News on the Lipkin study and Dr. Mikovits

ix..yes, he is doing 2 studies.

Tony Mach said

I would like to learn more about the problems of the BWG study, but I would like to hear what Judy Mikovits herself had to say about the study and what might have gone wrong. Can you point me to information from her? Did she say what could have gone wrong?

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So would I, Tony. Dr. Mikovits has not been in a position to comment on the BWG that I am aware of, but we know she was not happy with the protocol being used by VIPdx in their commercial test, and I seem to remember that it was her criticism of those that partially precipitated her sacking by Annette Whittemore.

The BWG study did not identify their negative controls to ensure they were not in contact with potentially infected individuals. I hope that the Lipkin study will not make the same error. The BWG study was testing high-throughput methods, which all failed. The BWG was not transparent in the matter of coding samples, and a failure in coding or decoding would have made the results meaningless, even if the rest of the study design was sound.

The Ruscetti results and the WPI results reported the same detection rates among positives (73%) and overall (31%). It is curious that whatever they were detecting, it was at the same rate. And the WPI found the same number of non-control positives as control negatives. All these could be explained by miscoding.

I am posting as an individual, who is concerned that the study billed to answer once and for all the question of HGRV's in people with ME has transparency in its study design, and avoids the potential errors that would produce meaningless results.

Furthermore, does Judy Mikovits share these reservations about the selection of patients/controls? If no, what reason do you have to doubt her judgement? If yes, why does she not speak out publicly and instead continues with this study wouldn't she only loose? You should ask her! This is all moot speculation and rumors otherwise.

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I made the post, not Dr. Mikovits. That much is clear. The statements in it about the Lipkin study design are speculation, which is inevitable as the study design is not published. Perhaps people have learned from the publication of the PACE protocol, which gave us a very clear knowledge of how they fudged the PACE study results (1,2).

More generally, all posts on forums are a combination of speculation and evidence. Speculation is part of both scientific and general human discourse.

1) PD White, MC Sharpe, T Chalder , JC DeCesare and R Walwyn for the PACE trial group; Protocol for the PACE trial: A randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy; BMC Neurology 2007, 7:6

2) White, PD; Goldsmith, KA; Johnson, AL et al Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial; The Lancet, Early Online Publication, 18 February 2011doi:10.1016/S0140-6736(11)60096-2

jace said:

Thank you for this bit of good news! I am relieved to hear that Mikovits and Ruscetti will be involved in this "Last word on XMRV" as it has been billed in the past. However, there are many concerns with the study design, and it would be great if there could be some more transparency on the details. From what we have heard, of the scientists involved, only Judy and Frank have an assay capable of detecting MRVs, and even they can only detect a small range.

They are also rumoured to be using contact controls, not a good idea if the virus is infective and has a long latent period. The patients are being supplied by physicians, based on subjective diagnosis - why not check their cytokine/chemokine profile, characteristic of activated microglia, against the profile discovered by Lombardi et al 2011 and Kadetoff 2001 (1&2) and cross-check by using the SPECT scan abnormalities known to be in ME/cfs patients? We know these ME profiles are different to those of Klimas, Bateman and Levine, whose patients have a profile characteristic of prolonged exposure to stress hormones or chronic herpes virus infection. If they don't get the cohort right, this "final word" will be on the wrong disease and the study will be rigged to fail.

Sorry to raise possible problems after a rare bit of good news, but after the debacle of the BWG one can't help but worry about these things. It is vital that no more money is wasted on poorly designed studies - heaven knows there's little enough of that about.

1. http://iv.iiarjournals.org/content/25/3/307.abstract
2. http://www.ncbi.nlm.nih.gov/pubmed/22126705

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Agree about the controls. I don't understand why they would actually do that.

I want to add.....The site I'm involved with for the Lipkin study is not supplying patients who have been diagnosed with me/cfs based only on subjective findings. The diagnosis has been made by a full work up of the best immune and infection labs, brain imaging with Spect and MRI, stress tests, as well as clinical presentation that meets the CCC. The assessment left no stone unturned, and the diagnosis was made by the best of the best. At least that's true of my site.

