Science Asks to Retract the XMRV-CFS Paper, it Should Never Have Accepted in the First Place.

2 06 2011

Wow! Breaking!

As reported in WSJ earlier this week [1], editors of the journal Science asked Mikovits and her co-authors to voluntary retract their 2009 Science paper [2].

In this paper Mikovits and colleagues of the Whittemore Peterson Institute (WPI) and the Cleveland Clinic, reported the presence of xenotropic murine leukemia virus–related virus (XMRV) in peripheral blood mononuclear cells (PBMC) of patients with chronic fatigue syndrome (CFS). They used the very contamination-prone nested PCR to detect XMRV. This 2 round PCR enables detection of a rare target sequence by producing an unimaginable huge number of copies of that sequence.
XMRV was first demonstrated in cell lines and tissue samples of prostate cancer patients.

All the original authors, except for one [3], refused to retract the paper [4]. This prompted Science editor-in-chief Bruce Alberts to  issue an Expression of Concern [5], which was published two days earlier than planned because of the early release of the news in WSJ, mentioned above [1]. (see Retraction Watch [6]).

The expression of concern also follows the publication of two papers in the same journal.

In the first Science paper [7] Knox et al. found no Murine-Like Gammaretroviruses in any of the 61 CFS Patients previously identified as XMRV-positive, using the same PCR and culturing techniques as used by Lombardi et al. This paper made ERV (who consistently critiqued the Lombardi paper from the startlaugh-out-loud [8], because Knox also showed that human sera neutralize the virus in the blood,indicating it can hardly infect human cells in vivo. Knox also showed the WPIs sequences to be similar to the XMRV plasmid VP62, known to often contaminate laboratory agents.*

Contamination as the most likely reason for the positive WPI-results is also the message of the second Science paper. Here, Paprotka et al. [9]  show that XMRV was not present in the original prostate tumor that gave rise to the XMRV-positive 22Rv1 cell line, but originated -as a laboratory artifact- by recombination of two viruses during passaging the cell line in nude mice. For a further explanation see the Virology Blog [10].

Now Science editors have expressed their concern, the tweets, blogposts and health news articles are preponderantly negative about the XMRV findings in CFS/ME, where they earlier were positive or neutral. Tweets like “Mouse virus #XMRV doesn’t cause chronic fatigue #CFS http://t.co/Bekz9RG (Reuters) or “Origins of XMRV deciphered, undermining claims for a role in human disease: Delineation of the origin of… http://bit.ly/klDFuu #cancer” (National Cancer Institute) are unprecedented.

Thus the appeal by Science to retract the paper is justified?

Well yes and no.

The timing is rather odd:

  • Why does Science only express concern after publication of these two latest Science papers? There are almost a dozen other studies that failed to reproduce the WPI-findings. Moreover, 4 earlier papers in Retrovirology already indicated that disease-associated XMRV sequences are consistent with laboratory contamination. (see an overview of all published articles at A Photon in the Darkness [11])
  • There are still (neutral) scientist who believe that genuine human infections with XMRV still exist at a relatively low prevalence. (van der Kijl et al: xmrv is not a mousy virus [12])
  • And why doesn’t Science await the results from the official confirmation studies meant to finally settle whether XMRV exist in our blood supply and/or CFS (by the Blood Working Group and the NIH sponsored study by Lipkin et al.)
  • Why (and this is the most important question) did Science ever decide to publish the piece in the first place, as the study had several flaws.
I do believe that new research that turns existing paradigms upside down deserves a chance. Also a chance to get disproved. Yes such papers might be published in prominent scientific journals like Science, provided they are technically and methodologically sound at the very least. The Lombardi paper wasn’t.

Here I repeat my concerns expressed in earlier posts [13 and 14]. (please read these posts first, if you are unfamiliar with PCR).

