboratories, Wright-Fleming Institute, Faculty of Medicine, Imperial College London, London W2 1PG, 2 Institute of Psychiatry, Kings College London, London SE5 8AF

m.mcclure@imperial.ac.uk
Research, doi:10.1136/bmj.c1018

 

[Sasha]

Sasha- I can't imagine that Shepherd doesn't have his retroviral contacts. I know over here the CFIDS Association has its scientific advisory Board - I would think that any organization that sponsors research would have a similar setup, and as I mentioned, they must be talking to people in the field.

I'm really surprised that MERUK has basically been silent since the initial finding. I believe they've been pretty outspoken about the direction of research in the UK. if they felt there are major problems with these studies I can't imagine why they're not saying that. They have excellent researchers there; I don't think they have retrovirologists on board but even so I feel that as an important patients supported research group they have an obligation to comment more fully on the studies. They must the doing the same thing we're doing just at a more advanced level; going over the studies picking them apart, talking to people.... I don't get it. If

My fear is that they don't want to be perceived as stepping on XMRV and so they're standing back and letting other organizations Such As Shepherds organization and the CFIDS Association to take the brunt. Maybe they just feel that outside of their core competency.

Beats me. Would you consider contacting, say, Dr Vernon and asking her about this? This might be one of those times when it's best not to keep the questions we raise on these boards to ourselves if it would result in better advocacy. I'm afraid I don't feel I understand the issues well enough to do this.

 

[ixchelkali]

Garbage In, Garbage Out

On the UK studies I was willing to give the researchers the benefit of the doubt. Or to be honest, at least on the second study, the one in Retrovirology, I was. Thats the way science works. You try different things and see what results you get. When all the results are in, you see what kind of picture emerges from all the data. Im willing to be patient while the process works.

BUT this one is just junk, not science. And then they engage in some politely worded trash-talking right in the paper, to boot: This report [the WPI Science paper] was considered a major scientific breakthrough and attracted a lot of attention. However, the paper fell short in the description of the patients: what was the nature of the cohort, what was the age and sex distribution, how well were the controls matched? Investigation of an independent cohort is therefore necessary before a causal association between XMRV infection and the development of chronic fatigue syndrome can be ascertained. The article in Science gave the web address on the Science website where the patient cohort was described. What, these people couldnt find it??? I did, and Im brain fogged!

The WPI study patients met both the 1994 CDC Fukuda Criteria (which is supposedly the international study standard) and the more exacting 2003 Canadian Consensus Criteria. This sorry excuse for a study from Nijmegen University in the Netherlands tested 32 patients & 43 controls from a 1992 study which used the OXFORD Criteria. That means that the patients were fatigued, not that they had CFS!

They say, All patients and controls examined in this study were part of a Dutch cohort of 298 patients, which has been described in detail. Yeah, they were described in detail, all right, in a 1994 article in the Journal of Psychosomatic Research which described the psychological assessment done on a group of patients with unexplained fatigue. And their were controls were friends and neighbors that the patients brought along, matched for age and sex. Puhh-leeze!

This one just ticks me off. Maybe because theyre not even pretending to do good science, but theyre being published in the BMJ. :Retro mad:

Okay, rant over. Deep cleansing breath...

 

[Gerwyn]

That's a good point - and for sure they are getting more mood disorder patients in there. And the definition isn't nearly as tight as the definition you mentioned or the Canadian consensus criteria but then again lots of CFS patients don't have any other organic disorders - that's why they end up seeing so many doctors - and the definition states organic disorders known to cause severe fatigue such as anemia. They didn't spell out all these disorders - so in the wrong hands that could be a big problem - it should just refer to things like anemia, thyroid, adrenal etc. disorders but I'm sure some physicians could expand that category greatly. Nevertheless I think, if done properly, a lot of CFS patients would fit in there -- they would just be watered down. That argument is just not resonating with me - I think zero results must still reflect primarily methodological problems on someone's part.