Tony Mach said:

This is good news that Lipkin will see to it that Mikovits can do this study. Either Judy Mikovits can replicate her own work in a new lab, or it will be a definitive confirmation that it was contamination all along there will be no maybe after this study. And no one can point their finger at others as the culprits.

(The pessimist in me waits for the day the results of the Mikovits/Lipkin study will be published and expects all kinds of elusions and subterfuges ala "Oh, the lab didn't follow my protocol.", "The phlebotomist handled the samples wrong." and "Lipkin choose the wrong patients." been there, done that, got the t-shirt)



Previous reports of the end of the world so far all turned out to be a tad bit exaggerated I won't hold my breath.

And furthermore, Lipkin only finds what is already there, he doesn't create these viruses. If some of these viruses are pathogens, they ARE ALREADY CAUSING DISEASE it's good if we find out the cause, won't you agree?

IMHO:
Finding novel pathogens for diseases which had no known cause = good
Stumbling on novel diseases without finding the pathogen = bad

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Of course I agree with your point that some of these viruses are already causing disease and knowing which ones is important. But consider how they might be transmitted--casual contact, for instance. How will this affect our behavior toward one another when that becomes known? What if some of these viruses have been transmitted by vaccines? There is a can of worms bursting wide open for you.

Tony Mach said:

This is good news that Lipkin will see to it that Mikovits can do this study. Either Judy Mikovits can replicate her own work in a new lab, or it will be a definitive confirmation that it was contamination all along there will be no maybe after this study.

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Or she might find something else. The thing is, she never got to complete her work. She never got to do her full sequencing to see if it was XMRV, a different HGRV, or who knows what.

I'm very glad that Lipkin is involved in this. He seems to be very good at keeping his eye on the ball.

What Andrew said.

And thank you, carolinetanderson.

Tristen said:

Agree about the controls. I don't understand why they would actually do that.

I want to add.....The site I'm involved with for the Lipkin study is not supplying patients who have been diagnosed with me/cfs based only on subjective findings. The diagnosis has been made by a full work up of the best immune and infection labs, brain imaging with Spect and MRI, stress tests, as well as clinical presentation that meets the CCC. The assessment left no stone unturned, and the diagnosis was made by the best of the best. At least that's true of my site.

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That's great, Tristen, thanks for letting us know. Another question partly answered! This is the 'good news about the Lipkin study' thread! Only a hundred more details to think about...

Hello,

Can anyone tell me if the Levy/Peterson response to Lombardi et al has yet been published? So sorry I have forgotten. It is referred to here (I was doing some background reading following this latest announcement about Mikovits and Lipkin you see): http://www.nature.com/news/2011/110314/full/471282a.html

The above also carries some information about the Lipkin study (there does seem to be a dearth of information doesn't there?) and I am trying to dig around to find more information about it really. This is what they said in March 2011 - it is just beneath the bit about Levy/Peterson by the way:

'Others, too, are rallying for a definitive answer. Ian Lipkin, a microbial epidemiologist at Columbia University in New York, has a reputation for getting to the bottom of mysterious diseasepathogen links. His team debunked the association between Borna disease virus and chronic fatigue, for example. Now he is spearheading the $1.3-million effort funded by the US government.

He is leaving the testing to three labs: Mikovits's at the WPI, Alter's at the NIH and the CDC. Each will receive coded samples of white blood cells and plasma from 150 patients with chronic fatigue and from 150 healthy controls. The labs will test for XMRV using their method of choice. Lipkin will crunch the data and unblind the samples.

But even if a study confirms the link to chronic fatigue, it won't be able to determine whether the virus is the cause. XMRV could, for example, be an opportunistic infection affecting those whose immune systems are already dampened by chronic fatigue. Even Mikovits can only hypothesize as to how it might cause disease.'

Now I must read through this thread properly before asking a few further - perhaps more relevant - questions...

Edit:

Hmm... OK. I can't get excited about any of this to be honest as the facts surrounding this study that again looks for 'XMRV' are few and far between. Mikovits and Ruscetti were both involved at the outset of BWG and signed off on it as participating authors I believe.