Shortcomings in PCR-technique and study design**:

  • No positive control and no demonstration of the sensitivity of the PCR-assay. Usually a known concentration or a serial dilution of a (weakly) positive sample is taken as control. This allows to determine sensitivity of the assay.
  • Aspecific bands in negative samples (indicating suboptimal conditions)
  • Just one vial without added DNA per experiment as a negative control. (Negative controls are needed to exclude contamination).
  • CFS-Positive and negative samples are on separate gels (this increases bias, because conditions and chance of contamination are not the same for all samples, it also raises the question whether the samples were processed differently)
  • Furthermore only results obtained at the Cleveland Clinic are shown. (were similar results not obtained at the WPI? see below)
Contamination not excluded as a possible explanation
  • No variation in the XMRV-sequences detected (expected if the findings are real)
  • Although the PCR is near the detection limit, only single round products are shown. These are much stronger then expected even after two rounds. This is very confusing, because WPI later exclaimed that preculturing PBMC plus nested PCR (2 rounds) were absolutely required to get a positive result. But the Legend of Fig. 1 in the original Science paper clearly says PCR after one round. Strong (homogenous) bands after one round of PCR are highly suggestive of contamination.
  • No effort to exclude contamination of samples with mouse DNA (see below)
  • No determination of the viral DNA integration sites.

Mikovits also stressed that she never used the XMRV-positive cell lines in 2009. But what about the Cleveland Clinic, nota bene the institute that co-discovered XMRV and that had produced the strongly positive PCR-products (…after a single PCR-round…)?

On the other hand, the authors had other proof of the presence of retrovirus: detection of (low levels of) antibodies to XMRV in patient sera, and transmissibility of XMRV. On request they later applied the mouse mitochondrial assay to successfully exclude the presence of mouse DNA in their samples. (but this doesn’t exclude all forms of contamination, and certainly not at Cleveland Clinic)

These shortcomings alone should have been sufficient for the reviewers, had they seen it and /or deemed it of sufficient importance, to halt publication and to ask for additional studies**.

I was once in a similar situation. I found a rare cancer-specific chromosomal translocation in normal cells, but I couldn’t exclude PCR- contamination. The reviewers asked me to exclude contamination by sequencing the breakpoints, which only succeeded after two years of extra work. In retrospect I’m thankful to the reviewers for preventing me from publishing a possible faulty paper which could have ruined my career (yeah, because contamination is a real problem in PCR). And my paper improved tremendously by the additional experiments.

Yes it is peer review that failed here, Science. You should have asked for extra confirmatory tests and a better design in the first place. That would have spared a lot of anguish, and if the findings had been reproducible, more convincing and better data.

There were a couple of incidents after the study was published, that made me further doubt the robustness of WPI’s scientific data and even (after a while) I began to doubt whether WPI, and Judy Mikovits in particular, is adhering to good scientific (and ethical) practices.

  • WPI suddenly disclosed (Feb 18 2010) that culturing PBMC’s is necessary to obtain a positive PCR signal.  As a matter of fact they maintain this in their recent protest letter to Science. They refer to the original Science paper, but this paper doesn’t mention the need for culturing at all!! 
  • WPI suggests their researchers had detected XMRV in patient samples from both Dr. Kerr’s and Dr. van Kuppeveld’s ‘XMRV-negative’ CFS-cohorts. Thus in patient samples obtained without a culture-enrichment step…..  There can only be one truth:  main criticism on negative studies was that improper CFS-criteria were used. Thus either this CFS-population is wrongly defined and DOESN’t contain XMRV (with any method), OR it fulfills the criteria of CFS and the XMRV can be detected applying the proper technique. It is so confusing!..
  • Although Mikovits first reported that they found no to little virus variation, they later exclaimed to find a lot of variation.
  • WPI employees behave unprofessional towards colleague-scientists who failed to reproduce their findings.
Other questionable practices 
  • Mikovits also claims that people with autism harbor XMRV. One wonders which disease ISN’t associated with XMRV….
  • Despite the uncertainties about XMRV in CFS-patients, let alone the total LACK of demonstration of a CAUSAL RELATIONSHIP, Mikovits advocates the use of *not harmless* anti-retrovirals by CFS-patients.
  • At this stage of controversy, the WPI-XMRV test is sold as “a reliable diagnostic tool“ by a firm (VIP Dx) with strong ties to WPI. Mikovits even tells patients in a mail: “First of all the current diagnostic testing will define with essentially 100% accuracy! XMRV infected patients”. WTF!? 
  • This test is not endorsed in Belgium, and even Medicare only reimbursed 15% of the PCR-test.
  • The ties of WPI to RedLabs & VIP Dx are not clearly disclosed in the Science Paper. There is only a small Note (added in proof!)  that Lombardi is operations manager of VIP Dx, “in negotiations with the WPI to offer a diagnostic test for XMRV”.
Please see this earlier post [13] for broader coverage. Or read the post [16] of Keith Grimaldi, scientific director of Eurogene, and expert in personal genomics, who I asked to comment on the “diagnostic” tests. In his post he very clearly describes “what is exactly wrong about selling an unregulated clinical test  to a very vulnerable and exploitable group based on 1 paper on a small isolated sample”.

