Information on the Science CFS Cohort - Inclusion of Cancer Patients?

[Anika]

I spent a lot of the last day independently cross checking the patient numbers mentioned by Suzanne Vernon in her recent article following the Dutch study. From that, I could verify that at least 4 of the5 patient ID numbers she cited are listed in both the published Science paper or online supplement, and in the online slides presented by Dan Peterson, listing cancer patients. I did not see the 5th patient referenced, WPI 1169, on Peterson's cancer slide
[Please note my initial post indicated I had cross checked and verified all five numbers, and the above reflects a correction. Because 1169 doesn't appear in the paper itself, only in the online materials, my cross check for 1169 only verified that it was somewhere in the Science materials, but it is still not in the Cancer slide.]

A link to the Vernon article is here: http://www.cfids.org/xmrv/022510study.asp
and here is the relevant excerpt:
"The WPI investigators conducted a number of assays to detect XMRV DNA, protein, infectious virus and antibodies against XMRV. I used the patient ID numbers provided in the paper to track results. Of the 101 CFS subjects reported in the paper, results for the various assays are shown for only 32 CFS subjects. Of the 32 CFS subjects whose results for any of the tests are displayed, 12 CFS subjects were positive for XMRV on more than one assay. The other 20 CFS subjects were documented as positive by just one testing method. Using information from a public presentation at the federal CFS Advisory Committee, five of the 12 CFS subjects (WPI1169, 1118, 1150, 1199 and 1125) included in the Science paper were also reported to have cancer – either lymphoma, mantle cell lymphoma or myelodysplasia. This once again raises questions about the lack of detailed clinical characteristics of the CFS subjects included in the Science paper, and the differing public reports about where the samples originated. "

She also provides a link to the slides used that show cancer patients with patient ID numbers:
http://www.hhs.gov/advcomcfs/meetings/presentations/xmrv_cfs.html . The relevant slide is at Part 5, first page.

Assuming no error in the patient numbers provided, there does appear to be a cancer overlap.

This is important to know, and I think demonstrates how important it is to patients as well as researchers that more information be provided about the cohort. I don't know how this would be done to help insure that other researchers are directed to the cohort information as well. Is there a way for WPI to supplement the online supplement?

 

[kolowesi]

Anika cancer patients in the Science study

There is a lot more detail in Dr. Dan Peterson's testimony to the CFSAC meeting in 2009. You probably listened to this already, but just in case, here are some youtube links:


http://www.youtube.com/watch?v=SA-o6QR5rK0
http://www.youtube.com/watch?v=I2EDfuuJoTA&NR=1
http://www.youtube.com/watch?v=F2ZMudHeo_A&NR=1

 

[Lesley]

Anika,

One more bit of information from the WPI website ():

Were any patients with lymphoma mentioned in the XMRV study?
Blood samples from the WPI repository were chosen at random and there were no patients chosen with lymphoma or mention of lymphoma in this study. Another preliminary study was done at a later date that had nothing to do with the XMRV Science publication.

This can only be true if there is some problem with the patient numbers. I hope they will clarify this.

 

[Anika]

Lesley,

My better, detailed comment to you just got eaten by the computer, darn.

But, as you can see from my quotes from you on the Study 4 thread, I really appreciate that you have done the work on the WPI cohort ahead of me. I just verified the re-appearing patient ID numbers. And,on reflection, I don't think it can be explained by typos.

I think some of the problems with cohort description may be growing pains in dealing with the relatively new WPI BioBank. Wasn't the Science paper the first that referred to the WPI biobank samples? There may actually be a wealth of information on the BioBank samples. But it may not have been pulled out and analyzed fully for the Science paper.

The likelihood of ANY initial study coming up with such a dramatic result as reported in Science is so small. Because they were so dramatic the details, including cohorts and methods, are coming under a microscope. And we may see a few blemishes....(but - let me note that I am referring to the cohort description, and not the testing methods here - whole different areas).

A separate thread that looks more closely at the WPI cohort, would probably be helpful. A closer examination of the WPI study and cohort can get lost in the threads on other studies. They focus, appropriately, on issues with the other studies and cohorts.

