XMRV Study No. 4

[fingers2022]

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.

Any thoughts on this?

 

[Gerwyn]

any thoughts on this?

both methods inadequate diagnosis a joke

 

[Sasha]

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.

Thanks, jspotila - do you know if she is planning to write to the BMJ?

 

[oerganix]

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.

It's both.

A study using poor cohort criteria tells us nothing useful re:ME/CFS, regardless of how good the methods might be, IF we're trying to find out the truth about XMRV.

A study using poor methods studying any cohort, good definition or bad, also tells us nothing useful, IF we're trying to find the truth.

So, we have to have both a proper cohort and good methods in order to have any meaningful results.

The Wessely denialists have influenced or done 2 out of 3 of these negative results studies. For them, it's a useful political strategy to divide and conquer, create smoke screens and diversions and try to out shout everyone else for public attention. They want to give the impression that they have found the answer so that no one else will continue to look for it.

It's interesting that no one to my knowledge has faulted McClure in her editorial, so right on the spot and ready, for not even mentioning that one of the studies she is so vigorously citing as proof that WPI's findings are wrong, is her own study! I'd like to see Dr Mikovits or any of the WPI study's scientists try to get away with this kind of spin in print, without a pack of critics coming down on them for inappropriate, unprofessional behavior!

 

[Esther12]

No way patient selection would lead to the difference between the WPI's results and the others: unless the others were being intentionally fraudulent, or the WPI were being way more selective than they've claimed.

It seems to me that either XMRV is surprisingly difficult to detect (which seems like it could well be the case), or there's some problem with the WPI's work, or both.

 

[jspotila]

Thanks, jspotila - do you know if she is planning to write to the BMJ?

I do not, Sasha, I'm sorry.

 

[fingers2022]

No way patient selection would lead to the difference between the WPI's results and the others: unless the others were being intentionally fraudulent, or the WPI were being way more selective than they've claimed.

It seems to me that either XMRV is surprisingly difficult to detect (which seems like it could well be the case), or there's some problem with the WPI's work, or both.

I agree Esther, the polls seem to support this too - one with high % +ve, other -ve. Thi sneeds to be sorted out before anything meaningful comes out.

 

[jspotila]

Questions and Points of Concern

I do not have a science background, so my reading of the Dutch paper is amateur at best. I have a couple questions, and some deep concerns as well.

Spiking experiments showed that we were able to detect at least 10 copies of XMRV sequences per 105 peripheral blood mononuclear cells by real time as well as by nested polymerase chain reaction, demonstrating high sensitivity of both assays.

Does this mean that they showed their PCR was sensitive enough by testing a known positive, such as from the prostate cancer cell line? Or are they saying that their assays were sensitive enough in theory?

In our study, we used the same primer sets as used by Lombardi et al.

How significant is the use of the same primer sets? This was one of many criticisms of the IC study (that they did not use the same primers). So my question is whether confidence in the accuracy of the Dutch results is affected by their use of the same primers?

However, the [Lombardi] 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?

This has to get straightened out. I keep reading statements like the one above, that the info is not in the Science paper. Then we have posts here on the forums that claim the information is available in the Science supplemental or other places. I cannot find anything in the Science paper or supplemental that describes age, gender distribution, or any characteristics of the control group. Some information was presented by Dr. Peterson at the CFSAC meeting in October 2009 (the 101 patients in the study were drawn from CFS practitioners in the US; mean age of 55; 67% female). But I also remember reading somewhere that Dr. Mikovits stated that when they broke the coding on samples in December 2009, some of the samples were from outside the US.

Precise replication of the Science paper can ONLY happen if the patient and control groups are replicated in every possible detail. We can't say whether age or geography or length of illness matters in the results unless a study replicates all those factors. To truly test replication, every single detail of the original study must be matched. Conflicting information (Peterson says US samples, Mikovits says US and non-US) is only going to complicate and slow the whole process.

