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How would you design a follow up study to WPI research?
- Thread starter Levi
- Start date
I have no idea how I would design a second study
but I thought you might find this interesting. The WPI posted this on their Facebook page about a week ago.
"Patient samples were donated from different locations around the US. This was not one cohort. All patients met the Fakuda and Canadian definitions for CFS and the study included age and sex matched controls with zip codes but Science did not feel that information was important to this publication. Not all patient samples that were positive had the biological markers of low NK cell function and RNase L defect."
I've had CFS for over two decades and lost my husband, who showed mild signs of CFS, to a rare non-hodgkin's lymphoma several years ago. So the inclusion of the lymphoma patients was obviously of great interest to me.
but I thought you might find this interesting. The WPI posted this on their Facebook page about a week ago.
"Patient samples were donated from different locations around the US. This was not one cohort. All patients met the Fakuda and Canadian definitions for CFS and the study included age and sex matched controls with zip codes but Science did not feel that information was important to this publication. Not all patient samples that were positive had the biological markers of low NK cell function and RNase L defect."
I've had CFS for over two decades and lost my husband, who showed mild signs of CFS, to a rare non-hodgkin's lymphoma several years ago. So the inclusion of the lymphoma patients was obviously of great interest to me.
Just thinking outloud here.
It's like to see a study that compares many different groups and shows if it is a current active infection or an old one.
The groups I'd like to see included would be
1. ME patients from the Royal Free Outbreak and other outbreaks (outside the USA)
2. ME patients who do not identify with any specific outbreak (outside the USA)
2. USA CFS outbreak patients (split into groups)
3. PWCFS who meet the Canadian criteria - acute onset
4. PWCFS who meet the Canadian criteria - slow onset
(5. and 6. the same to the CDC criteria)
7. A control group who have CF (idiopathic)
8. A control group who have depression who do not meet any criteria above
9. A control group of the general public (who are not relatives, same age and sex and location)
We obviously need the date on with and without Lymphoma and length of illness.
It's like to see a study that compares many different groups and shows if it is a current active infection or an old one.
The groups I'd like to see included would be
1. ME patients from the Royal Free Outbreak and other outbreaks (outside the USA)
2. ME patients who do not identify with any specific outbreak (outside the USA)
2. USA CFS outbreak patients (split into groups)
3. PWCFS who meet the Canadian criteria - acute onset
4. PWCFS who meet the Canadian criteria - slow onset
(5. and 6. the same to the CDC criteria)
7. A control group who have CF (idiopathic)
8. A control group who have depression who do not meet any criteria above
9. A control group of the general public (who are not relatives, same age and sex and location)
We obviously need the date on with and without Lymphoma and length of illness.
I want them to look at the genome and find out for sure that it's exogenous. If it happens to be located on the same place in the genome of all individuals it's endogenous and that is a whole different picture. To me that's huge and I'd like that done first.
Alice and Jen,
I hope we are lucky enough that what each if you proposes is researched.
Alice, I definately think the seperate UK ME groups is a good idea. Making the comparisons you state would help define which illness is what. My biggest fear is that there will be studies where so many different types of patients are lumped together that the results get diluted into insignificance or ambiguity.
Jen, you are so right - that issue is BIG.
Thanks,
Nina
I hope we are lucky enough that what each if you proposes is researched.
Alice, I definately think the seperate UK ME groups is a good idea. Making the comparisons you state would help define which illness is what. My biggest fear is that there will be studies where so many different types of patients are lumped together that the results get diluted into insignificance or ambiguity.
Jen, you are so right - that issue is BIG.
Thanks,
Nina
I believe the published study just tested for active infections?
Anyway, Joey posted a few days ago that Dr. Peterson told him his carefully selected cohort came back at 90% positive, while other tested groups came back at about 60% positive. And according to Mikovitz, all patients were screened to fit both the Fakuda and Canadian definitions...so there definitely needs to be more follow-up testing done by independant research groups.
Were the 90% the most severely ill -- or ill for the longest period of time, while the 60% were less disabled or perhaps more recently diagnosed?
Questions...questions...
d.
p.s. I too would appreciate more info from Jen. Me don't understand scientific lingo very well, as I'm sure many would confirm.
Anyway, Joey posted a few days ago that Dr. Peterson told him his carefully selected cohort came back at 90% positive, while other tested groups came back at about 60% positive. And according to Mikovitz, all patients were screened to fit both the Fakuda and Canadian definitions...so there definitely needs to be more follow-up testing done by independant research groups.