I do though share some of the same optimism I suppose (expressed above) that at least this time round Mikovits will be operating from a different lab. That might throw up some 'independent' verification I guess. However, if all this study seeks to achieve is confirmation or not that 'XMRV' is associated with 'CFS' in BLOOD - then [shrug] here we go again.

I was led to believe from reading posts by those who do believe in an association of a retrovirus with their condition, that we are no longer talking about 'XMRV' but something else - something perhaps associated with it - another 'form' of MLV? So how does searching for 'XMRV' discover something that isn't 'XMRV'?

And as the extract above intimates nothing has been published that suggests any 'retrovirus' found so far has anything to do with my debilitation. So we are searching for something that is more prevalent in 'CFS' patients' BLOOD than in controls. Will this result in the same concentrations as reported by Lombardi et al? Or is that now debunked. I mean in my mind it has been.

So, Mikovits/Ruscetti will be one of the three labs employing their own methods to try and find 'XMRV' in blinded samples of BLOOD. And that's about all we know about that. And Lipkin will also be looking for pathogens separately employing this Next Generation Sequencing.

NGS is not something that Mikovits or Ruscetti have previously employed. Am I right in thinking that Lipkin will presumably do this separately in his study for pathogens? I mean NGS has nothing to do with this 'XMRV' hunt, right? Or could it be used in that search as well?

I will I think keep searching for the previous articles relating to the Lipkin studies and see what I can ascertain from them. I don't expect much from the 'XMRV' hunt to be honest and I doubt very much if it will end the matter for some folk. Would be nice to know more about it though.

Edit:

'The Lipkin study is a multi-centre trial, headed by Ian Lipkin, a virologist at Columbia University in New York, trying to prove or disprove once and for all Mikovitss largely discredited hypothesis that chronic fatigue syndrome (also known as myalgic encephalopathy) is caused by a mysterious family of retroviruses, among them XMRV. We covered the controversy surrounding the research in March and Mikovitss dismissal in September.'

http://blogs.nature.com/news/2011/11/researcher_confesses_to_steali_1.html

One word keeps coming to my mind: assay. One interpretation of BWG's concluding statement is that the assays employed were just not capable of discovering whatever it is that is supposedly there.

In the 'Lipkin Study' I presume they will employ the same assays and any other ones that for example, Mikovits/Ruscetti have established but were unable (?!) to use in BWG.

How can you find something when that something has not yet been found? I am not being 'funny' I am trying to understand how this might work. The other two labs involved in this study presumably will only employ the methods and the assays used in BWG.

I further presume that the 'missing notebooks' were not as important as once thought and that Mikovits and Ruscetti between them are indeed capable of reproducing their methodology and any assays from what has been left with Ruscetti previously.

Hi Firestorm and everyone

I understand where your coming from, In the past i tended to see certian members views as just plain negative, however after whats happened this last year, even my faith in a retroviral cause has been shaken, despite symptoms suggesting some kind of immune involvement for years at a time.

One thing im hopefull for is the NGS part of this study Firestorm, Because i can 100% Say my illness started with a very powerful and frightening immune insult that had virus wrote all over it. I know what viruses feel like ( as we all do ) ive had flu confirmed by the fact my partner also had it at the same time, the usual banging head fever achs weakness ect. Chicken pox too another time

Well this illness started for me just like that. Very very similair to full on influenza. the first what i would call the onset periods. were always very powerful with very disturbing symptoms that mimic influenza. always with high termpetature achs, and chest infection irratation type involvement.
Now heres the rub, out of al least 6 or 7 of these disturbing viral like onslaughts over a period of about a year. a year and a half ( at the beggining) onset

My partner never caught this ? nor did my other family members.

So my question becomes what is this flu that is not the flu ?

We know retroviruses can weaken the immune system to allow these type of infections that others around us will not catch. which is the main reason i believed i was infected with xmrv after being part of the ashford 50 group study and was told i tested postive 3 out of the 4 tests ( i never did find out which 3? ) i also assumed maybe wrongly ? that these results correlated with the NCI part of the ashford 50 testing, and apparently another lab, that i didnt find out the name of. If the results did correlate how the hell does this all add up to the BWG results being such a mess ?