Unfortunately, the paper of Lombardi and colleagues lacked a clear description of their patient cohort. Recently, at the Tri-Society Annual Conference 2009 in Lisbon, a presentation reported that the peripheral blood mononuclear cells were derived from patients from the outbreak of chronic fatigue syndrome at Incline village at the northern border of Lake Tahoe, United States (1984-5).

This is another example of conflicting information, but the authors provide a citation for this statement. The citation is to a publication from Dr. Mikovits from a conference in Lisbon in October 2009: Mikovits J. Detection and immune correlates of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Lisbon: Tri-Society Annual Conference, 18-21 October 2009. Cytokine 2009;48:10. I can't access the full paper for free, but maybe someone else has access?

Will researchers give more weight to publications than oral presentations of unpublished data? I assume that it is similar to being on or off the record in journalism. If Dr Mikovits said on the record in the above reference that the positives came from Incline Village, then researchers will treat that statement as true and make the criticism we see in this paper - that XMRV might be related to the Incline outbreak only. But if there are conflicting statements out there, especially if those statements are from Dr. Peterson and Mikovits, then what will researchers believe? The publication? The press releases? Presentations at conferences? Presentations to patients?

We need a meticulous replication study. We need the federal data (CDC, NCI, NIH). We need it now. I am really concerned that the negative studies are building momentum. The real danger, in my personal opinion, is that pharma and academia will lose interest in this work, or decide it is easier to study XMRV in prostate cancer instead. This would be a problem, because apart from the federal government the big money resources are with pharma and high-profile academia. If the big money walks away, it might have a chilling effect on the whole field.

I think the quote from Dr. Goff is spot on: "His answer: everyone needs to exchange samples, and they are not doing it." The greatest service anyone can render to the CFS community would be to throw open the doors on information. Everybody needs to exchange primers, assays, samples, cohort data. Exchange everything. I know there must be intellectual property and other issues at stake, etc. but we need free exchange of ideas and information so we can unravel this puzzle.

 

[HowToEscape?]

And there's the problem with trying to track science with tools us non-scientists have. It is difficult to sort out truth vs noise vs willful ignorance (Wessely) vs genuine scientific difficulty. While I'm not versed in biology, find one or more unknown virii which probably have a key role in this disease - probably, not certainly - seems to be difficult even with the best available methods.

Do you think that some of these studies were just rushed a bit, or that they did not have the full details they needed to find an elusive target?

 

[Gerwyn]

No way patient selection would lead to the difference between the WPI's results and the others: unless the others were being intentionally fraudulent, or the WPI were being way more selective than they've claimed.

It seems to me that either XMRV is surprisingly difficult to detect (which seems like it could well be the case), or there's some problem with the WPI's work, or both.

I,m Afraid that patient selection is absolutely critical
igue: The patient must have a significant degree of new onset, unexplained, persistent, or recurrent physical and mental fatigue that substantially reduces activity levels.

2. Post-Exertional Malaise and/or Fatrigue: There is an inappropriate loss of physical and mental stamina, rapid muscular and cognitive fatigability, post exertional malaise' and/or fatigue and/or pain and a tendency for other associated symptoms within the patient's cluster of symptoms to worsen. There is a pathologically slow recovery period - usually 24 hours or longer.

3. Sleep Dysfunction: There is unrefreshed sleep or sleep quality or rhythm disturbances such as reversed or chaotic diurnal sleep rythms.

4. Pain: There is a significant degree of myalgia. Pain can be experienced in the muscles, and/or joints, and is often widespread and migratory in nature. Often there are significant headaches of a new type, pattern or severity.

5. Neurological/Cognitive Manifestations: Two or more of the following difficulties should be present:

* confusion,
* impairment of concentration and short-term memory consolidation,
* disorientation,
* difficulty with information processing,
* categorizing and word retrieval, and
* perceptual and sensory disturbances - e.g., spatial instability and disorienation and inability to focus vision.
* Ataxis, muscle weakness and fasciculations are common. There may be overload phenomena: cognitive, sensory - e.g., photophobia and hypersensitivity to noise - and/or emotional overload, which may lead to "crash" periods and/or anxiety.