Were the 90% the most severely ill -- or ill for the longest period of time, while the 60% were less disabled or perhaps more recently diagnosed?
Questions...questions...
d.
p.s. I too would appreciate more info from Jen. Me don't understand scientific lingo very well, as I'm sure many would confirm.
They are making the assumption that this virus actually causes the symptoms. They need to somehow figure out if that is the case. All viruses are different, but the symtom complext of CFS is very profound. Its kind of odd that the symptoms caused by the the other human retroviruses aren't really that profound - I mean you have have HIV and be pretty much normal before you get AIDS. And even then the symptoms seem to be caused by the other AIDS infections, not HIV... HTLV causes no symptoms in most people, etc... I'm not sure how they prove a virus causes symptoms unless they can get rid of it and people get better - without a sure shot treatment it would be a tough experiment.
They also need to figure out how people got it.
There are too many inconsistencies with the transmission. Most people in those outbreaks didn't get it sexually or via a transfusion. And likely neither did sporadic cases. Kids with no sexual exposure, people with no risky behavior or hospitalization requiring transfusion. Spouses that never got sick despite decades of sexual contact, etc... So for a virus that supposedly is communicated only via bodily fluids, that doesn't make a whole lot of sense.
If they are gonna claim you only get it if you have genetic predisposition, they need to figure out what that genetic predisposition is. They already stated in their paper that the defective RNASE-L gene that they thought was responsible for allowing infection in prostate cancer wasn't consistently present in CFS. So is there another phenomenon there on another gene? An environmental co-factor that allows infection in some but not others? A co-infection?
And finally, they need to test a whole lot more people both who have symptoms of CFS and who are in the general public. People in large cities, people in rural areas, people of different sexual orientations, people who are not sexually active yet, high risk people (IV drug users, people with multiple partners, etc..) and they need to just screen the blood bank. Test people who are infected with HIV. Test people with other major illnesses.
ummm I think thats it for now
They also need to figure out how people got it.
There are too many inconsistencies with the transmission. Most people in those outbreaks didn't get it sexually or via a transfusion. And likely neither did sporadic cases. Kids with no sexual exposure, people with no risky behavior or hospitalization requiring transfusion. Spouses that never got sick despite decades of sexual contact, etc... So for a virus that supposedly is communicated only via bodily fluids, that doesn't make a whole lot of sense.
If they are gonna claim you only get it if you have genetic predisposition, they need to figure out what that genetic predisposition is. They already stated in their paper that the defective RNASE-L gene that they thought was responsible for allowing infection in prostate cancer wasn't consistently present in CFS. So is there another phenomenon there on another gene? An environmental co-factor that allows infection in some but not others? A co-infection?
And finally, they need to test a whole lot more people both who have symptoms of CFS and who are in the general public. People in large cities, people in rural areas, people of different sexual orientations, people who are not sexually active yet, high risk people (IV drug users, people with multiple partners, etc..) and they need to just screen the blood bank. Test people who are infected with HIV. Test people with other major illnesses.
ummm I think thats it for now
I've expressed this view elsewhere but I now feel so strongly about it that I'm saying it again on this relevant thread that I've just found.
The very first thing they should be testing in my opinion is for XMRV infection in a wide range of ideopathic neuro-immune conditions, cancers, and any other conditions with an unexplained rise since the 1980s.
It's crucial to get early knowledge of what other conditions are related to XMRV infection for so many reasons:
- List of other associated conditions would give huge clues as to what CFS actually is, and how XMRV might be operating
- Would enable an overall assessment of the risk posed by XMRV
- Would provide a context in which to assess the significance of the WPI findings
- Would bring in all of the detailed knowledge already gained from study of other conditions
- At this stage, gathering as much knowledge as possible is far more important than obtaining rock-solid proof of the one piece of knowledge we have.
- Gaining precise knowledge is in any case impossible until tests have been refined
- Would have the biggest potential impact of any study in changing the whole direction of future research towards the most relevant/important areas
- Would bring in loads of funding for research into other conditions
There's a very good chance of finding other associated conditions because:
- XMRV is already linked with fibromyalia, autism and prostate cancer, and suspected to be linked to some Multiple Sclerosis, Gulf War Syndrome, Childhood Alzheimer's, Asperger's and Irritable Bowel Syndrome, suggesting it may be implicated in a wide range of conditions
- There are many ideopathic conditions with similar definitions to CFS, which have all risen in incidence during the same time period, with similar gender biases
- There is no reason to believe XMRV is not associated with other conditions
A quick, imprecise, wide-ranging study is quite simply the right, best, most efficient way to begin exploring a problem space. In my line of work, it's called a "horizontal slice". You would also conduct a "vertical slice" study of CFS, just as Alice_Band has outlined very well in this thread. Alice's approach would yield a huge amount of information about what CFS and XAND are and are not, for the same reasons that the horizontal slice would yield loads of information: you can cross-reference the results with all the other known data about the various categories to reveal a wealth of clues.