Fact there is immune involvment. fact there is infection likely caused by a virus or bacteria. My own body proved this to me time and time again. The interesting thing is after the devasting Onset attacks mentioned, the illness shifted into a new and strange pattern with many of the symptoms experianced through the onset of this illness, but somewhat weakened, meaning the fevers stopped or became very mild. while in the begining we was talking 102 F fevers but the chest irratation, infection continued, the weakeness continued the appetite loss, one experiances with flu continued, the nausea, visual and hearing disturbances achs ect. But to a less severe and measurable degree as was the case during onset of this disease. Also the periods between attacks shifted from 8 to 12 weeks as was the case in the begining to roughly weekly. And this shift conincided with the symptoms weakening somewhat at that time.

I mention all this to try to understand what possibly the NGS may find, How the immune system copes with uknown bacteria or viruses. or how a retro virus plays havoc with the immune system to allow this kind of viral like illiness to take hold. This trend of weakening response to umknown pathogen or pathogens continued for years ( about 17 ) leading to where im at now. Partly recovered. with only minor attacks very infrequently and lasting for shorter periods of time. So whatever it was it appears the immune system was trying to find a way to cope with it, beat it, live with it. coincide with it. But it struggled to do so for many years, and im sure its still struggling as i still get ill infrequently, and to a much milder degree.

I do belive there becomes a possible auto immune end result to all this. I do have psoriasis ( have had for years ) i get the itchy eyes and dry mouth in the morning bone and joint problems Stomach problems ( bad at present ) but strangely at night my eyes water and sting often. which is strange if i developed Sjogrens syndrome, As i thought it was supposed to attack these glands preventing tear production ? i have both ? it does feel like grit in my eyes in the morning.Nose goes very dry. almost always blocked on one side. and it makes a rumbling sound when i breath. Full of contradictions. But there you go. I still belive its lead to some kind of auto immune response. So i think there right in norway too.

What a puzzle this illness is
My hopes are now with with Dr Lipkin and NGS i feel like sending this message to him. Just so he knows what patterns of illness are crippling us al
And that NGS really is worth while

Firestormm said:

Hello,

Can anyone tell me if the Levy/Peterson response to Lombardi et al has yet been published? So sorry I have forgotten. It is referred to here (I was doing some background reading following this latest announcement about Mikovits and Lipkin you see): http://www.nature.com/news/2011/110314/full/471282a.html...

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Is this the paper you were thinking of, Firestormm? I *think* Dan Peterson supplied some of the blood samples.

Science. 2011 Jul 1;333(6038):94-7. Epub 2011 May 31.

No evidence of murine-like gammaretroviruses in CFS patients previously identified as XMRV-infected.

Knox K, Carrigan D, Simmons G, Teque F, Zhou Y, Hackett J Jr, Qiu X, Luk KC, Schochetman G, Knox A, Kogelnik AM, Levy JA.

Full text can be found here.

why did dr. cheney post that Roche found XMRV using NGS?? there is no other info about it anywhere but on his clinic website. did roche do the study on the 8 CFS patients or did some other scientist use roche's NGS equipment??? i have asked many people but no one knows anything.

Several have implied he was just repeating info from the Ottawa conference Daffodil. I don't know if that is correct or not, it would be nice to have more information.

Sam Carter said:

Is this the paper you were thinking of, Firestormm? I *think* Dan Peterson supplied some of the blood samples.

Science. 2011 Jul 1;333(6038):94-7. Epub 2011 May 31.

No evidence of murine-like gammaretroviruses in CFS patients previously identified as XMRV-infected.

Knox K, Carrigan D, Simmons G, Teque F, Zhou Y, Hackett J Jr, Qiu X, Luk KC, Schochetman G, Knox A, Kogelnik AM, Levy JA.

Full text can be found here.

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Many thanks Sam. Yes it is. I do have them all stored together on the old PC but couldn't see for looking. Thanks.

Just to confirm then. Two 'Lipkin' studies are underway:

1. Looking for 'XMRV' in patient blood from three labs including Mikovits, Ruscetti and Alter as well as CDC.
2. Looking for any and all possible viruses in blood and any and all other possible sources employing among other techniques Next Generation Sequencing.

Is that right? I think it is.