It is really surprising this wasn’t picked up by the media, by the government or by the scientific community. Will the new findings have any consequences for the XMRV-diagnostic tests? I fear WPI will get away with it for the time being. I agree with Lipkin, who coordinates the NIH-sponsored multi-center CFS-XMRV study that calls to retract the paper are premature at this point . Furthermore, -as addressed by WSJ [17]- if the Science paper is retracted, because XMRV findings are called into question, what about the papers also reporting a  link of XMRV-(like) viruses and CFS or prostate cancer?

WSJ reports, that Schekman, the editor-in chief of PNAS, has no direct plans to retract the paper of Alter et al reporting XMRV-like viruses in CFS [discussed in 18]. Schekman considers it “an unusual situation to retract a paper even if the original findings in a paper don’t hold up: it’s part of the scientific process for different groups to publish findings, for other groups to try to replicate them, and for researchers to debate conflicting results.”

I agree, this is a normal procedure, once the paper is accepted and published. Fraud is a reason to retract a paper, doubt is not.

Notes

*samples, NOT patients, as I saw a patient erroneous interpretation: “if it is contamination in te lab how can I have it as a patient?” (tweet is now deleted). No, according to the contamination -theory” XMRV-contamination is not IN you, but in the processed samples or in the reaction mixtures used.

** The reviewers did ask additional evidence, but not with respect to the PCR-experiments, which are most prone to contamination and false results.