The need for an overview is so urgent that it should be done right away, 'quick and easy' - extreme scientific rigour is not a priority in the first instance. A similar but slower, more rigorous study could proceed in parallel, and more rigorous condition-specific studies would then follow. For the first, quick, urgent test, just 10 samples from each condition would be enough to give a good idea of the overall picture.
Of course we on this forum are liable to be blinded somewhat by our interest in focusing on CFS, but surely we can see there could be much wider issues at stake, potentially affecting hundreds of millions of people worldwide. I find the fact that this hasn't been a major immediate focus of research (not having been mentioned yet in any prospective study) quite terrifying. It tells me there is "nobody driving". It tells me there is no intelligent co-ordination of at least this particular area of medical research. It tells me that there is no overall focus on the speed and efficiency of how to gain knowledge vital to the lives of people who are suffering and dying now. And it tells me why it takes decades rather than years to realise the benefits of medical breakthroughs.
To whom could comments, suggestions, recommendations from this thread be communicated, I wonder?...
The very first thing they should be testing in my opinion is for XMRV infection in a wide range of ideopathic neuro-immune conditions, cancers, and any other conditions with an unexplained rise since the 1980s.
It's crucial to get early knowledge of what other conditions are related to XMRV infection for so many reasons:
- List of other associated conditions would give huge clues as to what CFS actually is, and how XMRV might be operating
- Would enable an overall assessment of the risk posed by XMRV
- Would provide a context in which to assess the significance of the WPI findings
- Would bring in all of the detailed knowledge already gained from study of other conditions
- At this stage, gathering as much knowledge as possible is far more important than obtaining rock-solid proof of the one piece of knowledge we have.
- Gaining precise knowledge is in any case impossible until tests have been refined
- Would have the biggest potential impact of any study in changing the whole direction of future research towards the most relevant/important areas
- Would bring in loads of funding for research into other conditions
There's a very good chance of finding other associated conditions because:
- XMRV is already linked with fibromyalia, autism and prostate cancer, and suspected to be linked to some Multiple Sclerosis, Gulf War Syndrome, Childhood Alzheimer's, Asperger's and Irritable Bowel Syndrome, suggesting it may be implicated in a wide range of conditions
- There are many ideopathic conditions with similar definitions to CFS, which have all risen in incidence during the same time period, with similar gender biases
- There is no reason to believe XMRV is not associated with other conditions
A quick, imprecise, wide-ranging study is quite simply the right, best, most efficient way to begin exploring a problem space. In my line of work, it's called a "horizontal slice". You would also conduct a "vertical slice" study of CFS, just as Alice_Band has outlined very well in this thread. Alice's approach would yield a huge amount of information about what CFS and XAND are and are not, for the same reasons that the horizontal slice would yield loads of information: you can cross-reference the results with all the other known data about the various categories to reveal a wealth of clues.
The need for an overview is so urgent that it should be done right away, 'quick and easy' - extreme scientific rigour is not a priority in the first instance. A similar but slower, more rigorous study could proceed in parallel, and more rigorous condition-specific studies would then follow. For the first, quick, urgent test, just 10 samples from each condition would be enough to give a good idea of the overall picture.
Of course we on this forum are liable to be blinded somewhat by our interest in focusing on CFS, but surely we can see there could be much wider issues at stake, potentially affecting hundreds of millions of people worldwide. I find the fact that this hasn't been a major immediate focus of research (not having been mentioned yet in any prospective study) quite terrifying. It tells me there is "nobody driving". It tells me there is no intelligent co-ordination of at least this particular area of medical research. It tells me that there is no overall focus on the speed and efficiency of how to gain knowledge vital to the lives of people who are suffering and dying now. And it tells me why it takes decades rather than years to realise the benefits of medical breakthroughs.
To whom could comments, suggestions, recommendations from this thread be communicated, I wonder?...