Sasha- I can't imagine that Shepherd doesn't have his retroviral contacts. I know over here the CFIDS Association has its scientific advisory Board - I would think that any organization that sponsors research would have a similar setup, and as I mentioned, they must be talking to people in the field.

I'm really surprised that MERUK has basically been silent since the initial finding. I believe they've been pretty outspoken about the direction of research in the UK. if they felt there are major problems with these studies I can't imagine why they're not saying that. They have excellent researchers there; I don't think they have retrovirologists on board but even so I feel that as an important patients supported research group they have an obligation to comment more fully on the studies. They must the doing the same thing we're doing just at a more advanced level; going over the studies picking them apart, talking to people.... I don't get it. If

My fear is that they don't want to be perceived as stepping on XMRV and so they're standing back and letting other organizations Such As Shepherds organization and the CFIDS Association to take the brunt. Maybe they just feel that outside of their core competency.

If you are to exclude patients with an organic disorder without recourse to blood tests how are you going to do it.Imagine that you are a doctor

 

[Lesley]

Me association summary and comment

Just received this. Bolding is mine.

A third European XMRV study, which has attempted to find the human retrovirus XMRV in people with ME/CFS, has failed to do so.

Results from the case-control study by Kuppeveld et al is reported today in the British Medical Journal: http://www.bmj.com/cgi/content/full/340/feb25_1/c1018 along with an accompanying editorial from Professors Myra McClure and Simon Wessely: http://www.bmj.com/cgi/content/extract/340/feb25_1/c1099


BRIEF SUMMARY OF THE LATEST XMRV RESEARCH

This latest XMRV study was carried out by a research group based in the Netherlands.

The virologists examined peripheral blood mononuclear cells in blood samples that were taken from a cohort of Dutch ME/CFS patients whose diagnosis met with (the very broad) Oxford research criteria for CFS. They also tested blood samples from some neighbourhood controls. Blood samples were taken between December 1991 and April 1992 and were cryopreserved.

The virologists used a polymerase chain reaction (PCR) assay to target the XMRV integrase gene and/or a nested PCR assay targeting the XMRV gag gene. PCR is a way of detecting viral genetic material in the blood samples. PCR testing was carried out on 32 patient samples and 43 control samples - which are low numbers for this type of scientific study. The authors state that their PCR technique is sensitive enough to detect low virus copy numbers.

No XMRV sequences were detected in any of the patient or control samples in any of the assays.

The authors conclude that their data casts doubt on the claim that XMRV is associated with chronic fatigue syndrome in the majority of patients.


ME ASSOCIATION COMMENT

The first and so far only study to positively link XMRV to ME/CFS was reported in October 2009 in Science by Lombardi et al.

Since then this is the third XMRV follow up study to be reported in the medical literature. All three follow up studies have emphatically failed to confirm the presence of XMRV in people with ME/CFS. The previous two studies involved much larger CFS patient cohorts (meeting Fukuda research criteria) numbering 186 (Erlwein et al) and 170 (Groom et al).

This latest study, along with the other two negative studies from the UK, will again be criticised for not being a true replication study because (a) the patient cohort did not meet the same strict entry criteria as was used in the American study (ie Fukuda CFS as well as Canadian clinical criteria) and (b) differing laboratory protocols were used to try and identify the presence of XMRV. These are perfectly valid criticisms regarding the interpretation of what constitutes a replication study - an essential part of the scientific evaluation of new findings and theories.

However, it should be noted that under the umbrella of either Oxford or Fukuda CFS research criteria there are going to be a significant number of people who will also meet Canadian clinical criteria if the patient cohorts from all three negative studies are added together. In addition, Kuppeveld et al appear to be unaware of the use of the Canadian criteria in the US study - probably because this was not mentioned in the paper that appeared in Science. It also has to be accepted that the various laboratory investigations for finding XMRV have been carried out in very reputable microbiological research centres and involved retrovirologists of international repute. So the scientific testing procedures and results for XMRV must be taken seriously.