  1. Chronic-Fatigue Paper Is Questioned (online.wsj.com)
  2. Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH, & Mikovits JA (2009). Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science (New York, N.Y.), 326 (5952), 585-9 PMID: 19815723
  3. WPI Says No to Retraction / Levy Study Dashes Hopes /NCI Shuts the Door on XMR (phoenixrising.me)
  4. http://wpinstitute.org/news/docs/FinalreplytoScienceWPI.pdf
  5. Alberts B. Editorial Expression of Concern. Science. 2011 May 31.
  6. Science asks authors to retract XMRV-chronic fatigue paper; when they refuse, issue Expression of Concern. 2011/05/31/ (retractionwatch.wordpress.com)
  7. K. Knox, Carrigan D, Simmons G, Teque F, Zhou Y, Hackett Jr J, Qiu X, Luk K, Schochetman G, Knox A, Kogelnik AM & Levy JA. No Evidence of Murine-Like Gammaretroviruses in CFS Patients Previously Identified as XMRV-Infected. Science. 2011 May 31. (10.1126/science.1204963).
  8. XMRV and chronic fatigue syndrome: So long, and thanks for all the lulz, Part I [erv] (scienceblogs.com)
  9. Paprotka T, Delviks-Frankenberry KA, Cingoz O, Martinez A, Kung H-J, Tepper CG, Hu W-S , Fivash MJ, Coffin JM, & Pathak VK. Recombinant origin of the retrovirus XMRV. Science. 2011 May 31. (10.1126/science.1205292).
  10. XMRV is a recombinant virus from mice  (Virology Blog : 2011/05/31)
  11. Science asks XMRV authors to retract paper (photoninthedarkness.com : 2011/05/31)
  12. van der Kuyl AC, Berkhout B. XMRV: Not a Mousy Virus. J Formos Med Assoc. 2011 May;110(5):273-4. PDF
  13. Finally a Viral Cause of Chronic Fatigue Syndrome? Or Not? – How Results Can Vary and Depend on Multiple Factor (laikaspoetnik.wordpress.com: 2010/02/15/)
  14. Three Studies Now Refute the Presence of XMRV in Chronic Fatigue Syndrome (CFS) (laikaspoetnik.wordpress.com 2010/04/27)
  15. WPI Announces New, Refined XMRV Culture Test – Available Now Through VIP Dx in Reno (prohealth.com 2010/01/15)
  16. The murky side of physician prescribed LDTs (eurogene.blogspot.com : 2010/09/06)
  17. Given Doubt Cast on CFS-XMRV Link, What About Related Research? (blogs.wsj.com)
  18. Does the NHI/FDA Paper Confirm XMRV in CFS? Well, Ditch the MR and Scratch the X… and… you’ve got MLV. (laikaspoetnik.wordpress.com : 2010/08/30/)

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38 responses

3 06 2011
ERV

WPI suggests their researchers had detected XMRV in patient samples from both Dr. Kerr’s and Dr. van Kuppeveld’s ‘XMRV-negative’ CFS-cohorts.

Yes, the WPI did find XMRV+ samples in vanKuppenvelds negative samples.

What WPIs press machine neglected to mention to everyone, was that they found ‘XMRV’ equally in the CFS samples and the healthy controls.

*nod* Im working on a similar summary post– its the longest thing Ive ever written on ERV so far, and Im not even halfway done… :-/

5 06 2011
laikaspoetnik

Hi Erv. Thanks for commenting.

Where does it say that WPI “found ‘XMRV’ equally in the CFS samples and the healthy controls”. Do you have a link?

I’ve read your 3rd post XMRV and chronic fatigue syndrome: So long, and thanks for all the lulz, Part III. I think I have to read it again, because I still have to recover from the first paragraph where you compare Judy Mikovits to whack-a-mole champ in her responses to the legion of anti-XMRV papers published to date….

“she bitches about one thing, or another thing, as the papers are published, but she misses the big picture. Its not that there are moles randomly popping up. The problem is youre entire 3 acre lot is full of fucking moles. Its not one thing or another that is ‘the problem’. A negative paper here or there wouldnt be a problem. The problem is the implications of all the negative papers taken together in their entirety.

Thanks for all the Lulz, Erv

btw I love the colored alignments of XMRV-positive sequences, because it is clear at a glance that “there is no sequence diversity in the WPIs reported sequences and that they are all the same relative to one another, and relative to a laboratory plasmid VP62 that everyone is using as positive controls in the negative studies.”

And thanks for all the *nods* ;)

5 06 2011
ERV

LINKY! Letter from Professor Frank van Kuppeveld to the WPI in response to their libel. Technically, WPI ‘found’ XMRV in 33% of healthy controls, and 28.6% CFS patients, but the sample size was small ;)

Also, the program I used for the alignments is called DNA Strider. It was invented in 1991. Its not like I used some brand-new-super-awesome technology, its something every lab has (or something similar to it). No excuse for the ‘diversity’ excuse. No excuse for why the sequencing of PCR products wasnt done initially (thus would have avoided this whole fiasco).

5 06 2011
laikaspoetnik

Thanks for the link.

I was just saying that your alignments nicely visualized the homogeneity of the sequencing products (although I have never seen the program, having left the lab for quite a while…).