A
Mark, I keep hearing that it's COMING. That retrovirologists are getting on the case. There was just a meeting at Cleveland Clinic with 75 XMRV researchers, including Silverman (of course) and Mikovits. We haven't heard a report from that meeting yet.
Meanwhile, Dr. P said they are getting tissue samples from all over the country from researchers wanting to look at XMRV in their diseases. So I think it's coming.
Meanwhile, Dr. P said they are getting tissue samples from all over the country from researchers wanting to look at XMRV in their diseases. So I think it's coming.
You've perfectly articulated what I've been thinking, Mark.
don't put the cart before the horse
I think some good suggestions have been made for narrowing down how XMRV operates in CFS and some other diseases, once we know that XMRV is in fact a causal element, or even a co-factor in CFS. But the Science article, Dr Bell, and pretty much everyone involved with WPI has stated clearly that their XMRV finding is tentative, preliminary, and needs follow-up.
I believe replication studies right now should address the basic weaknesses of the WPI study and determine whether or not XMRV is a factor in CFS. That is not yet proven. Speculation about XMRV makes a lot of sense for CFS, but that type of logic is not the same as empirical confirmation.
The Science article specifically raised several issues that need to be addressed. Additionally there are some obvious issue based on what one sees in similar studies.
Here are a few replication goals that come partly from conversations I have had with a retroviral expert. These are my words, not his, but I believe I have captured the essence of what he said.
1. Basic replication is essential. Several independent labs would use their own tests and collect their own CFS blood samples. There are over 20 types of PCR and many other types of tests that could be run. Just reproducing the WPI result this way would be a first step, often this type of scientific announcement falls apart at this first step, basic replication.
2. If WPI used a subset of the CFS population there is significant risk for the XMRV finding. A replication study should characterize the sample traits better. If XMRV is only in one subset then it can not explain all CFS as WPI is suggesting it might. Conflicting statements have been made by Dr Peterson (says they picked the sickest), and on the WPI website (says it was random from their 8,000 samples). Therefore, we do not really know if this is a finding of XMRV as yet another co-infection in a subset, or if it applies to all CFS. A replication study could stratify their samples and present data showing infection rate at different levels of CFS severity.
3. WPI made a statement early in the Science article that there was risk of contamination from MLV type species sometimes found in media. Although they believed they controlled adequately for this, not all agreed. So that issue must be addressed in a replication study. A replication could use more internal controls for contamination by other MLV type species that might share some XMRV DNA. They did sequence two samples, which addresses contamination risk, but that is not enough to be statistically valid.
4. WPI used an MLV type of antibody for their study, and if I understood that Science article properly, might not have an XMRV specific antibody. The 95% positive finding claimed by WPI might actually be MLV type antibodies, not specifically a finding of XMRV. Therefore replication studies should look for an XMRV antibody, or if they find only MLV type antibodies present in PWC, should throw out that conclusion of WPI.
5. WPI noted that XMRV might be a passenger virus. A replication study should look into that possibility. For instance, some immune bio-markers should be analyzed, and data correlated to XMRV infection rate and CFS severity levels. There are probably ways to analyze the data and give some probability that XMRV is a passenger virus. In other words, if XMRV is only present in CFS patients with collapsed immune systems and not found in most ordinary PWC it is probably a passenger virus. An unbiased CFS sample would be needed for that.
6. WPI has noted in the follow-up talks and interviews that XMRV may be a gatekeeper, lowering some immune functions and allowing co-infections to proliferate and cause CFS. This can be tested in a follow-on study, and really should be. To test for 'gatekeeper' status a study would have to be designed that compared XMRV infection rates in PWC with their own co-infection rates. For instance, do those with high XMRV viral load have more co-infections, particularly co-infections that might explain CFS symptoms? In my opinion, this is the most important replication study because it would present a possible causal model for CFS from an XMRV infection.
Several types of replication studies need to be run before clinical trials will make sense. Starting clinical trials based on unconfirmed research is a really, really bad idea, because then if you have success OR failure, you can not be confident of the reason why.
I think getting emotionally invested in XMRV as an explanation of CFS at this time is premature. The emotionally liable CFS population should not be encouraged to expect a cure from XMRV treatment before these types of replication studies have been completed, and even then only after successful clinical trials.
Some PWC here are pouncing on the XMRV-retroviral idea as a vehicle for CFS advocacy and politics, before ANY replications have been completed. I hope that does not come back to haunt us if XMRV fails to meet expectations.