Thanks to all and to Tristen (previously) for giving some more detail on the testing undertaken for the main Lipkin study.

Maybe more news will be forthcoming in the new year?

I did see that Lipkin et al made Discover:

'Discover Magazine's Jan/Feb 2012 issue lists the 100 Top Stories of 2011.

#99: Study Deepens the Mystery of Chronic Fatigue:

In 2009 a controversial study published in Science made an extraordinary claim: CFS, whose cause had long been unknown, could be linked to a retrovirus that first arose in mice. According to the retroviral immunologist Judy Mikovits at the Whittemore Peterson Institute (WPI) in Reno, Nev., XMRV was present in 68 out of 101 people with CFS, compared to only 8 of 218 healthy controls. Extraordinary finds like these must be replicated at other labs, however, and subsequent studies could not corroborate the results.

Then, last Sept., a crushing blow came when Science published a study by 9 independent labs, including Mikovits's own, that failed to confirm the presence of XMRV in patients with CFS. In fact, researchers at WPI could identify only 6 out of 10 positive samples that they themselves had supplied. The theory came under additional fire when one of the authors of the original Science study, Robert Silverman, announced that further research on his part showed the positive specimens from CFS patients had actually been contaminated with XMRV DNA. All the authors, including Mikovits, offered a partial retraction of the paper.

Nevertheless, Mikovits is not giving up on her search for a retroviral cause for the illness. At an October presentation on her work at the IACFS/ME in Ottawa, she suggested that a related retrovirus in the same family as XMRV (gammaretroviruses) was actually behind CFS. Other scientists have grown increasingly skeptical, however. In the fall WPI announced that Mikovits had been terminated.

The final word may have to wait until completion of a multicenter study coordinated by Ian Lipkin, a molecular biologist at Columbia Univ. "Even if we cannot implicate gammaretroviruses like XMRV in CFS," says Lipkin, "their discovery must be credited with focusing new researchers and resources on the complex and crippling disorder."'

http://www.zinio.com/pages/Discover/Jan-Feb-12/416200266/pg-86

Unfortunately, it hit Science too (though a glaring error was made in their write-up. Can you spot it...)

News & Opinion

Top Science Scandals of 2011

A list of this years most high-profile retractions and controversies in science

Mouse virus and chronic fatigue

'The link between a mouse leukemia virus and chronic fatigue syndrome made waves when it was first announced in 2009. But after several labs failed to recreate the link, the paper, which was cited 200 times, was retracted. The story took a turn for the dramatic when Whittemore Peterson Institute director Judy Mikovits, who led the retracted 2009 study, refused to hand over key lab notebooks. She allegedly had an underling take the notebooks, then skipped town to California. She has been arrested on counts of felony theft, jailed overnight, and is now awaiting trial.'

http://the-scientist.com/2011/12/19/top-science-scandals-of-2011/

Oh dear. Never mind.

This was from September 2010 but it gives perhaps more insight into the composition of the XMRV Study from Lipkin - though the number of samples has increased and obviously WPI are no longer involved:

'The new study, Lipkin says, will involve fresh blood samples from 100 CFS patients and 100 similar, but healthy people 25 of each group from four different sites around the country, to provide geographic diversity.

The samples will be processed, blinded and sent to the FDA, the CDC and the Whittemore Peterson Institute, which led the team that published the original Science paper.

If a lab finds a sample is positive for XMRV, further tests will be needed to confirm the result. If one lab finds a positive sample but another lab doesnt, the same samples can be shipped again, with a new blinded code, to be tested again. If you get the same result, it is valid, Lipkin says.

He adds that it may turn out that certain labs are simply more proficient than others at finding XMRV and related viruses. And he says hes open to whatever the outcome is, which is one reason why NIAID asked his group to run the study. We have no horse in this race, he says.'

http://blogs.wsj.com/health/2010/09/08/world-class-virus-hunter-to-head-up-the-latest-xmrv-study/

There was also this comment posted today I believe from Dr Mikovits which is relevant:

'I am committed to moving forward this work and am working as the PI on the Lipkin study according to the original study design and we are confident that no matter what the results with MRVs, this study will move the field forward...'

http://lymebook.com/vogan-blog/?p=130

You might disagree of course but I take that to mean the 'original' Lombardi et al. study design. But we will all see in due course I suppose.