 

[Lesley]

Anika,

I agree with everything you've said. If you start another thread, I will re-post the information I posted on the Dutch study thread. Or perhaps it would be easier to refocus this thread to include a broader discussion of the Science cohort, instead of just the cancer issue. A moderator could change the title.

I share your interest in this topic, and I feel reasonably competent to discuss it. That is not the case with the testing methods!

Lesley

 

[Hope123]

The best way to handle this is to analyze the data both excluding the people with lymphoma and including the people with lymphoma.

I believe that 20 people had lymphoma (confirm, anyone?); I do have in my notes that Peterson noted all with lymphoma were XMRV (+).

If we assume all 20 were in the Science study and we excluded them from analysis:

1. 68 PCR(+) - 20 = 48 PCR (+)
2. 101 (all CFS pts.) - 20 = 81
3. 48/81= 59% PCR(+)

A slightly smaller % positive but not a huge effect. Note that I'm assuming the cancer cohort is PCR(+) and this might be wrong. They could have been positive by the other tests but no one knows without the raw data.

On a clinical level, I'm not sure whether excluding these folks is the correct thing to do. After all, we're still talking about people who had CFS and had it for 20-odd years before they developed an unusual cancer. (Sure it could be a coincidence but shouldn't we explore the possibilities? But to quell the criticisms, WPI should do a separate analysis without the cancer patients.

 

[Anika]

The best way to handle this is to analyze the data both excluding the people with lymphoma and including the people with lymphoma.

I believe that 20 people had lymphoma (confirm, anyone?); I do have in my notes that Peterson noted all with lymphoma were XMRV (+).

If we assume all 20 were in the Science study and we excluded them from analysis:

1. 68 PCR(+) - 20 = 48 PCR (+)
2. 101 (all CFS pts.) - 20 = 81
3. 48/81= 59% PCR(+)

A slightly smaller % positive but not a huge effect. Note that I'm assuming the cancer cohort is PCR(+) and this might be wrong. They could have been positive by the other tests but no one knows without the raw data.

On a clinical level, I'm not sure whether excluding these folks is the correct thing to do. After all, we're still talking about people who had CFS and had it for 20-odd years before they developed an unusual cancer. (Sure it could be a coincidence but shouldn't we explore the possibilities? But to quell the criticisms, WPI should do a separate analysis without the cancer patients.

Hope123,

Thanks for doing this work. I was just about to send a reply late last night when a slip of the hand "ate my homework." The second time on this thread it's happened to me - I've got to give my brain and computer a rest.

My initial sense, also, was that removing the cancer patients would have diluted some of the positive percentages, but there still would have been an eye-popping result, as your analysis indicates. I checked my print of Peterson's slide showing cancer patients with XMRV, and there were indeed 20. I don't know if this represents all CFS samples in the BioBank known to have developed cancer.

Also, the Cancer slide doesn't show WPI 1169, one of the five referenced by Vernon - I thought I had somehow accounted for this when I was cross checking ID numbers over the weekend, but I only confirmed that 1169 was in the supplement as it wasn't in the paper; still, it's not on the cancer slide. I edited my initial post to reflect this, maybe need to highlight the correction on another post.

The WPI site says that the BioBank samples were collected from 2006 - 2009, and that Peterson's private repository of samples from the 80s through 2005 weren't used in the Science study. (I think to get in the BioBank, new samples and consents had to be provided.) Though they did access the private repository for some tests that were done, not reported in the study.

Clinically, I don't think it makes sense to say a well-defined long-term CFS patient who develops a cancer, doesn't still have CFS, just for that reason. (Although I think there have been some remissions, maybe even recoveries, after cancer treatments in some patients.) But, technically, I think most research studies would exclude cancer patients, at least those not in a documented remission from a CFS cohort. When you do that consistently, the result is that studies don't pick up those CFS patients developing cancer (or heart problems etc. that might account for fatigue) - because presto chango, they no longer have CFS!?