But even if XMRV fails to explain CFS, the Science article has helped to raise awareness of our illness in some irreversable ways. More researchers are now aware that CFS is a problem and that we lack a proven causal model. That is the type of challenge researchers love to pursue. Also, we may have other retroviral infections that could be treated with ART, some good might come from this situation even if replication fails.
I think some good suggestions have been made for narrowing down how XMRV operates in CFS and some other diseases, once we know that XMRV is in fact a causal element, or even a co-factor in CFS. But the Science article, Dr Bell, and pretty much everyone involved with WPI has stated clearly that their XMRV finding is tentative, preliminary, and needs follow-up.
I believe replication studies right now should address the basic weaknesses of the WPI study and determine whether or not XMRV is a factor in CFS. That is not yet proven. Speculation about XMRV makes a lot of sense for CFS, but that type of logic is not the same as empirical confirmation.
The Science article specifically raised several issues that need to be addressed. Additionally there are some obvious issue based on what one sees in similar studies.
Here are a few replication goals that come partly from conversations I have had with a retroviral expert. These are my words, not his, but I believe I have captured the essence of what he said.
1. Basic replication is essential. Several independent labs would use their own tests and collect their own CFS blood samples. There are over 20 types of PCR and many other types of tests that could be run. Just reproducing the WPI result this way would be a first step, often this type of scientific announcement falls apart at this first step, basic replication.
2. If WPI used a subset of the CFS population there is significant risk for the XMRV finding. A replication study should characterize the sample traits better. If XMRV is only in one subset then it can not explain all CFS as WPI is suggesting it might. Conflicting statements have been made by Dr Peterson (says they picked the sickest), and on the WPI website (says it was random from their 8,000 samples). Therefore, we do not really know if this is a finding of XMRV as yet another co-infection in a subset, or if it applies to all CFS. A replication study could stratify their samples and present data showing infection rate at different levels of CFS severity.
3. WPI made a statement early in the Science article that there was risk of contamination from MLV type species sometimes found in media. Although they believed they controlled adequately for this, not all agreed. So that issue must be addressed in a replication study. A replication could use more internal controls for contamination by other MLV type species that might share some XMRV DNA. They did sequence two samples, which addresses contamination risk, but that is not enough to be statistically valid.
4. WPI used an MLV type of antibody for their study, and if I understood that Science article properly, might not have an XMRV specific antibody. The 95% positive finding claimed by WPI might actually be MLV type antibodies, not specifically a finding of XMRV. Therefore replication studies should look for an XMRV antibody, or if they find only MLV type antibodies present in PWC, should throw out that conclusion of WPI.
5. WPI noted that XMRV might be a passenger virus. A replication study should look into that possibility. For instance, some immune bio-markers should be analyzed, and data correlated to XMRV infection rate and CFS severity levels. There are probably ways to analyze the data and give some probability that XMRV is a passenger virus. In other words, if XMRV is only present in CFS patients with collapsed immune systems and not found in most ordinary PWC it is probably a passenger virus. An unbiased CFS sample would be needed for that.
6. WPI has noted in the follow-up talks and interviews that XMRV may be a gatekeeper, lowering some immune functions and allowing co-infections to proliferate and cause CFS. This can be tested in a follow-on study, and really should be. To test for 'gatekeeper' status a study would have to be designed that compared XMRV infection rates in PWC with their own co-infection rates. For instance, do those with high XMRV viral load have more co-infections, particularly co-infections that might explain CFS symptoms? In my opinion, this is the most important replication study because it would present a possible causal model for CFS from an XMRV infection.
Several types of replication studies need to be run before clinical trials will make sense. Starting clinical trials based on unconfirmed research is a really, really bad idea, because then if you have success OR failure, you can not be confident of the reason why.
I think getting emotionally invested in XMRV as an explanation of CFS at this time is premature. The emotionally liable CFS population should not be encouraged to expect a cure from XMRV treatment before these types of replication studies have been completed, and even then only after successful clinical trials.
Some PWC here are pouncing on the XMRV-retroviral idea as a vehicle for CFS advocacy and politics, before ANY replications have been completed. I hope that does not come back to haunt us if XMRV fails to meet expectations.
But even if XMRV fails to explain CFS, the Science article has helped to raise awareness of our illness in some irreversable ways. More researchers are now aware that CFS is a problem and that we lack a proven causal model. That is the type of challenge researchers love to pursue. Also, we may have other retroviral infections that could be treated with ART, some good might come from this situation even if replication fails.