Overall, these three negative studies now place a very serious question mark over the proposition that XMRV is present in a significant proportion of the ME/CFS population and that the infection plays a significant role in most cases of sporadic ME/CFS.

Various explanations are being put forward to explain the stark differences between the US and European findings - including geographical variation in the prevalence of XMRV and the possibility that the US patient cohort came from geographical clusters of XMRV that are not representative of the wider and sporadic ME/CFS population. But it seems more likely that the explanation lies with the differing ways of testing for XMRV in the lab.

The MEA believes that it is vital to quickly resolve why these stark differences are occurring. One small but important step we are discussing with both researchers and people with ME/CFS is whether people in the UK who have sent their blood to the US and tested positive would be willing to have it retested by a UK research group. We also believe it would be helpful if a fresh cohort of ME/CFS patients could be agreed by all and their blood tested for XMRV in the different laboratories involved in these four studies. If the explanation does appear to be with laboratory testing methods for XMRV we hope that the international retrovirology experts will step in and help to achieve an agreed position.

In the meantime we eagerly await the results of further XMRV studies and once again point out that the MEA Ramsay Research Fund is very willing to consider funding high quality research proposals relating to XMRV, especially any proposal that would include the use of a fresh cohort of patients that would meet Fukuda CFS research criteria and Canadian clinical criteria.


MEA SUMMARIES

The MEA has a very comprehensive XMRV website summary (>> Quick Links) covering the publication of the Science study and events that followed publication.

Summaries covering the two follow up studies from the UK can be found in the MEA website news archives for January and February 2010.

COMMERCIAL TESTS FOR XMRV

Our position on individual XMRV testing remains exactly the same. We do not see any point in spending a large sum of money on a test that cannot, at present, be used as a diagnostic marker or for the purpose of management.


MEA website: http://www.meassociation.org.uk


Dr Charles Shepherd
Hon Medical Adviser, MEA
26 February 2010

 

[fingers2022]

What a *&$%ing waste of time

Sorry folks.

Why can't these guys just agree on how to do the tests. Then do them. Then report them.

A very frustrated Fingers:headache:

 

[Esther12]

Here is my take on her editorial:

I agree with a lot of what you say. Wessely is good at spin and we, as a group, tend not to be. We should read and learn from him how it's best to present arguments to a general audience. He does it very well, and is able to slip in all sorts of contentious claims as if they were widely accepted, while distancing himself from the more controversial aspects of his own work. Without ever giving you a clear cut lie, or presenting a point where most readers would insist on more information.

 

[Gerwyn]

Just received this. Bolding is mine.

A third European XMRV study, which has attempted to find the human retrovirus XMRV in people with ME/CFS, has failed to do so.

Results from the case-control study by Kuppeveld et al is reported today in the British Medical Journal: http://www.bmj.com/cgi/content/full/340/feb25_1/c1018 along with an accompanying editorial from Professors Myra McClure and Simon Wessely: http://www.bmj.com/cgi/content/extract/340/feb25_1/c1099


BRIEF SUMMARY OF THE LATEST XMRV RESEARCH

This latest XMRV study was carried out by a research group based in the Netherlands.

The virologists examined peripheral blood mononuclear cells in blood samples that were taken from a cohort of Dutch ME/CFS patients whose diagnosis met with (the very broad) Oxford research criteria for CFS. They also tested blood samples from some neighbourhood controls. Blood samples were taken between December 1991 and April 1992 and were cryopreserved.

The virologists used a polymerase chain reaction (PCR) assay to target the XMRV integrase gene and/or a nested PCR assay targeting the XMRV gag gene. PCR is a way of detecting viral genetic material in the blood samples. PCR testing was carried out on 32 patient samples and 43 control samples - which are low numbers for this type of scientific study. The authors state that their PCR technique is sensitive enough to detect low virus copy numbers.

No XMRV sequences were detected in any of the patient or control samples in any of the assays.

The authors conclude that their data casts doubt on the claim that XMRV is associated with chronic fatigue syndrome in the majority of patients.