I think I've also heard about the possibility that long-term CFS patients might not meet research criteria and be excluded from longitudinal studies if at some point during the study their symptom count under Fukuda becomes less than 4 of the specified, even if other symptoms are worse. I'm not sure exactly how the definition is applied in those research protocols. It highlights a problem with applying the definition when the illness can go through phases and waxes and wanes.

 

[Gerwyn]

Hope123,

Thanks for doing this work. I was just about to send a reply late last night when a slip of the hand "ate my homework." So I'm trying to recapture my thoughts.

My initial sense, also, was that removing the cancer patients would have diluted some of the positive percentages, but there still would have been an eye-popping result. I checked my print of Peterson's slide showing cancer patients with XMRV, and there were indeed 20. I don't know if this represents all CFS samples in the BioBank known to have developed cancer.

Also, the Cancer slide doesn't show WPI 1169, one of the five referenced by Vernon - I thought I had somehow accounted for this when I was cross checking ID numbers over the weekend, but I can't confirm right now that I did - I believe that's the number that showed up only in the Supplement, not the actual paper, but it still isn't on the Peterson cancer slide. I may go back and edit my initial post to reflect this.

The WPI site says that the BioBank samples were collected from 2006 - 2009, and that Peterson's private repository of samples from the 80s through 2005 weren't used in the Science study. (I think to get in the BioBank, new samples and consents had to be provided.) Though they did access the private repository for some tests that were done, not reported in the study.

Clinically, I don't think it makes sense to say a well-defined long-term CFS patient who develops a cancer, doesn't still have CFS, just for that reason. (Barring a recovery from CFS after cancer treatments, which I think may have been reported in some cases, not I think from Dr. Peterson's patients.) But, technically, I think most research studies would exclude them from a CFS cohort. When you do that consistently, the result is that studies don't pick up those CFS patients developing cancer (or heart problems etc. that might account for fatigue) - because presto chango, they no longer have CFS!!??

I think I've also heard about the possibility that long-term CFS patients might not meet research criteria and be excluded from longitudinal studies if at some point during the study their symptom count under Fukuda becomes less than 4 of the specified, even if other symptoms are worse. I'm not sure exactly how the definition is applied in those research protocols, but it highlights a problem with applying the definition when the illness can go through phases and waxes and wanes.

petersons samples were not used in the science study as far as i can ascertain

 

[Hope123]

Hope123,

Also, the Cancer slide doesn't show WPI 1169, one of the five referenced by Vernon - I thought I had somehow accounted for this when I was cross checking ID numbers over the weekend, but I can't confirm right now that I did - I believe that's the number that showed up only in the Supplement, not the actual paper, but it still isn't on the Peterson cancer slide. I may go back and edit my initial post to reflect this.

Clinically, I don't think it makes sense to say a well-defined long-term CFS patient who develops a cancer, doesn't still have CFS, just for that reason. (Barring a recovery from CFS after cancer treatments, which I think may have been reported in some cases, not I think from Dr. Peterson's patients.) But, technically, I think most research studies would exclude them from a CFS cohort. When you do that consistently, the result is that studies don't pick up those CFS patients developing cancer (or heart problems etc. that might account for fatigue) - because presto chango, they no longer have CFS!!??

I think I've also heard about the possibility that long-term CFS patients might not meet research criteria and be excluded from longitudinal studies if at some point during the study their symptom count under Fukuda becomes less than 4 of the specified, even if other symptoms are worse. I'm not sure exactly how the definition is applied in those research protocols, but it highlights a problem with applying the definition when the illness can go through phases and waxes and wanes.

Thanks for confirming that '20' number. Glad to know I wasn't hallucinating.

Actually what I just did is pretty common in science papers. It's a simple "sensitivity analysis" which is used by researchers when they aren't sure of the effect of a particular group of samples. So they throw them out and see how it affects the overall results. Then they write up the results with both numbers for people to judge.