Btw I thought that homogeneity was established earlier. It is already mentioned it in my first post about XMRV and M/CFS (http://laikaspoetnik.wordpress.com/2010/02/15/finally-a-viral-cause-of-chronic-fatigue-syndrome-or-not-how-results-can-vary-and-depend-on-multiple-factors/). Here I quote Charles Chiu [Faculty of 1000 Biology, 19 Jan 2010 http://f1000biology.com/article/id/1166366/evaluation%5D:

“In their Dissenting Opinion of this article, Moore and Shuda raise valid concerns regarding the potential for PCR contamination in this study. Some concerns include 1) the criteria for defining CFS/ME in the patients and in controls were not explicitly defined, 2) nested PCR was used and neither in a blinded nor randomized fashion, 3) the remarkable lack of diversity in the six fully sequenced XMRV genomes (<6 nucleotide average difference across genome) — with Fig. S1 even showing that for one fully sequenced isolate two of the single nucleotide differences were “N’s” — clearly the result of a sequencing error, 4) failure to use Southern blotting to confirm PCR results, and 5) primary nested PCR screening done in one lab as opposed to independent screening from start to finish in two different laboratories. Concerns have also been brought up with respect to the antigen testing” …

(probably more sequences have been determined thereafter. Nonetheless, it was questioned from (almost) the start….)

5 06 2011
KAL

Abby – Libel is a specific legal term with very specific criteria that have to be met. Lying or disagreement or even calling people nasty names do not in and of themselves constitute libel. Which quite frankly is fortunate for you as well.

Not defending the WPI or Dr. Mikovits or attacking you personally, but I believe this has all been handled very badly on many sides. But is the specific response you referred to libel? Not really.

6 06 2011
laikaspoetnik

FORGOT TO PUBLISH MY OWN COMMENT [12h ago]: @kal lets not discuss semantics here. If it is not legally libel, lets call it defamation and insult, because they made unfounded insinuations (accusing others of of malpractice in a way: deliberately not replicating studies etc). That is unprecedented in the scientific world and very unprofessional.
ERV (Abby) is the author of a blog with blunt, but well-founded critic. I would not use the same wording, but can still appreciate it. And often is so to the point, I can heartily laugh about it.

5 06 2011
ERV

laikaspoetnik– Ah, I was being snarky towards WPI not using Strider, not you :) Its ridiculously simple and ridiculously necessary software for any lab, not just retrovirologists. No excuse for their oversight.

KAL– I am aware of the legal definition of libel. Saying Judy Mikovits is a moron and displaying behaviors reflective of a woo-meister is not libel. Accusing other professional scientists of manipulating data, accepting bribes, and conspiring with government officials to withhold/misrepresent data in print is.

Mikovits and the WPI should count their blessings McClure et al did not take advantage of Britians libel laws. I would have.

6 06 2011
KAL

Abby,

Having read many of your posts, “moron” was probably the nicest thing you ever called Dr. Mikovits – most people who behave that way have no idea their slurs reflect as much on them as on the person they are attacking.

I was being neutral – this is not an attack, but simply pointing out a fact. You stepped over the line into defamation many times and given the tone of your multiple posts malice wouldn’t be that hard to prove. Probably a good thing Dr. Mikovits didn’t choose to sue you as well.

Both you and Judy probably need to clean up your acts in those specific areas and have a care. Her behavior doesn’t get you off the hook.

I respect your comments from a scientific standpoint for the most part, but your consistent inability to express your differences with others without stooping to defamation and curse words is highly unprofessional. I’ve not seen it from any other professional I’ve read and I read widely.

6 06 2011
Willow

ERV, how much does this Strider software cost? The reason I ask is that WPI operates on 1.2 million budget a year, for the facility and everything. That’s a fraction of the budget of single studies for other diseases.

6 06 2011
laikaspoetnik

The strider software is nice, because it visualizes the differences, but it is possible to see differences or lack thereof with the bare eye….

