99/101 CFS patients in SCIENCE Paper had XMRV infection

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DysautonomiaXMRV

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Dr Mikovits XMRV talk: Q&A Session

XRMV in 33 PCR Negative CFS Patients from Science paper

19/33 Antibodies in Plasma
30/33 Transmitable Virus in Plasma
10/33 Protein Expression (Latent Virus)


Which means....

Add these to the people who were PCR positive in the same Science paper

99 out of 101 people in SCIENCE Paper had XMRV which equates to 10 to the minus 35 chance of having CFS and not having XMRV in this study.

NB: Editor of SCIENCE paper took out 'Virtually Impossible' to not have had CFS without having XMRV - in the study in the Science Paper and made the WPI write

:eek: Then..... ;)
 

Dainty

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Just to clarify, the study was done with CFS patients who matched the Canadian criteria for CFS, correct? It seems those statistics would be expected to hold true for those who meet the Canadian criteria and might possibly be different for those who do not.

Still, those are pretty striking odds. Thanks for posting it!
 

Anika

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Virus Culture 30 plus 68 PCR is 98? where is 99th?

Dr Mikovits XMRV talk: Q&A Session

XRMV in 33 PCR Negative CFS Patients from Science paper

19/33 Antibodies in Plasma
30/33 Transmitable Virus in Plasma
10/33 Protein Expression (Latent Virus)


Which means....

Add these to the people who were PCR positive in the same Science paper

99 out of 101 people in SCIENCE Paper had XMRV which equates to 10 to the minus 35 chance of having CFS and not having XMRV in this study.

NB: Editor of SCIENCE paper took out 'Virtually Impossible' to not have had CFS without having XMRV - in the study in the Science Paper and made the WPI write

:eek: Then..... ;)
At first I couldn't figure this out. Then I realized the positive PCR results (68?) had to be added, but if you add the positive culture, they only add up to 98. So, if I am counting right, there appears to be a sample that had a positive result on another test (not culture or PCR, but only another test).

If that's right - I wonder if that is why they are saying they are now using a newer more sensitive culture test? Perhaps it would pick up all the PCR plus culture from original sample, plus the odd one out.

Or maybe I am missing something....could well be.

Anika
 

kurt

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Can somebody explain the probability?
Yea, how did that calculation work Dys? Were you talking about a probability, like a T-score maybe?

By my figuring there was a 2% chance of not having XMRV if you had CFS in that study.
 
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99 out of 101 people in SCIENCE Paper had XMRV which equates to 10 to the minus 35 chance of having CFS and not having XMRV in this study.
Dr. Mikovits isn't a statistician and got this a bit mixed up. First, the additional 31 positives were after the paper was written, and the 10^-35 was in the original paper. So the 10^35 refers to the 68/101 positives. 10^-35 is the probability that the correlation between XMRV and CFS occurred due to random chance. Basically it is "almost possible" that it is just a coincidence that most CFS patients had XMRV and most controls didn't.
 

kurt

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Dr. Mikovits isn't a statistician and got this a bit mixed up. First, the additional 31 positives were after the paper was written, and the 10^-35 was in the original paper. So the 10^35 refers to the 68/101 positives. 10^-35 is the probability that the correlation between XMRV and CFS occurred due to random chance. Basically it is "almost possible" that it is just a coincidence that most CFS patients had XMRV and most controls didn't.
That's what I thought, he was referring to a statistical test, which is purely a mathematical probability that groups are correlated or uncorrelated. So this does not take into account any of the science, for example, the probability that this was a false positive. That would be entirely different. And it is NOT the probability of having CFS and not having XMRV in the study, that really was 2%.
 

dannybex

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Huh?

That's what I thought, he was referring to a statistical test, which is purely a mathematical probability that groups are correlated or uncorrelated. So this does not take into account any of the science, for example, the probability that this was a false positive. That would be entirely different. And it is NOT the probability of having CFS and not having XMRV in the study, that really was 2%.
Okay, so now I'm confused.

Whatever the 'truth' is, or the facts are...then perhaps the title of this thread should be changed if possible, to reflect that...

???

thanks in advance,

d.
 

natasa778

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All these additional tests... I am wondering if they were carried out on healthy samples. In other words can we be sure that only 3.7% of healthy individuals have the virus. How many of 96.3% of them that tested negative on PCR test would have been positive on these additional tests?
 

fds66

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Natasha, somewhere I saw that the controls were negative on at least some of those other tests but at the moment I don't recall where I saw that information. If I find it I will post a link - maybe someone else can remember that. It certainly wasn't in the original paper because I believe they did these tests to the patients that were negative on the original paper.
 

bullybeef

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I have had the following response to XMRV by Dr. Bell from early Nov '09. It does come across as relevant and I'll be surprised if this has never been posted before:

XMRV by Dr. David Bell.