ME ASSOCIATION COMMENT

The first and so far only study to positively link XMRV to ME/CFS was reported in October 2009 in Science by Lombardi et al.

Since then this is the third XMRV follow up study to be reported in the medical literature. All three follow up studies have emphatically failed to confirm the presence of XMRV in people with ME/CFS. The previous two studies involved much larger CFS patient cohorts (meeting Fukuda research criteria) numbering 186 (Erlwein et al) and 170 (Groom et al).

This latest study, along with the other two negative studies from the UK, will again be criticised for not being a true replication study because (a) the patient cohort did not meet the same strict entry criteria as was used in the American study (ie Fukuda CFS as well as Canadian clinical criteria) and (b) differing laboratory protocols were used to try and identify the presence of XMRV. These are perfectly valid criticisms regarding the interpretation of what constitutes a replication study - an essential part of the scientific evaluation of new findings and theories.

However, it should be noted that under the umbrella of either Oxford or Fukuda CFS research criteria there are going to be a significant number of people who will also meet Canadian clinical criteria if the patient cohorts from all three negative studies are added together. In addition, Kuppeveld et al appear to be unaware of the use of the Canadian criteria in the US study - probably because this was not mentioned in the paper that appeared in Science. It also has to be accepted that the various laboratory investigations for finding XMRV have been carried out in very reputable microbiological research centres and involved retrovirologists of international repute. So the scientific testing procedures and results for XMRV must be taken seriously.

Overall, these three negative studies now place a very serious question mark over the proposition that XMRV is present in a significant proportion of the ME/CFS population and that the infection plays a significant role in most cases of sporadic ME/CFS.

Various explanations are being put forward to explain the stark differences between the US and European findings - including geographical variation in the prevalence of XMRV and the possibility that the US patient cohort came from geographical clusters of XMRV that are not representative of the wider and sporadic ME/CFS population. But it seems more likely that the explanation lies with the differing ways of testing for XMRV in the lab.

The MEA believes that it is vital to quickly resolve why these stark differences are occurring. One small but important step we are discussing with both researchers and people with ME/CFS is whether people in the UK who have sent their blood to the US and tested positive would be willing to have it retested by a UK research group. We also believe it would be helpful if a fresh cohort of ME/CFS patients could be agreed by all and their blood tested for XMRV in the different laboratories involved in these four studies. If the explanation does appear to be with laboratory testing methods for XMRV we hope that the international retrovirology experts will step in and help to achieve an agreed position.

In the meantime we eagerly await the results of further XMRV studies and once again point out that the MEA Ramsay Research Fund is very willing to consider funding high quality research proposals relating to XMRV, especially any proposal that would include the use of a fresh cohort of patients that would meet Fukuda CFS research criteria and Canadian clinical criteria.


MEA SUMMARIES

The MEA has a very comprehensive XMRV website summary (>> Quick Links) covering the publication of the Science study and events that followed publication.

Summaries covering the two follow up studies from the UK can be found in the MEA website news archives for January and February 2010.

COMMERCIAL TESTS FOR XMRV

Our position on individual XMRV testing remains exactly the same. We do not see any point in spending a large sum of money on a test that cannot, at present, be used as a diagnostic marker or for the purpose of management.


MEA website: http://www.meassociation.org.uk


Dr Charles Shepherd
Hon Medical Adviser, MEA
26 February 2010

someone has not done their homework you can have me/cfs by feduca and oxford but not meet the canadian criterea at all.Why on earth haven,t they commented that the Oxford criterea differ markedly from the NICE guidelines They are supposed to be on our side!!!In THE CCD neuroendocrine symptoms are obligatory

 

[fingers2022]

What's the problem?

So as a group do we think it's te selection criteria or the testing methods/protocols?

I vote for the latter, but many posts seem to focussing on the former.