6. At least one symptom from two of the following categories:

a. Autonomic Manifestations: orthostatic intolerance - neurally mediated hypotension (NMH), postural orthostatic tachycardia syndrome (POTS), delayed postural hypotension; light-headedness; exreme pallor; nausea and irritable bowel syndrome; urinary frequency and bladder dysfunction; palpitations with or without cardiac arrythmias; exertional dyspnea.

b. Neuroendocrine Manifestations: loss of thermostatic stability - subnormal body temperature and marked diurnal fluctuation, sweating episodes, recurrent feelings of feverishness and cold extremities; intolerance of extremes of heat and cold; marked weight change - anorexia or abnormal appetite; loss of adaptibility and worsening of symptoms with stress.

c. Immune Manifestations: tender lymph nodes, recurrent sore throat, recurrent flu-like symptoms, general malaise, new sensitivities to food, medications and/or chemicals.

7. The illness persists for at least six months: It usually has a distinct onset, although it may be gradual. Preliminary diagnosis may be possible earlier. Three months is appropriate for children.

To be included, the symptoms must have begun or have been significantly alered after the onset of this illness. It is unlikely that a patient will suffer from all symptoms in criteria 5 & 6. The disturbances tend to form symptom clusters that may fluctuate and change over time. Children often have numerous prominent syptoms but their order of severity tends to vary from day to day. There is a small number of patients who have no pain or sleep dysfunction, but no other diagnosis fits except ME/CFS. A diagnosis of ME/CFS can be entertained when this group has an infectious illness type onset. Some patients have been unhealthy for other reasons prior to the onset of ME?CFS and lack detectable triggers at onset or have ore gradual or insidious onset.

Oxford does not even come close!

 

[ixchelkali]

XMRV was found not only in the WPI's healthy controls, but also in Japanese healthy community. So if this study could actually find XMRV in every sample if it were there - How come there was not one XMRV positive blood sample from the 43 healthy controls, and actually, from the 75 blood samples altoghether, assuming that there is no reason for ME/CFS patients to be less susciptble to XMRV than the healthy population?).

omerbasket, I wondered about that, too.

 

[Lesley]

The fact that these researchers seem unaware of readily available information regarding the cohort for the WPI study is mind boggling to me (not that it takes much). Here is the description from the supplemental materials to the Science study, which are available at http://www.sciencemag.org/cgi/data/1179052/DC1/1.

Patient samples. Banked samples were selected for this study from patients
fulfilling the 1994 CDC Fukuda Criteria for Chronic Fatigue Syndrome (S1) and
the 2003 Canadian Consensus Criteria for Chronic Fatigue Syndrome/myalgic
encephalomyelitis (CFS/ME) and presenting with severe disability. 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.
DNA and RNA isolation. Whole blood was drawn from subjects

Information regarding the cohort can be found on the WPI website page regarding the BioBank here: http://www.wpinstitute.org/research/research_biobank.html. Some key points:

Where did the samples come from for the XMRV study?
The WPI repository samples came from patients who live in many different locations around the US. Physicians who contributed patient samples include: Dr. David Bell, Dr. Paul Cheney, Dr. Daniel Peterson, and Dr. Eric Gordon. Other individual patient samples came from individuals who became ill while living in California, Wisconsin, South Dakota, etc.

What about Dr. Peterson's private repository? [view answer...]
Dr. Peterson has a repository of samples from the original out break in Incline Village, Nevada which also includes longitudinal samples taken from patients from the 1980's through 2005. None of these samples were used in the XMRV study.

There is a lot more on that page, but you get the idea.

 

[fingers2022]

I,m Afraid that patient selection is absolutely critical

Sorry Gerwyn, but surely, if the testing's not right, the selection is irrelevant?

