Lipkin bad news folks

[Mula]

My favourite quote from Ian Lipkin re CFS/ME, from the press conference, talking about his previous investigations into CFS/ME in the 1990's:

"The one thing that did impress me was that there was an enormous amount of immuno-activity that appeared to be non-specific in these individuals.
So at a time when people were saying that this was a psycho-somatic disorder, I said:
Two thirds to three quarters of the individuals whom we studied had polyclonal B cell activation.
They're sick. We don't know why, but they are sick."

http://cii.columbia.edu/blog.htm?cid=tM5E7V

Dr Lipkin reported this as a finding from 20 years ago. Why then did he not have patients for the last study screened for this maker? It would have been an advantage to marry the PCR and serology results to that marker.

 

[Bob]

Tweets from CII

Tweet 1:
As usual, Carl Zimmer nails it: The Slow, Slow Road to De-Discovery
http://bit.ly/PGYICECII @carlzimmer #MECFS#CFS #ME #XMRV #pMLV
https://twitter.com/CII722/status/248499426853785600

Tweet 2:
Also check out the comments section. Some great science writers weigh in:
http://bit.ly/PGYICECII #CFS#ME#XMRV#MECFS
https://twitter.com/CII722/status/248499568218603520


Link to article (in Discover Magazine):
http://blogs.discovermagazine.com/loom/2012/09/18/the-slow-slow-road-to-de-discovery/

I'm unimpressed by both the article and the comments.
The article is fair enough, but it's very simple.
The comments are a mixture of (mainly positive) discussion about how XMRV has affected wider ME research and awareness, and also a number of negative attacks on the original XMRV/ME researchers from a minority of commenters.

 

[jace]

I'm unimpressed by the Lipkin study, and so are just a few others: http://me-advocacy.com/Lipkin_study_review.html

It seems to me that all the faults we know so well from other negative papers have been repeated. I'm amazed by some of the comments to Lipkin on that groupcard: http://www.groupcard.com/c/69gsXCmslG7

There's one message in that card, asking Dr Lipkin to disprove retroviral involvement in AIDS too, and another that says "Let's put all that stuff back in the box and close it"

Seriously, Kafka ain't in it. Pandora might be.

 

[biophile]

Grrrr, I lost another post when I accidentally activated a different browser mode, but basically I just wanted to say this:

I was initially impressed by the "Lipkin study", but have since become concerned about the patient cohort, largely because of rlc's detailed comments on another thread about how sparse the tests were to exclude other diseases. Also because there was no obvious emphasis on post-exertion symptom exacerbation or relapse (as opposed to vague post-exertional fatigue which will meet the minimum linguistic requirement in the CCC).

As for the virology, I have not had a chance to have a closer look at the paper, but AFAIK the authors had freedom with their methods to detect XMRV/pMLV. I am also vaguely aware of allusions that the entire study was rigged to debunk the previous findings, and Mikovits cannot speak out because she signed what amounts to a gag order or whatever.

I have no problem with people searching for potential flaws, but I am not well enough right now to investigate all the claims being made about various aspects of the study, and I doubt all of them will be accurate. No one at the conference seemed to know what really happened in the earlier studies, but it is my impression that there are uncertainties about the blinding and differences in the handling of samples, and that contamination is a plausible explanation.

As for "next generation sequencing", this is a general term for a range of much faster techniques with high-throughput due to parallelization, allowing for more to be done. However, NGS is not necessarily more accurate than the previous gold standard, so "deep sequencing" (repetition) is used to improve the accuracy. As I understand it, although NGS was not used in the recent XMRV/pMLV study (the primary purpose of which was to investigate the associations made in the previous two papers on XMRV and pMLV), there are other projects underway which do use NGS and perhaps should find anything which was not found in the recent study due to a much broader search, assuming adequate sampling?

 

[Bob]

Grrrr, I lost another post when I accidentally activated a different browser mode

Bad luck biophile!
I think we should organise some sort of forum consolation prize, for when people lose a post or private message!
It might make it slightly less distressing!

I was initially impressed by the "Lipkin study", but have since become concerned about the patient cohort, largely because of rlc's detailed comments on another thread about how sparse the tests were to exclude other diseases. Also because there was no obvious emphasis on post-exertion symptom exacerbation or relapse (as opposed to vague post-exertional fatigue which will meet the minimum linguistic requirement in the CCC).