 

[Gerwyn]

That's a good point - and for sure they are getting more mood disorder patients in there. And the definition isn't nearly as tight as the definition you mentioned or the Canadian consensus criteria but then again lots of CFS patients don't have any other organic disorders - that's why they end up seeing so many doctors - and the definition states organic disorders known to cause severe fatigue such as anemia. They didn't spell out all these disorders - so in the wrong hands that could be a big problem - it should just refer to things like anemia, thyroid, adrenal etc. disorders but I'm sure some physicians could expand that category greatly. Nevertheless I think, if done properly, a lot of CFS patients would fit in there -- they would just be watered down. That argument is just not resonating with me - I think zero results must still reflect primarily methodological problems on someone's part.

Sasha- I can't imagine that Shepherd doesn't have his retroviral contacts. I know over here the CFIDS Association has its scientific advisory Board - I would think that any organization that sponsors research would have a similar setup, and as I mentioned, they must be talking to people in the field.

I'm really surprised that MERUK has basically been silent since the initial finding. I believe they've been pretty outspoken about the direction of research in the UK. if they felt there are major problems with these studies I can't imagine why they're not saying that. They have excellent researchers there; I don't think they have retrovirologists on board but even so I feel that as an important patients supported research group they have an obligation to comment more fully on the studies. They must the doing the same thing we're doing just at a more advanced level; going over the studies picking them apart, talking to people.... I don't get it. If

My fear is that they don't want to be perceived as stepping on XMRV and so they're standing back and letting other organizations Such As Shepherds organization and the CFIDS Association to take the brunt. Maybe they just feel that outside of their core competency.

Hi Cort I think I might know what are communication issues are.did you know that organic disease in this context also includes organic psychiatric disease.Common symptoms(which diagnosis is initaily based on) include confusion memory impairment,cognitive dysfunction impairment of judgement, IQ reduction agitation encephalopathy(neuroendocrine symptoms etc) obviously this is not common knowledge.This is what I meant be excluding Patients with ME.Putting it another way psychiatric diseases can also be organic I hope this helps.It appears that the ME society dont understand this either.We all think of organic disease as physical and neglect the biggest organ of all.

 

[jspotila]

Beats me. Would you consider contacting, say, Dr Vernon and asking her about this?

Dr. Vernon is working on an analysis of this study. I don't have an exact publication time, but it will appear on the Association's XMRV webpage. I'll also post it here as soon as I can.

 

[gracenote]

I wish this thread was titled differently. I don't think it is helpful to list the three "replication" attempts with the Science study. There is the Science study, and then there are, and will be, attempts to show if the Science conclusions hold up. The second study from the UK is titled #2. Maybe something like:

Failure to Find XMRV in CFS: Study #3

I can come up with very different critical titles (including words like stupid, biased, huh?), but in the interest of fairness (HA!), I think we can have a neutral title followed by our reasoned critiques.

I think all of you who are commenting here are brilliant. Thank you so much.

 

[spindrift]

My money is on the much-vaunted Faroe Islands study to finally put this ‘why can’t we find XMRV in our studies‘ conundrum, to bed.

Due to post in May 2023, the Faroe Islands team results are expected in after the Lichenstein study, who like the WPI, have ditched PCR, in favour of using a far more sensitive method. In their case, the revolutionary BMG technique (for those of you who don’t know about BMG, it is a fairly old method, often overlooked these days, but very reliable and VERY cheap).

The FI study is due in before the Lapland project, who are apparently experiencing problems with frozen blood samples.

The BMG technique involves a highly polished circular piece of glass welded to a stick, which when held close to the eye makes the object being observed - in this case, blood taken from people feeling a little bit under the weather, look a lot, well…bigger.

NB. I think the B in BMG stands for big? But not that hot on sciencey stuff as they say.

Gerwyn et al?

Rumours are circulating; which they do have a habit of doing, don’t they, that the Faroe Islands scientists are collaborating with a number of major corporations around the globe, and that several double blind trials are already under way and reporting excellent results into the efficacy of a nice hot cup of tea to cure the afflicted.

* Apologies in advance to citizens of Faroe Islands, Lapland and Lichtenstein.

:tear::tear::tear: :Sign Good one:

The bad thing is, I read half way through it before I noticed. :scared: