Article: The CDC XMRV Study: How Not to Find XMRV?

You can view the page at http://www.forums.aboutmecfs.org/content.php?180-The-CDC-XMRV-Study-How-Not-to-Find-XMRV

 

I think I get where they are going with this. If they exclude all the neurological symptoms, and most of the true defining factors of CFS such as PEM, they can steer those people into a new disease set with a new name, and what will be left in the CFS definition will be people like the cohort they used for the current study. Then they can say that they were right all along and save their butts when it comes to accusations of malfeasance. Call me crazy, but I don't think this is outside the realm of possibility.:innocent1:

 

I think I get where they are going with this. If they exclude all the neurological symptoms, and most of the true defining factors of CFS such as PEM, they can steer those people into a new disease set with a new name, and what will be left in the CFS definition will be people like the cohort they used for the current study. Then they can say that they were right all along and save their butts when it comes to accusations of malfeasance. Call me crazy, but I don't think this is outside the realm of possibility.:innocent1:

I think that's the logical conclusion. The big problem is where do you put all those people who have all these weird symptoms...they clearly don't fit anywhere else - that's how, after all, they ended up in the CFS waste-basket. Now the CDC is saying toss them- but where? They don't fit anywhere else. And what percentage of patients would go? It might be a very high percentage. If you create a vague disease definition I think you're obligated to take all patients that fit that disease definition so long as they don't fit another.....

I dont think the CDC is a better diagnostician of CFS than Dan Peterson or Paul Cheney....

 

I also hope that this was a last gasp by reeves and the paper will be seen for what it is. But we should demand they take down the cdc webpage on the study which slants their results. that could hurt uninformed new patients.

Things wrong with the CDC study.
1 they do not use CFS patients in their study.
2 the blood tubes are the wrong type for pathogens as pointed out by Vernon.
3 PCR can only detect proteins from budding viruses. The should have used r-pcr or stimulated the cells.
4 env is the most specific to XMRV and is not used in all of the tests.
5 they did not use positive human blood which is available for a control. By using non-human blood they had to process samples differently. There is no evidence that they would have identified a positive human sample.

 

The CDC have a difficult problem on their hands: how to make the disease go away without losing the funding, which they have repeatedly misappropriated in the past - as revealed in official testimony about doing better in the future. The way out of this is to maintain confusion, which they have succeeded in doing.


A series of papers early in the year attracted criticism about their failure to validate their tests against samples drawn from living infected human beings. This paper is no exception, despite months of prior opportunity. Spiking samples will not necessarily produce anything like you get from an infected person. The only evidence that this was taken into account is a paragraph about the lack of the availibility of a control panel. Why didn't CDC researchers address this issue before wasting time in the laboratory, let alone publishing? Is this potential pathogen peculiarly outside their scope?

While there is a statement that CDC laboratories were able to detect XMRV in samples from people they trusted, there is no supporting data to show how well they can detect virus if the sample is not labeled positive. This amounts to saying, "yes, we know how to detect this virus, trust us." We have no idea how close to the margin their results are. A double-blind study independent of CFS/ME is called for. Blinding should not be controlled by a group which has a demonstrated record of nonfeasance, misfeasance and malfeasance involving millions of dollars, plus Congressional testimony about same approaching perjury.

Among the criticisms of previous papers easily available prior to this publication, there were very specific statements about activating cells in the samples, then allowing these to divide several times, in order to raise the number of copies available to PCR. This paper does not appear to address these concerns in any way. Have I missed something, or is this an attempt to ignore opponents and proceed by sheer bluff?

In assessing sensitivity of tests it is important to consider the number of cells available at the start. We already know very few cells in the blood will show active infection. The difficulty of finding this may not bother those with highly specialized backgrounds, who can read between the lines. For me, this is a mystery. I also wonder about the relation between numbers of cells and amounts of DNA, as this can give an idea of the effectiveness of techniques for processing samples and extracting DNA prior to PCR. Why were such simple measures omitted? It is far too easy to think this was deliberate obfuscation. Responsible researchers should take pains to dispel such doubts.

It is clear that researchers working on this virus in relation to prostate cancer are also working at the limits of the state of the art. They have not been subject to the kind of prejudgment apparent here.

I think there are lots of good issues here. Financing for CFS at the CDC, however, is miniscule - I think it's down to about $3 million a year - they're not spending any real money on it. I imagine the program - given the unhappiness of the patients in the research community towards it - is not worth the little money they're getting for it. I imagine that they'd be happy if it just went away.

I really don't know the pros and cons of spiking samples with XMRV vs finding it in positive samples of human beings. The CDC did show they could find very low levels of the virus in samples but does it matter or how does it matter where the samples came from. That would be great to find out.