The only major issue I can see with Lipkin's cohort is if the selection criteria accidentally excluded all ME patients, and only included patients with some other unknown illness. But I don't think this can be the case. I think it would only have ruled out a subset of CFS/ME patients.

I agree that Lipkin's cohort isn't perfect, and it's a shame that they didn't set about excluding alternative diagnoses, or at least make some effort towards it. There have been at least a couple of papers over the past couple of years that demonstrated that a high proportion of ME diagnoses are incorrect.

But the patients came from well established clinicians, such as Peterson and Klimas, so hopefully they know what they are doing, more than a normal family doctor would do. So there would have been an 'ME' diagnosis from a well established physician.

An ME cohort can never be perfect until we understand the cause, and there are always going to be issues with cohorts. Lipkin's cohort is much better than many CFS cohorts that have been used in other research, because Lipkin selected patients with a viral-type onset, with some physical signs of illness. So this ruled out ideopathic fatigue, at least. This seems better than the alternative of a loosely defined CFS cohort.

Lipkin has stated that he is interested in establishing subsets, and that he is not expecting his cohort to be a single discrete disease. So, he's aware of the difficulties.

Some people have said that the cohort could be the reason that no viruses were detected.
But this can't be the case, because roughly 5% positives would still have been detected in the control group, if that was the case.

As for the virology, I have not had a chance to have a closer look at the paper, but AFAIK the authors had freedom with their methods to detect XMRV/pMLV. I am also vaguely aware of allusions that the entire study was rigged to debunk the previous findings, and Mikovits cannot speak out because she signed what amounts to a gag order or whatever.

Yes, Mikovits used her own methodology, at least after the blood collection/processing/storage stage.
And from the accounts that I've read, she played a major role in designing the blood collection/processing/storage methodology, and agreed to the methodology before the study went ahead.

Lipkin wouldn't have gone ahead with it until all the researchers were signed up to the methodology. And my interpretation is that Lipkin went out of his way to accommodate Mikovit's needs and criteria.

So the only way I can see the study was flawed, is if either Mikovits didn't know what she was doing, or if the samples were purposely tampered with. Neither of which is worth devoting any mental energy to, in my opinion.

As for "next generation sequencing", this is a general term for a range of much faster techniques with high-throughput due to parallelization, allowing for more to be done. However, NGS is not necessarily more accurate than the previous gold standard, so "deep sequencing" (repetition) is used to improve the accuracy. As I understand it, although the recent XMRV/pMLV study did not use NGS (the primary purpose of which was to investigate the associations made in the previous two papers on XMRV and pMLV), there are other projects underway which do use NGS and perhaps should find anything which was not found in the recent study due to a much broader search?

One other reason for NGS, is to find out if a virus is integrated into the human genome.
But, as Lipkin said, the purpose of this study was only to replicate the original study, and not to go further.
Lipkin says that if retroviruses are there, then he would hope they would show up in his pathogen studies.
He is carrying out NGS on RNA and DNA, and is also looking at proteins.
I've read that he is investigating faeces, tears, saliva, blood, and spinal fluid.

So his ongoing research seems to be a very powerful investigation.

 

[rlc]

Hi Biophile RE

Grrrr, I lost another post when I accidentally activated a different browser mode, but basically I just wanted to say this

:

The Answer to losing posts which seems to be a common problem here and one that I have experienced is to write your posts in a word file first and save it, then copy and paste to post, if anything goes wrong, you can just copy and paste again, and don’t have to rewrite anything.

Hope this helps

All the best

 

[Undisclosed]

Hi Biophile RE

:

The Answer to losing posts which seems to be a common problem here and one that I have experienced is to write your posts in a word file first and save it, then copy and paste to post, if anything goes wrong, you can just copy and paste again, and don’t have to rewrite anything.

Hope this helps

All the best

You can also use Lazarus Form Recovery if you use Firefox, Chrome, or Safari. It works like a charm and you don't have to use another program to write posts

Kina.

 

[currer]

I'm unimpressed by both the article and the comments.
The article is fair enough, but it's very simple.
The comments are a mixture of (mainly positive) discussion about how XMRV has affected wider ME research and awareness, and also a number of negative attacks on the original XMRV/ME researchers from a minority of commenters.

Yes I was also disappointed to see the attacks on MIkovits from a few familiar sources. I thought it true that it took great integrity to submit her findings to further investigation of this kind, as it did for Alter and Ruscetti, too.
We were correct on this forum in our belief that the papers had been retracted by the journals against the wishes of the authors.
I dont think that the questioning of the validity of the Lipkin study that I have seen on some threads has any real basis.
As far as I am concerned, XMRV/MRVs and their association with ME has been conclusively disproved.
But I am glad that the Lipkin study went ahead - I wanted to see the claim fully investigated.