And I agree whole-heartedly about what you said re: excluding people who develop other diagnoses or conditions. In fact, the 3-yr. follow-up study of Wichita subjects which the CDC did threw out people who developed say thyroid disease, sleep apnea, or even were overweight. Then in their discussion, they mention that some of these folks likely would still be regarded as having 'CFS' by their own docs in practice. Howver, in the summing up, the message they gave were that people "recovered" rather than alluding to these areas. (Nevermind that they never asked these subjects DIRECTLY if they recovered, they just used the criteria as you stated. And never mind that in fact there are very few CFS follow-up studies beyond 5 years! And the few beyond 5 yrs. only look at a vague notion of "recovery' and don't look at co-morbid illnesses developing in the meantime much.)

 

[Gerwyn]

Blood samples from the WPI repository were chosen at random and there were no patients chosen with lymphoma or mention of lymphoma in this study. Another preliminary study was done at a later date that had nothing to do with the XMRV Science publication.

 

[Hope123]

Blood samples from the WPI repository were chosen at random and there were no patients chosen with lymphoma or mention of lymphoma in this study. Another preliminary study was done at a later date that had nothing to do with the XMRV Science publication.

I hope this is true but the WPI's unclear statements, changing of statements, and dribbling out of information makes it hard for even those of us who are supportive of them to trust everything they do.

Why didn't Dr. Peterson state this clearly during CFSAC? My brain's fuzzy but I don't remember him saying clearly that these were separately analyzed. If criticism came out about this, the WPI needs to do more than post this info on their site. They need to do a formal letter or correction somewhere in a printed journal. (Please correct me if they've done so.)

Also, they keep talking about other studies but where's the published data? There are many types of ways to report data. They could do a "short report" or "letter" to a journal and write solely about Peterson's lymphoma results or about the "95%" antibody figure. They need to come out with something soon fast as I am concerned we will lose momentum/ credibility with CFS research in general.

 

[Gerwyn]

I hope this is true but the WPI's unclear statements, changing of statements, and dribbling out of information makes it hard for even those of us who are supportive of them to trust everything they do.

Why didn't Dr. Peterson state this clearly during CFSAC? My brain's fuzzy but I don't remember him saying clearly that these were separately analyzed. If criticism came out about this, the WPI needs to do more than post this info on their site. They need to do a formal letter or correction somewhere in a printed journal. (Please correct me if they've done so.)

Also, they keep talking about other studies but where's the published data? There are many types of ways to report data. They could do a "short report" or "letter" to a journal and write solely about Peterson's lymphoma results or about the "95%" antibody figure. They need to come out with something soon fast as I am concerned we will lose momentum/ credibility with CFS research in general.

Ietersons biobank was not used I think people are trying to muddy the water This info has been with .us since the science publication But they did do a seperate analysis for another project I am also confused because this is clearly stated why is Vernon not asking questions about the other studies who provide no patient info at all?

 

[Lesley]

Since Peterson's repository goes through 2005 and the WPI biobank starts in 2006, I think samples from Peterson's patients taken in 2006 or later are probably in the WPI biobank. It would not surprise me if this is where some confusion comes from.

To me the bigger issue is WPI's statement on their website that no lymphoma patients were in the study, and their failure to respond to the issue of the matching patient numbers in the Science paper and Peterson's cancer slide. Given the way they have responded in the past, their silence concerns me.

 

[Samuel]

And I agree whole-heartedly about what you said re: excluding people who develop other diagnoses or conditions. In fact, the 3-yr. follow-up study of Wichita subjects which the CDC did threw out people who developed say thyroid disease, sleep apnea, or even were overweight. Then in their discussion, they mention that some of these folks likely would still be regarded as having 'CFS' by their own docs in practice. Howver, in the summing up, the message they gave were that people "recovered" rather than alluding to these areas.

So you are saying that if they developed apnea, they were basically described as recovered to a casual reader?

That needs to be shouted from the rooftops. Loudly.

You just contributed to my list of fallacies. Thanks.

 

[Anika]

Since Peterson's repository goes through 2005 and the WPI biobank starts in 2006, I think samples from Peterson's patients taken in 2006 or later are probably in the WPI biobank. It would not surprise me if this is where some confusion comes from.