While there is a statement that CDC laboratories were able to detect XMRV in samples from people they trusted, there is no supporting data to show how well they can detect virus if the sample is not labeled positive.

They showed they could pick up antibodies in control versus infected lysates (they used cells infected with polytropic MuLV's)that they produced but they did not have any positive samples in the mix when they did the actual testing of CFS patients and controls. Nor did Koch Institute - one would think they would have had some positve MuLv samples in there. So there was initial testing using positive samples but no testing after that.

there were very specific statements about activating cells in the samples, then allowing these to divide several times, in order to raise the number of copies available to PCR. This paper does not appear to address these concerns in any way. Have I missed something, or is this an attempt to ignore opponents and proceed by sheer bluff?

I think this is the most interesting issue of all. I don't think they activated the cells either! Which doesn't seem to be upsetting people much. I did hear a researcher say, if I heard him correctly, that culturing can be dangerous because of dangers of contamination. It could be that instead of culturing cells to raise viral levels they are upping the level at which they can detect the virus.

If culturing does increase the possibility of contamination, it would seem to me that it would be very simple to determine if this is happening - simply do the procedure in clean cells using that specific culture technique - and see if XMRV turns up....if it turns up the culture was responsible. I can't imagine that the WPI or NCI or Cleveland Clinic didn't check this out a long time ago. In any case no one yet has appeared to activate the cells. I wish we could get an expert on here.

 

Can this be pursued as a crime of deception or conspiracy with intent to deceive? They have clearly not used the same methodology cohort group etc

I think it is a misuse of congressionally mandated funds for CFS which they got in trouble for before.

I think I get where they are going with this. If they exclude all the neurological symptoms, and most of the true defining factors of CFS such as PEM, they can steer those people into a new disease set with a new name, and what will be left in the CFS definition will be people like the cohort they used for the current study. Then they can say that they were right all along and save their butts when it comes to accusations of malfeasance. Call me crazy, but I don't think this is outside the realm of possibility.:innocent1:

But if everyone neurological leaves, how many fatigued or depressed people are going to want to be forced into CBT? ( Maybe the CDC can have a reality show.)

 

Financing for CFS at the CDC, however, is miniscule - I think it's down to about $3 million a year - they're not spending any real money on it. I imagine the program - given the unhappiness of the patients in the research community towards it - is not worth the little money they're getting for it.

But We need that 3 milliion for research.

 

I think there are lots of good issues here. Financing for CFS at the CDC, however, is miniscule - I think it's down to about $3 million a year - they're not spending any real money on it. I imagine the program - given the unhappiness of the patients in the research community towards it - is not worth the little money they're getting for it. I imagine that they'd be happy if it just went away.

While $3 million/year is miniscule at the CDC's burn rate, compared to all HHS extramural grants in the field it is a windfall.

I really don't know the pros and cons of spiking samples with XMRV vs finding it in positive samples of human beings. The CDC did show they could find very low levels of the virus in samples but does it matter or how does it matter where the samples came from. That would be great to find out.

The problem is that DNA floating around loose may well be easier to detect than DNA integrated into cells. The issue involves both sensitivity and selectivity. Being able to detect DNA in an artificial solution is very different from separating it from various components of whole blood. We don't really know their scorecard on those different components. Based on this publication we are generally at a loss to know what took place prior to PCR testing.

...So there was initial testing using positive samples but no testing after that.

What I have said before is that data developed during the validation process were not published in the copy I have. Do you have something I missed?

There is a logical inference concerning the "exclusionary conditions" which was left hanging: if a subset of patients with, e.g. MS, can bias results so that 67% of subjects appear to have the virus, there must be a phenomenal correlation between XMRV and that illness. Does anyone at CDC act like they think they've found the cause of MS? Do they act like they are looking?

Test validation is not merely a concern with CFS, there has been considerable disparity between XMRV results of different labs w.r.t. prostate cancer. This brings in an entirely new line of argument which has apparently escaped those who keep trying to reassure the dumb public that blood supplies are 100% safe. Even if none of us existed there would still be large numbers of people with prostate cancer who might contaminate the blood supply.

Most prostate cancers are slow growing. People often survive for years before the cancer is detected. In the early stages of illness, it is unlikely any discomfort would stop them from donating blood. About 200,000 new cases are discovered every year. Without biopsies, diagnosis is often uncertain. Common clinical tests have both false positives and false negatives. About 2,000,000 people who are known to have had prostate cancer are now alive in this country. Among oncologists the fatigue associated with the disease is notorious, even after tumors are removed. The possibility of concurrent infections has to be taken seriously.