 

[Hope123]

I

Will researchers give more weight to publications than oral presentations of unpublished data? I assume that it is similar to being on or off the record in journalism. If Dr Mikovits said on the record in the above reference that the positives came from Incline Village, then researchers will treat that statement as true and make the criticism we see in this paper - that XMRV might be related to the Incline outbreak only. But if there are conflicting statements out there, especially if those statements are from Dr. Peterson and Mikovits, then what will researchers believe? The publication? The press releases? Presentations at conferences? Presentations to patients?

We need a meticulous replication study. We need the federal data (CDC, NCI, NIH). We need it now. I am really concerned that the negative studies are building momentum. The real danger, in my personal opinion, is that pharma and academia will lose interest in this work, or decide it is easier to study XMRV in prostate cancer instead. This would be a problem, because apart from the federal government the big money resources are with pharma and high-profile academia. If the big money walks away, it might have a chilling effect on the whole field.

I think the quote from Dr. Goff is spot on: "His answer: everyone needs to exchange samples, and they are not doing it." The greatest service anyone can render to the CFS community would be to throw open the doors on information. Everybody needs to exchange primers, assays, samples, cohort data. Exchange everything. I know there must be intellectual property and other issues at stake, etc. but we need free exchange of ideas and information so we can unravel this puzzle.

Jspotila - I agree with you - scientists rely on papers published in peer-review scientific journals (which can be online)above all, not press releases, patient presentations, conference presentations (which are a bit more trustworthy but still taken as preliminary). This was explained to me by a trusted mentor when I was a young student who wasn't sure if I wanted to publish.

The WPI, as much as I admire and have donated to it, needs to be clear and consistent in its presentation of the data and keep the research world as aprised of its updates as it has its constituents. I've had several friends in science doubt the PR methods of the WPI and this also affects their perception of the research there.

From my notes and reviewing the Science materials:
- age/sex of cohort first revealed at CFSAC, not in supplementary Science materials
- breaking code and samples found to be international - Dr. Mikovits talk, in Santa Barbara January
- control cohort being people identified as "healthy" by several MD practices and people from paternity clinic - Dr. M talk in January

It's taken a bit of work to piece this info together, which it shouldn't have. These are basic points. WPI needs to get out a paper or good statement to SCIENTISTS about the subjects in their study, who are not going to attend talks geared towards patients or visit their website necessarily. Also, the points about the subjects on their website were added little bit by little bit AFTER the Science paper had already come out. They needed to have some of this data on there BEFORE the paper came out and as complete as possible. Hopefully, they've done this with the scientific community behind the scenes but a published paper would help many scientists not in the loop already but interested in XMRV research.

 

[sunnyslumber]

Well as a CFS/ME patient this really worries me even with the Oxford Criteria... I find it hard to believe the psychiatric people would out and out LIE in a scientific journal like BMJ. I do think they might do a sort of half-***ed study and hope it doesn't find anything but I can't believe scientists would be actively malevolent.

So what is the reason? The oxford criteria? Even if not one of those patients had the real CFS/ME which is unlikely (imo) some of the controls should have tested positive. The prostate cancer studies have never found XMRV in Europe either to my knowledge.

So what do you guys think it is? Is XMRV just not in Europe or they have a substantially different variant? Maybe retroviruses in human beings are common and there are a subset that can trigger CFS/ME such as XMRV and Defrietas's Virus? Those explanations fail at explaining why the WPI *IS* finding XMRV in other countries and in Europe though which (I believe, please correct if wrong) was mentioned in one of the Mikovits Lectures.

So what do you all think the reason is? To back up my assertion that scientists wouldn't outright lie to other scientists (or that it is rare) even Wessely has done studies where there were some biological abnormalities which he promptly proceeded to dismiss, *but* he didn't deny they were there when his study found them. Right now I am thinking, for whatever good it will do, how to explain finding XMRV by WPI and by Cleveland Clinic (in Prostate Cancer) but not by others.

Especially if WPI is finding it internationally... I can't see how the "undetectable variant hypothesis" would still work to explain everything.