It is still possible that other retroviruses or retroviral fragments are involved in the pathogenesis of ME but personally post-Lipkin I am more inclined to see ME as an autoimmune disorder - although given the rise in cases since the fifties we still need to understand why autoimmune disease is becoming more common.
ASIA is my preferred hypothesis - which incidentally provides a clue as to why our illness must be kept psychological.
http://www.the-rheumatologist.org/d...SIA_A_New_Way_to_Put_the_Puzzle_Together.html

The prostate cancer findings could still suggest some kind of MRV there. I wonder what Singh is doing now? There is good reason to look for an infectious agent in Prostate cancer as cases have tripled in all age groups in the past thirty years and it s hard to see how this could be without a contagious agent of some kind.

 

[xrayspex]

Currer, this is how I see it, Jamie eloquently states in her most current blog the general direction of my thoughts but has the medical training to round it out.
Again, its not that I wouldn't accept a negative study but the spin they allowed the papers to have- saying no viruses- is very suspicious. That sort of behavior puts everything in question for me.

http://www.x-rx.net/blog/

"I’m not even going to question the study design, patient selection, specimen handling, that the patients chose their own controls, etc. I accept at face value that Dr. Lipkin put together a convincing study in order to put the final nail in the coffin about XMRV. No surprise there. I assumed the study would be negative. But I expected the authors to have the intellectual integrity to state that ruling out XMRV does not rule out retroviruses. Instead they allowed the press to distort in predictable ways. I therefore must conclude that Dr. Lipkin plays for the home team. His task was to kill it and reassimilate the renegade scientists into the group. To make sure that nobody does any clinical trials of arv’s, the paper suggests that the patient community has been saved from that terrible fate by this definitive paper. Mikovits’ name right there with Coffin’s. Task accomplished. But even Coffin said that it might be another retrovirus. Smart people allowing distortion and partial truths. It looks to me like we’ve been thrown back on the trash heap. From the Wall Street Journal. Viruses not to blame for chronic fatigue syndrome after all. Thank you Mr. WSJ editor for that headline, suitable for a tabloid."

and:
"But Dr. Lipkin told Dr. Racaniello:

I know some in the community –the scientific community—feel that this was not money well spent, but the fact is, I think that we have obviated a lot of, you know, missteps that might have followed with clinical trials and such for antiretrovirals. And in addition, we have been able to establish a sample bank that will be helpful for years to come. And we’ve been able to hold, I think, the attention of the community.​

So Dr. Snyderman, Ali and I are missteps…
From the 3rd paragraph of the paper:

Since the index publications, clinics have been established for the treatment of ME/CFS with antiretroviral drugs…​

This is a complete fabrication. Where are these clinics?
It is completely incorrect, and unscientific, to conclude anything from the Lipkin study other than they didn’t find XMRV or a particular pMLV sequence. That’s a long way from no viruses or even no retroviruses in CFS. How is it that 2 million dollars was spent to tell us what we already knew a year ago? No reproducible assay. 2 million dollars and all that effort to prove what isn’t. For three years, we’ve been waiting for the scientific community to run with the ball. Now it is pretty clear, the ball has been dropped, while they huddle to congratulate each other on a job well done. The status quo is restored.

 

[Bob]

Currer, this is how I see it, Jamie eloquently states in her most current blog the general direction of my thoughts but has the medical training to round it out.
Again, its not that I wouldn't accept a negative study but the spin they allowed the papers to have- saying no viruses- is very suspicious. That sort of behavior puts everything in question for me.

Lipkin was clear that his study only relates to XMRV and p-MLV in relation to the blood.

The press release was not misleading either.

He even said that this study does not rule out other retroviruses, and that if they are there, then he hopes that they would show up in his pathogen studies.

 

[Lou]

I'm getting the sense he's got a hard-on from all the attention, so just wanking even harder to keep the.
wave of hack-journalistic orgasm coming.

That is just too funny! Gets my vote for most witty, thanks for a good laugh.

 

[5150]

It has occurred to me that, when ME goes unsolved as to origins and effective treatments(so the name Chronic Fatigue Syndrome was assigned), as the disease progresses into neurological disorder and still is not solved, the name Multiple Sclerosis is given. Check the Wikipedia page on MS. All of those symptoms are so familiar to long-time sufferers of ME.