This is relevant because XMRV was originally discovered in some patients with prostate cancer, and is commonly grown in the laboratory on cell lines cloned from prostate cancer. The same uncertainty in detecting XMRV is affecting studies of its incidence in all types of prostate cancer.

Under these circumstances it seems highly unlikely the incidence of XMRV in the general population is 0%, even if it plays no causative role in any disease. Studies reporting 0% may be useful for reassuring gullible people, but responsible public officials ought to know better.

Finally, I want to get back to a point raised before: the CDC are about the last group to be asking plaintively 'who is responsible for providing a panel of positive samples from infected human beings?' What government agency is responsible for monitoring and detecting infectious agents? Irrespective of CFS, what have they been doing in the years since XMRV was discovered? To some it looks like they have been derelict in their duty, and then, when someone else developed a panel and validated a methodology for detecting the virus, they devoted the bulk of their efforts to undermining those with the temerity to find anything infectious ahead of them. Thinking of the toast, "Confusion to our enemies!" it would appear they have classified a remarkable number of medical and scientific professionals as enemies. The general public must be counted in the same list.

The successors of this group at the CDC will now have an uphill battle in gaining cooperation of anyone knowledgeable about this virus. They have managed to take swipes at not just Judy Mikovits, Dan Peterson, and the usual suspects, but also the Ruscetti's, John Coffin, Harvey Alter, and even if indirectly, Robert Silverman. They have probably alienated researchers I haven't mentioned.

The issues have become much bigger than our pitiful CFS/ME community.

 

Very thoughtful post, AD.

The issues have become much bigger than our pitiful CFS/ME community.

Which is one important reason this cannot be buried by the CDC.

One thing that will come out of all this, regardless of which way the XMRV question is settled, is that much more scientific and public scrutiny will have been applied to the CDC, particularly over their CFS program. That can only be for the better.

 

Can't we just call our illness CCCFS (Canadian Criteria Chronic Fatigue Syndrome) and clarify that this is a different illness from CDCCFS (Centre for Disease Control Chronic Fatigue Syndrome)?

It is already proven that XMRV is connected with CCCFS (WPI study, cf. selection of patient cohort), and that it is not connected with CDCCFS (Kings college study, Dutch study).

We need to get the separation of patient cohorts publicly established and accepted, and stop going along with the charade of pretending two completely different illnesses are one. I actually wish the WPI had come straight out saying that they had discovered that some patients incorrectly diagnosed with CFS actually had a new, distinct illness called XAND and thus we could have avoided all this sheer nonsense.

But the WPI cant say that those with XMRV have been incorrectly diagnosed with CFS as they still dont know if that causes CFS or is just a opportunitistic virus (eg infecting us due to the CFS).
........

I like the idea of CFS patients catagorising illness as CCCFS or CDCCFS. If all CFS patients put it onto ourselves to subgroup instead of using the general CFS, it would get doctors and the general public more aware of the subgroups.

 

"I like the idea of CFS patients catagorising illness as CCCFS or CDCCFS. If all CFS patients put it onto ourselves to subgroup instead of using the general CFS, it would get doctors and the general public more aware of the subgroups"

I'm not disagreeing with your general sentiments but we need to get away from talking about sub-groups at all.

As I said before - sub-groups of what? Conditions which may cause fatigue?

Talking about sub-groups is a cop out. What it really means is that these people have nothing in common apart from the common symptom of fatigue.

Even PEM as a cardinal symptom fails to capture it as discussed ad nauseaum (exertion is misconstrued as physical only and malaise hardly captures the degree of morbidity) and I would much prefer the focus to be on the immune dysfunction.

In fact, perhaps the focus should be on the pathology rather than the symptoms.

I feel researchers and advocates are equally culpable when talking about discrepant findings. I can appreciate the constraints they are under but as long as they use terms like sub-groups, the CFS wastebasket is perpetuated.

Rather than talking about sub-groups, can't those clinicians and researchers dealing with real ME say something like - 'well that patient cohort doesn't look anything like the people I deal with', or more diplomatically 'its difficult to make comparisions if the only symptom studied is fatigue which is a common finding in many illnesses'.

On a personal level, I always use the term ME/CFS when corresponding with officials and medics. In fact I state that I have ME/CFS as described by the clinical defintion in the CCD and do not have ideopathic 'chronic fatigue'. Whether or not this means anything to the bureacrats or medics is irrelevant. I'm lucky to have ME clearly stated on my medical records and I'm damned sure its staying there.

I only use the CFS bit because ME isn't universally recognised. I'd prefer to use ME/CFIDS but CFIDS is rarely recognised in Europe.