Does anyone have any ideas? Is it just that the replication studies are so sloppy? The one with Kerr presumably was not so that not explain away everything( you'd think).

I have no doubt XMRV will be important but I am having a hard time making sense of all this right now.

 

[bullybeef]

It is plain to see that they made absolutely sure they wouldn't find XMRV, no matter whom they tested. It is now 3-1 to Wessely and the quacks. The WPI need some help desperately. We all know the science is dodgy but the headlines simply show their results, to the layman, the methodology means nothing: http://uk.reuters.com/article/idUKTRE61P04L20100226

I really fear that we in the UK may be left behind. ME politics is huge over here, and I think as far as Wessely is concerned, XMRV will not be linked with ME, not only in the UK, but maybe Europe too. How has this shrink become so powerful?

I heard mention elsewhere that we need a political investigative journalist from outside the UK to find an interest in this. If there is evidence out there that Wessely has been unethical in regards to the treatment and management of ME, then surely it could be uncovered?

 

[fingers2022]

Don't worry BB & SS,it's all noise. The truth will come through, it always does (flat earth?).

Once they (we?) agree on a standard test protocol, and coordinate some studies (same cohort, same procedure), we'll get the picture. I'm not pre-empting who's right, but at the moment, somebody is wrong.

 

[Angela Kennedy]

Sorry Gerwyn, but surely, if the testing's not right, the selection is irrelevant?

No, it's not 'irrelevant' - it's a serious confounding factor. If they were looking for the HIV virus in 'AIDS' patients without any of the cardinal signs/symptoms of AIDS, without relevant medical histories, AND they used poor techniques for detecting the HIV, The problem of cohort would STILL be extant.

Basically, problems in technique of testing and in patient cohort just compound the confounding.

 

[sunnyslumber]

I can't speak for myself (wasn't there), but can anyone comment on how similar/different the overall response to the Defrietas study was to the response to the WPI study?

In my mind similar responses would lend it credence that maybe we are dealing with a virus with a/some very unique feature(s)?

Thanks fingers! I think we can all feel how close we are... and it is somewhat frustrating. Even knowing "science" to experience the slow pace of it firsthand like this (if that is all this is) is quite the pain.

 

[Gerwyn]

Well as a CFS/ME patient this really worries me even with the Oxford Criteria... I find it hard to believe the psychiatric people would out and out LIE in a scientific journal like BMJ. I do think they might do a sort of half-***ed study and hope it doesn't find anything but I can't believe scientists would be actively malevolent.

So what is the reason? The oxford criteria? Even if not one of those patients had the real CFS/ME which is unlikely (imo) some of the controls should have tested positive. The prostate cancer studies have never found XMRV in Europe either to my knowledge.

So what do you guys think it is? Is XMRV just not in Europe or they have a substantially different variant? Maybe retroviruses in human beings are common and there are a subset that can trigger CFS/ME such as XMRV and Defrietas's Virus? Those explanations fail at explaining why the WPI *IS* finding XMRV in other countries and in Europe though which (I believe, please correct if wrong) was mentioned in one of the Mikovits Lectures.

So what do you all think the reason is? To back up my assertion that scientists wouldn't outright lie to other scientists (or that it is rare) even Wessely has done studies where there were some biological abnormalities which he promptly proceeded to dismiss, *but* he didn't deny they were there when his study found them. Right now I am thinking, for whatever good it will do, how to explain finding XMRV by WPI and by Cleveland Clinic (in Prostate Cancer) but not by others.

Especially if WPI is finding it internationally... I can't see how the "undetectable variant hypothesis" would still work to explain everything.

Does anyone have any ideas? Is it just that the replication studies are so sloppy? The one with Kerr presumably was not so that not explain away everything( you'd think).

I have no doubt XMRV will be important but I am having a hard time making sense of all this right now.

The chief medical officer of the UK savagely critises the Oxford criterea and psychiatrists are not scientists