Tony Mach said:

IMHO:
Finding novel pathogens for diseases which had no known cause = good
Stumbling on novel diseases without finding the pathogen = bad

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Amen to that!

And, about the possibility of a discovery of a ME pathogen, I've come to the conclusion that judging from the way ME arises (triggered by temporarily immune suppressing events like EBV, vaccines, the flu, giardia etc), the only thing which would make sense to me would be that it's endogenous. Endogenous, thereby latent in pretty much everyone, and triggered by those events. Much like the proposed HERV-W in MS (Perron et al, fascinating research). Looking at the classes of retroviruses (http://upload.wikimedia.org/wikipedia/commons/a/a9/Classes_of_ERVs.jpg), HERV W is a gammaretrovirus. When it comes to Mikovits's/Lipkin's hunt, could it be that the proposed virus they are sequencing is endogenous? Despite that the original research pointed towards exogenous.

Any experts who could weigh in?

Ian Lipkin: the NIH study continues with Judy Mikovits on board, 28 December 2011:

A Message from CII Director W. Ian Lipkin Regarding the XMRV/MLV CFS/ME Study

Dear Colleagues and Friends in the CFS/ME Community:

This letter is written to clarify the status of the XMRV/MLV CFS/ME study I am coordinating at the request of the National Institutes of Health.

Although frequently described as the Lipkin Study, it is in fact the Alter, Bateman, Klimas, Komaroff, Levine, Lo, Mikovits, Montoya, Peterson, Ruscetti, and Switzer study, designed by these 11 investigators to bring their best methods for case ascertainment and characterization and state-of-the-art molecular and serological diagnostic tools to address the question of whether a retrovirus is associated with disease.

My role in conjunction with Mady Hornig and Bruce Levin at Columbia University is to ensure that the study represents an appropriately powered, definitive, representative sample of CFS/ME patients across the United States; to receive and distribute samples; and to assess results obtained in individual laboratories for consistency and evidence for or against an association between retroviral signal and disease.

I use the term signal because any finding related to a retrovirus, whether infectious or noninfectious, genetic material, protein, or antibody, may provide insights into disease or allow development of diagnostic tests even if a causative relationship is not established. My condition on accepting this charge from the NIH and the clinical and laboratory investigators is that each participant agree to unconditionally accept group criteria for defining cases to be used in this study.

Laboratory investigators were also required to unequivocally endorse their results at the conclusion of the study. Several months were required to develop clinical criteria for case and control definition and to complete approvals for human subject protection.

We encountered additional delays when Dr. Mikovits could no longer pursue her work at the WPI. At that juncture, some parties suggested that the work proceed at WPI without her. However, in my judgment, the value of this study rests in its inclusion of the original investigators who reported the XMRV/MLV findings.

Thus, I was grateful when we found a way to fully engage Dr. Mikovits. At the time of this writing we have collected and distributed for laboratory analysis samples from 123 CFS/ME patients and 88 matched control subjects. We intend to complete collection and analysis of samples from 150 patients and 150 controls in early 2012.

There is criticism in some quarters that this study is unnecessary given results obtained by other investigators with other samples. However, the participating clinical and laboratory investigators and our team at Columbia do not agree. We are fully committed to completing the work rapidly and rigorously.

For those who continue to express concerns that this study is an inappropriate use of resources in a challenging fiscal environment, please be assured that more than 85% of the funding associated with this initiative is invested in patient recruitment and characterization and sample collection, archiving, and distribution.

Thus, irrespective of study outcome there will be unprecedented opportunity to explore hypotheses other than that disease is due to XMRV or MLV infection.

Sincerely yours,

W. Ian Lipkin, MD
Director, Center for Infection and Immunity

Hooray ! - thanks firestormm.

The Lipkin message answered my question "I use the term signal because any finding related to a retrovirus, whether infectious or noninfectious, genetic material [read: endogenous], protein, or antibody, may provide insights into disease or allow development of diagnostic tests even if a causative relationship is not established."

Did anyone see the paper on cainines out this week?
Interesting!!