I will never use CFS in isolation and thereby perpetuate the nonsense of grouping people together on the basis of fatigue only.

 

I'm thinking these are still the early studies, where everyone tries PCR first. They must really like PCR.

 

Marco said:

"...we need to get away from talking about sub-groups at all.

As I said before - sub-groups of what? Conditions which may cause fatigue?

Talking about sub-groups is a cop out. What it really means is that these people have nothing in common apart from the common symptom of fatigue.

Even PEM as a cardinal symptom fails to capture it as discussed ad nauseaum (exertion is misconstrued as physical only and malaise hardly captures the degree of morbidity) and I would much prefer the focus to be on the immune dysfunction.

In fact, perhaps the focus should be on the pathology rather than the symptoms.

I feel researchers and advocates are equally culpable when talking about discrepant findings. I can appreciate the constraints they are under but as long as they use terms like sub-groups, the CFS wastebasket is perpetuated.

Rather than talking about sub-groups, can't those clinicians and researchers dealing with real ME say something like - 'well that patient cohort doesn't look anything like the people I deal with', or more diplomatically 'its difficult to make comparisions if the only symptom studied is fatigue which is a common finding in many illnesses'. "

Sorry I've had to put Marco's quotes in italic- for some reason computer won't let me use 'reply with quotes' facility on his post.

These are excellent, key points. For years I've felt the 'subgroup' claims were inaccurate, and the tendency for doctors and charity reps to use the term confusing. An over focus on a ubitquitous human symptom, though sometimes not even experienced specifically by 'Canadian Criteria' patients, for whom 'fatigue' is something at least some may WISH they had.

(I'm certainly not belittling sufferers from 'fatigue' here. I've been suffering from anaemia these past few months. I understand how an organic illness can cause prolonged 'fatigue' which can make life extremely 'difficult', shall we say. But the problem here is the way a patient's specific descriptions of CNS dysfunction, cardiac dysfunction, drowsiness (especially in the initial phases of an illness) and other impairments seems to often get written into a doctor's report as 'fatigue' and downplayed even further into 'tiredness'. )

The problem is of course that some of the researchers in 'CFS/ME', as Marco indicates, have been thinking in terms of 'sub-groups' and have built research around it. They are not going to like that their discrepancy in analysis (because that is what it is: 'sub-groups of CFS' is a flawed construct) is being highlighted.

Also Marco- LOVED your earlier comment about the Atlanta population in high summer suffering month-long 'fatigue' and sleep difficulties. Managed to be comical, but completely accurate.

 

Thank you Angela and Marco for your very interesting comments on "subgroups." I've often found myself asking, "Subgroups of what?" It seems premature to be looking for subgroups without having a clearly defined group first.

I found this statement from the CDC's "Absence of Evidence" paper particularly puzzling.

The Lombardi et al. study specifies that samples were selected from
patients fulfilling the 1994 international CFS case definition [23] and the 2003 Canadian
Consensus Criteria for CFS/ME [25]. Lombardi et al. did not specify if patients were
evaluated for exclusionary conditions, or if the study subjects met both definitions, or
which patients met either CFS definition. The 1994 International CFS case definition and
the Canadian Consensus Criteria are different and do not necessarily identify similar
groups of ill persons. Most notably, the Canadian Criteria include multiple abnormal
physical findings such as spatial instability, ataxia, muscle weakness and fasciculation,
restless leg syndrome, and tender lymphadenopathy. The physical findings in persons
meeting the Canadian definition may signal the presence of a neurologic condition
considered exclusionary for CFS and thus the XMRV positive persons in the Lombardi et
al. study may represent a clinical subset of patients [11].

In the last sentence, the authors seem to want to exclude persons meeting the Canadian definition and, at the same time, consider them a subset of CFS -- a masterful piece of doublespeak. Does it make any sense?

 

"Also Marco- LOVED your earlier comment about the Atlanta population in high summer suffering month-long 'fatigue' and sleep difficulties. Managed to be comical, but completely accurate."

Thanks Angela. I'm off now to recline on the veranda with a mint julep!

 

The CCD, Canadian Case Definition, is the clearest, most accurate one we have and should be used as the basis for selecting test subjects. The doctor who presented an excellent webinar a month or more ago on the subject of the different definitions explained thoroughly why the CCD ought to be the common case definition for research. (I'm sorry I have forgotten his name. Can someone help?)

 

That was Chicago's own Leonard Jason, Sing. He's a psychologist at DePaul University. He's also written an excellent paper completely trashing the CDC's revised International definition, AKA Reeves' empirical definition.