In the CFSAC meeting October 29, Dr. Dan Peterson filled in several blanks. I will present much of what he said at the lecture December 6th. But here is the important piece:

XMRV DNA was found from 68 of 101 patients (67%), and this was in the Science paper. That leaves 33 patients with CFS who were negative. But on further testing 19 of these 33 are XMRV antibody positive, 30 of these 33 had transmissible virus in the plasma, and 10 of these 33 had protein expression. Overall 99 of the 101 patients show evidence of XMRV infection.

These results have interesting implications. The most important is that there is not a simple test now that will tell you if you have XMRV or if the virus is active in your system. And we need a good control study using all three measures to accurately know control presence of the virus. This is not a fly-by-night operation. Right now, it is necessary to do several tests to know the XMRV status:

a) DNA by PCR
b) Viral infectivity
c) Detection of viral proteins
d) Antibody to the XMRV envelope

As time goes on and we learn more, this process will be simplified. What I do not want is poor science that will cast doubts on an illness that already has its fill of doubters. Let’s do it right from the beginning. If by doing it right XMRV proves not to be the cause, so be it. Something is the cause.

Dr. Coffin of Tufts University and the National Cancer Institute presented some very interesting observations. He is a true veteran (45 years) of retroviral research. There have been comments from various people saying that there are lots of viruses associated with CFS, so what is the big deal? Among the points raised by Dr. Coffin:

A) it is relatively difficult to isolate live retrovirus from patients with HIV infection, but relatively easy to isolate live XMRV in CFS. There is a high percentage of infected cells.

B) The percentage of positive controls for XMRV not that much different between CFS controls and prostate cancer controls, 4 or 5%. However, much work needs to be done to verify the control incidence. This is particularly true because the nations' blood supply could be contaminated. (By the way, no patient with ME/CFS should donate blood - personal opinion) The Japanese Red Cross has said that there is a "low incidence" of XMRV in their blood supply.

C) Could some mouse have contaminated the tests by shedding some XMRV in the lab? XMRV is a big family of "simple" retroviruses. In the XMRV strains isolated in CFS patients there is a 0.3% diversity from what are carried in mice - a relatively large diversity. This virus does not vary with replication as much as HIV does. In two weeks of HIV replication the diversity is greater than 0.3%. And this is both good and bad news. Good news for the ultimate production of a vaccine. The diversity has been a roadblock in the production of a HIV vaccine. Bad news for the antiviral therapy implications. But that is way down the road.

D) Dr. Coffin presented a slide of the many things we do not know about XMRV. There are lots of things to do.


E) Dr. Coffin mentioned that there is excitement in the retroviral scientific community - very good news for the ME/CFS community. We will get confirmation, or lack of confirmation, from many good scientists. It will be difficult for biased scientists to squelch this, if it is, in fact, true.
The statement that made my socks roll up and down all by themselves was a reply to a question from the committee. Dr. Coffin said "This was as good as it gets for a first paper, but it is still just a first paper."

Theory of Mechanism of XMRV and ME/CFS
Dr. Peterson presented an update of a theory of mechanism that has been circulating for many years. Ironically enough, it was once called the "X factor theory."

Step 1: Infection with XMRV. No idea of how this happens. Could it be that the tiny XMRV piggybacks onto some huge, lumbering herpes virus like EBV, or HHV6. That mechanism is known to occur. Lots of other possibilities
Step 2: Infection of B, T lymphocytes and NK cells. Dr. Klimas has said that up to 70% of lymphocytes are "activated". Something is going on.
Step 3: Impairment of NK cell number and activity. Because of the retroviral infection, the NK cells are impaired. This is parallel to what is known to happen in HIV disease with the CD4 lymphocytes

As a result of poor NK cell and function (and other T & B cell problems) the person now has an immunodeficiency. NK cells are important in the control of herpes viruses and other agents.
Step 4: Reactivation of other agents. Increased viral load of EBV and other agents cause cytokine production, activation of 2'-5'A Synthetase, RNAse L which contribute to symptoms. It is interesting to note that AIDS patients feel better with suppression of secondary infections. This could explain why treatment with antibiotics, antivirals, gamma globulin and other agents make some patients with ME/CFS feel better for a while.

History
Archived video of Dr. Daniel Peterson's presentation of the CFSAC 10/29/09 should be available at: http://videocast.nih.gov/PastEvents.asp. It is my personal opinion that it is history in the making. Time will tell.

And while I am making rash predictions, let’s talk about the name of this illness. It has been a favourite topic of mine since the "Disease of a Thousand Names." Chronic fatigue syndrome is a miserable name. I think that XMRV is going to turn out to be the puppet-master that pulls the strings of illnesses variously called CFS, ME, fibromyalgia, atypical multiple sclerosis, chronic mononucleosis…. And if it does, the name should be XAND, for Xmrv Associated Neuroimmune Disease. I heard Mrs. Annette Whittemore use this term and it feels right. History.
 

garcia

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At first I couldn't figure this out. Then I realized the positive PCR results (68?) had to be added, but if you add the positive culture, they only add up to 98. So, if I am counting right, there appears to be a sample that had a positive result on another test (not culture or PCR, but only another test).