To me the bigger issue is WPI's statement on their website that no lymphoma patients were in the study, and their failure to respond to the issue of the matching patient numbers in the Science paper and Peterson's cancer slide. Given the way they have responded in the past, their silence concerns me.

Of the three conflicting statements - patient numbers in the Science paper, Peterson's slides on cancer patients with IDs, and the WPI website statement that no patients with lymphoma were in the study, isn't the website's general statement most likely to be wrong? The Science study probably did pick samples at random from the Biobank, but if Peterson's slides for the cancer study are correct, some of those samples happened also to have lymphoma or other cancer history.

There should be a couple of grad students at least scouring the cohort data, and then there should be a more detailed and authoritative source of information somewhere that presents it. I'd be happy to make an additional contribution to help make that happen.

Apart from researchers who'd like more cohort information, most all of us patients would really like to know more about the cohort, not to mention the BioBank generally. It's there to be a resource for future studies and the CFS patient samples may have some of the more comprehensive immune and other testing.

No one is trying to replicate the other studies - the Science study is still king of the hill. And Science is the only study published on that cohort. I think the interest in information about the Science cohort is appropriate and good news for us.

 

[Gerwyn]

Of the three conflicting statements - patient numbers in the Science paper, Peterson's slides on cancer patients with IDs, and the WPI website statement that no patients with lymphoma were in the study, isn't the website's general statement most likely to be wrong? The Science study probably did pick samples at random from the Biobank, but if Peterson's slides for the cancer study are correct, some of those samples happened also to have lymphoma or other cancer history.

There should be a couple of grad students at least scouring the cohort data, and then there should be a more detailed and authoritative source of information somewhere that presents it. I'd be happy to make an additional contribution to help make that happen.

Apart from researchers who'd like more cohort information, most all of us patients would really like to know more about the cohort, not to mention the BioBank generally. It's there to be a resource for future studies and the CFS patient samples may have some of the more comprehensive immune and other testing.

No one is trying to replicate the other studies - the Science study is still king of the hill. And Science is the only study published on that cohort. I think the interest in information about the Science cohort is appropriate and good news for us.

do we know what the exlusion criterea were the wpi statement and the science study seem to match dr peterson seems the odd one out.i would also like to know a LOT more about the patient cohorts in the other studies yet Vernon seems completely silent on this

 

[usedtobeperkytina]

WPI needs to make a statement in Science Journal to clear this up. If there was a mistake, then correction is in order with explanation of how it occurred. If the claims of others are false, then it would be good to explain how it is that Vernon got it messed up.

PR lesson: best to have the information come from you, where you can control it and set the tone, than to have everyone find it out on their own, when they can then claim cover up.

Tina

 

[Lesley]

I agree Tina. And as much as I hang on every word uttered by anyone connected to this study, all the presentations about XMRV and discussions of unpublished data have really hurt them.

 

[Anika]

I commented on this immediately after Dr. Vernon posted the note. They have already corrected it on both the Web site and Facebook note. It is 4 instead of 5.

Thank you, charityfundraiser! It sounds like you were ahead of the pack. If I did Facebook, I would have known this and saved myself a lot of work. At least now I know I don't have to go back and check a third time.

It is so easy to go cross-eyed doing this kind of thing - that's why it's important whenever possible to have multiple sets of eyes going over things.

Anika

 

[Gerwyn]

I agree Gerwyn. It would be great to see Dr Vernon turn her attention to the Dutch and UK studies. For instance Wessely's frozen samples seem to have originated from these two cognitive behaviour therapy studies:



More than 400 patients were involved in these two studies but only 186 samples made it into the XMRV study. Which patients did Wessely select and why? Is a cognitive behaviour therapy cohort which excludes people who refuse CBT and people who are too ill to attend 12-15 sessions of CBT over 6 months, really a representative cohort for a retroviral study? Does it resemble the WPI cohort in any way?

The 19 year old Dutch 'Oxford' samples seem to have originated from these two studies:



A thorough analysis of these 4 studies is overdue. If Dr Vernon doesn't have any comments perhaps these studies could be posted to the library and we could analyse them ourselves.

Could you get me the links please