In the CDC's XMRV paper, they try to pass off Reeves' empirical as 1994 Fukuda. They ain't the same as Jason has shown. Don't get me started....

 

Hi Jerry,

You know, looking at the paragraph you've quoted again (I've read it a couple of times) - yes- I see what you mean! They actually are claiming Canadian defined patients are both exclusionary for 'CFS' AND THUS (they're the words they use- not OR) represent some 'clinical subset'. That is incoherent.

But before that, note how they claim that Lombardi et al "did not specify if patients were evaluated for exclusionary conditions, or if the study subjects met both definitions, or which patients met either CFS definition..."

Notwithstanding the problem that Lombardi et al, in their supplementary paper, did not say 'BOTH' Fukuda and Canadian (that single word would have saved a lot of problems) or that this latest CDC paper is not actually using Fukuda, but Reeve's 'empiric' criteria, to imply Lombardi et al might not have evaluated for exclusionary conditions is - er- interesting. What 'exclusionary' conditions are they insinuating are present in the Lombardi cohort? Are Lombardi et al not competent enough to exclude correctly?

 

I'm thinking these are still the early studies, where everyone tries PCR first. They must really like PCR.

Nested PCR can be exquisitely sensitive and selective, it also offers great opportunities for excluding things you don't want to find. Part of the problem with old samples is that they have been frozen and thawed, perhaps repeatedly. Another problem is that the collection techniques used at the beginning may not be appropriate for the kind of tests you want to run at a later time. And, a big catch, you can't easily go back and get more to confirm results. If you don't want to find anything, these features offer a kind of safety net.

This brings us to a question I omitted before: what percentage of DNA in cells survives collection and extraction? It is not enough to have a particular weight of DNA fragments; long molecules between sections matched by primers must remain intact. This is an important difference between positive control samples created by spiking and those from clinical infections. Untangling DNA from components of cells can easily damage it. Freezing and thawing also often breaks long molecules. In the published paper, I can find nothing to illustrate concern about these problems. Indeed, the variation in collection techniques points to a lack of concern about preserving possible material in different components of blood until it reaches the bench.

All this is probably excessive analysis w.r.t. CFS as the cohort they describe looks remarkably like the general population, which works 40 hours a week and feels tired at times. Still, if you lump all results together you should still find some background level of infection, based on arguments like those I've made above.

 

Thanks, Angela. My thoughts exactly. To use the late Mayor Daley's term, they're using "insinuendo." Trying to pin these guys down is like eel wrestling. I'm off to watch Wiimbledon now and try to clear my head.

 

"I like the idea of CFS patients catagorising illness as CCCFS or CDCCFS. If all CFS patients put it onto ourselves to subgroup instead of using the general CFS, it would get doctors and the general public more aware of the subgroups"

I'm not disagreeing with your general sentiments but we need to get away from talking about sub-groups at all.

As I said before - sub-groups of what? Conditions which may cause fatigue?

Talking about sub-groups is a cop out. What it really means is that these people have nothing in common apart from the common symptom of fatigue.

Even PEM as a cardinal symptom fails to capture it as discussed ad nauseaum (exertion is misconstrued as physical only and malaise hardly captures the degree of morbidity) and I would much prefer the focus to be on the immune dysfunction.

In fact, perhaps the focus should be on the pathology rather than the symptoms.

I feel researchers and advocates are equally culpable when talking about discrepant findings. I can appreciate the constraints they are under but as long as they use terms like sub-groups, the CFS wastebasket is perpetuated.

Rather than talking about sub-groups, can't those clinicians and researchers dealing with real ME say something like - 'well that patient cohort doesn't look anything like the people I deal with', or more diplomatically 'its difficult to make comparisions if the only symptom studied is fatigue which is a common finding in many illnesses'.

On a personal level, I always use the term ME/CFS when corresponding with officials and medics. In fact I state that I have ME/CFS as described by the clinical defintion in the CCD and do not have ideopathic 'chronic fatigue'. Whether or not this means anything to the bureacrats or medics is irrelevant. I'm lucky to have ME clearly stated on my medical records and I'm damned sure its staying there.

I only use the CFS bit because ME isn't universally recognised. I'd prefer to use ME/CFIDS but CFIDS is rarely recognised in Europe.

I will never use CFS in isolation and thereby perpetuate the nonsense of grouping people together on the basis of fatigue only.

Completely agree. Excellent points. I, too, really do not like PEM and fatigue being the defining markers. I'd only add that neurological symptoms/dysfunction be added to immune system dysfunction. Fatigue is not an accurate term and is a major reason why CFS is not taken seriously by the medical profession and public.