If that's right - I wonder if that is why they are saying they are now using a newer more sensitive culture test? Perhaps it would pick up all the PCR plus culture from original sample, plus the odd one out.

Or maybe I am missing something....could well be.

Anika
You are nearly there. Lets look at the 33 people who were PCR-negative:

19/33 Antibodies in Plasma
30/33 Transmitable Virus in Plasma
10/33 Protein Expression (Latent Virus)
To show evidence of infection all you need is one of the above 3 measures to be positive. So how many in total of the 33 were positive? Clearly its more than 30, since 30 test positive for transmissible virus in plasma. Also it must be less than 33 since there are only 33 people. And actually the number is 31 (though it is not explicity stated anywhere), since 99-68 = 31. This means 1 person didn't have transmissible virus in plasma, but did test positive for either antibodies or protein expression (or both). In other words 31/33 of the PCR-negative group show evidence of infection.

Think Venn diagrams.
 

Hope123

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Just to clarify, the study was done with CFS patients who matched the Canadian criteria for CFS, correct? It seems those statistics would be expected to hold true for those who meet the Canadian criteria and might possibly be different for those who do not.

Still, those are pretty striking odds. Thanks for posting it!
From the multiple versions I've heard of the WPI study, it was done with patients who matched the 1994 Fukuda criteria, some of whom also matched the Canadian criteria. Patients were hand-picked by Dr. Peterson I believe.

Dr. Mikovits isn't a statistician and got this a bit mixed up. First, the additional 31 positives were after the paper was written, and the 10^-35 was in the original paper. So the 10^35 refers to the 68/101 positives. 10^-35 is the probability that the correlation between XMRV and CFS occurred due to random chance. Basically it is "almost possible" that it is just a coincidence that most CFS patients had XMRV and most controls didn't.
Yes, I agree. Dr. M. is not a statistician and mixed up the numbers like a lot of well-educated but non-statistics oriented people do. How they calculate this is first by ASSUMING that the results are purely due to random chaos. So the chance of seeing the percentages of 68% in CFS vs. 4% in normals due just to random chaos is very, very low - the 8X 10 to the 35 number. If random chaos is very unlikely to explain the results then it is more likely the association is true and has some merit to it. Note that many studies use a p-value of 0.05 (this is 5 X 10 to the -2) as their gauge so 8 X10 to the -35 is much much better.

The actual STRENGTH of the association is measured by the odds ratio of 54.1 -- that is people exposed to XMRV are 54 times more likely to have CFS than those who have not been exposed. 54 times is a big number.

For p-values: http://en.wikipedia.org/wiki/P-value
For odds ratio (OR): http://www.childrens-mercy.org/stats/definitions/or.htm

If you understand what we've tried to explain, give yourself a pat on the back. You've done better than probably 90% of MDs.
 

natasa778

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sorry if this has been posted, but there has been lots of discussion (on this thread?) about whether they tested healthy controls for antibodies, as they did with CFS samples. just read Judy's presentation she said yes, in total about 60-70 of healthy controls - who were negative on PCR, have also tested negative for antibodies.
 

garcia

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sorry if this has been posted, but there has been lots of discussion (on this thread?) about whether they tested healthy controls for antibodies, as they did with CFS samples. just read Judy's presentation she said yes, in total about 60-70 of healthy controls - who were negative on PCR, have also tested negative for antibodies.
Natasa, I made this mistake too. The "antibodies" that Judy Mikovits was talking about were exogenous antibodies to viral proteins, basically added to show if there were viral proteins present.

What we generally mean when we talk about antibodies is the human endogenous antibody response, i.e. to show whether the body has mounted an immune response to the virus. I can't find any evidence of the controls having had their antibodies tested.
 

natasa778

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Garcia, yes but isn't that the same thing that was used to double-check CFS samples? When they said that "19 of these 33 (PCR-negative CFS samples) are XMRV antibody positive" - could that mean simply that they also added exogenous XMRV antibody and this revealed that there were viral proteins present in their blood? Or did they detect endogenous antibodies in CFS sample?
 

garcia

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When they said that "19 of these 33 (PCR-negative CFS samples) are XMRV antibody positive" - could that mean simply that they also added exogenous XMRV antibody and this revealed that there were viral proteins present in their blood? Or did they detect endogenous antibodies in CFS sample?
They are talking about endogenous antibodies when they talk about the 19/33 being antibody positive.

The antibodies for the protein are to do with the 10/33 who had Protein positive expression in Decitibine. First they added Decitibine to de-methylate, then they added exogenous antibodies to show whether the XMRV proteins were expressed.

 

Advocate

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They are talking about endogenous antibodies when they talk about the 19/33 being antibody positive.

The antibodies for the protein are to do with the 10/33 who had Protein positive expression in Decitibine. First they added Decitibine to de-methylate, then they added exogenous antibodies to show whether the XMRV proteins were expressed.

Hey, Garcia, thanks for clearing that up!