A firestorm of replies will be appreciated.

 

[xrayspex]

Bob, I agree, I had noticed that Lipkin et all reported as you said, that it doesn't rule out other (retro)viruses, but Jamie's blog suggests important point, was there something they could have done differently with their press release and statements to prevent the bogus misleading headlines, was there some slight of hand there? I am pretty cynical in my old age about the ways of the world and in particular the nature of politics around medicine and money.......lets not be niave.

 

[xrayspex]

case in point, I am listening to NPR right now about some groundbreaking cancer research that found there are at least 4 different types of breast cancer and its much more complex than they previously realised yada yada yada and seasoned interviewer is surprised when researcher mentions the need for more funding to continue the research and he innocently seemed perplexed and asked if there are issues with funding for cancer research etc and she wearily but patiently pointed out well yes, in these economic times yada yada yada the govmt has cut back money to this sort of research

unless someone has been sick with chronic or serious health issue they have no clue sometimes, they assume the govmts of course make time and money for these seemingly important research and treatment matters

the question is why don't they? where does all the money go? anyway, I just think that if people have time to read all of Dr Jamies blog the link I put above she lays out intriguing thoughts related to all these sort of issues.

AT the same time I want to be positive as well and support the efforts that are going on. I suspect the powers that be just want to put the brakes on some of the research and have it be spoonfed out over 10-40 years for a variety of motivations

 

[currer]

Hi xrayspex,

I think we must accept the Lipkin study at face value. If we don't there is no end to the conspiracy theories that could be generated!
Mikovits and Ruscetti were unable to reproduce their findings.
This does not mean that there is no retrovirus involved in the pathogenesis of ME, just that we do not know of one.
It is not XMRV or a closely related PMLV.
Apart from that it could be anything. There could be other retroviruses or other viruses, we just do not know.
Or there could be another reason for people to develop ME.

I am glad the science was examined fully and I assume that Alter, Ruscetti and Mikovits accept these findings too.
It was necessary to complete this study as we were correct in thinking that the original studies had been withdrawn against the authors' wishes.
I hope I am correct in thinking that this is one instance in which science has trumped politics.

I am still interested in research in other diseases where retroviruses appear to be involved. Although XMRV has not been succesfully associated with prostate cancer, we do not know whether another virus or retrovirus may be involved or how they may interact with the defences of the human host.

Lipkin has little or no control over the way his research is reported by others. This is the advantage of the internet - that we can access the original work and are not reliant on other sources.

 

[xrayspex]

Yep, I think we knew already xmrv per se was probably not the answer...it wasn't news. Sociology was one of my majors so I am just very aware of the context around events.......again, my beef isn't the negative xmrv study, it was all the circumstances around it and the reporting and I guess I am not as trusting as you

 

[alex3619]

On the question of why ME might be increasing if its an autoimmune or autoinflammatory disease, I think there is a general increase in autoimmune conditions over the last decades. ME is just one of them.

Having said that the evidence is slowly growing that ME is blood transmissable. If this is the case, and its not a pathogen that is being transmitted, what is the factor in the blood that leads to ME in new patients? Is it cytokines? Abnormal B cells? Something else? A pathogenic trigger is still likely.

Bye, Alex

 

[Bob]

Having said that the evidence is slowly growing that ME is blood transmissable.

Is there any recent evidence for this, alex?

 

[alex3619]

Hi Bob, yes. If you look at the paper on cancer and CFS that was published a few months ago, there are two things that stand out as associated with CFS (they do not use an ME diagnosis) other than lymphoma. The first is Rheumatoid Arthritis. The second is history of blood transfusions. The p factor for both is very very small.

I noted this in post 10:

http://forums.phoenixrising.me/index.php?threads/lymphoma-more-common-in-cfs.19566/

Added to that when I went back and checked the 1955 paper showing ME is blood transmissable, they found (unspecified) spinal ganglia lesions. Since we have dorsal root ganglia lesions, I find that very interesting.

Bye, Alex

 

[currer]

Yep, I think we knew already xmrv per se was probably not the answer...it wasn't news. Sociology was one of my majors so I am just very aware of the context around events.......again, my beef isn't the negative xmrv study, it was all the circumstances around it and the reporting and I guess I am not as trusting as you

I am not that trusting!

It is just that it is impossible as things stand to pursue this hypothesis further.

My partner still insists MLVs exist and we are the victims of a conspiracy.
Having put the idea into his head I find I cannot put it out!