6 06 2011
ERV

KAL–Having read many of your posts, “moron” was probably the nicest thing you ever called Dr. Mikovits…
Thats the nicest handle she deserves.

It is clear you are not a lawyer. It is also clear you do not have any form of legal council. This is all clear because you clearly have no idea what you are talking about.

Its also clear you are attempting to silence dissent via putative legal threats.

Unfortunatley for you, I do have legal council, and I am not easily intimidated.

Pathetic.

6 06 2011
laikaspoetnik

@erv Just a quick response from my mobile: I find this an unnecessary hostile comment towards @kal.

6 06 2011
KAL

Abby – ROFL. Grow up sweetie. Nuff said.

6 06 2011
KAL

@Laika – Sorry. Wordsmiths, especially ones who have taken communications law, do have a tendency to focus on the lexicon. :D

I happen to agree with you regarding some of Dr. Mikovits conduct. I thought I was clear that I was not defending her or her chosen actions. I actually have made the same neutral points to the WPI. However it doesn’t make Abby’s insults and petty attacks on anyone she disagrees with professional simply because Dr. Mikovits pulls the same ridiculous and childish stuff.

I was also specific in saying I didn’t have a problem with Abby’s scientific analysis necessarily just the lack of professionalism. And yes, she has made me laugh as well when she manages to produce a piece that isn’t dripping with venom and laced with profanity.

Guess I’m just old fashioned. I was brought up that if you weren’t articulate enough to make your point without using profanity it was better to keep your mouth shut. Abby and I obviously were not raised the same way.

I think it is time to move on don’t you. :D

7 06 2011
Willow

There’s a simple explanation for finding XMRV in similar or equal proportions in van Kuppeveld’s cohort as the controls. Van Kuppeveld’s cohort was selected using Oxford inclusion for “CFS”, which is an inclusion which selects basically anyone who has prolonged fatigue, and (when used for research, as opposed to clinical, purposes) excludes anyone who has any obvious evidence of neurological or immune dysfunction. These are patients which, according to the CDC’s Fukuda criteria, have “chronic fatigue” or “idiopathic fatigue”, not “Chronic Fatigue Syndrome.”

The Lombardi cohort, on the other hand, was selected using Canadian criteria, which requires signs and symptoms of neurological and immune dysfunction (they also mentioned the Fukuda criteria, apparently to ground the research to recent findings and give a nod to the most widely accepted of currently-used criteria… pretty much anyone who meets Canadian criteria will also meet Fukuda, although a significant minority of patients who meet Fukuda, do not meet Canadian criteria; the Fukuda does not require any sign or symptom specific to ME/CFS and can be easily met by someone with a missed diagnosis of Lupus, MS, MDD, etc).

Thus the Oxford and Canadian criteria are mutually exclusive, and the van Kuppeveld cohort probably contains no true ME/CFS cases (with post-exertional malaise; ME/CFS is registered with WHO as a neurological disease, and the Canadian criteria most closely matches the Ramsay criteria for ME which earned this listing, so it is easy to see which is the “right” cohort… besides common sense which tells you you can no more study a disease by finding people with fatigue, than you can by finding people with cough or breathlessness). This is not to say the van Kuppeveld isn’t sick with something, and something which may be serious, important, disabling, etc. Just that whatever diseases the patients in that cohort have, it’s probably a collection of various different diseases, probably none of which are ME/CFS or any other neurological conditions.

van Kuppeveld’s cohort has no evidence of apoptosis in white blood cells, unlike better-characterized ME/CFS patients:
http://www.ncbi.nlm.nih.gov/pubmed/8568312 van der Meer
“Expression of CD11b on CD8 cells was significantly decreased in CFS patients… There was no obvious difference in apoptosis in leukocyte cultures, circulating cytokines, and ex vivo production of interleukin (IL)-1 alpha and IL-1 receptor antagonist. Endotoxin-stimulated ex vivo production of tumor necrosis factor-alpha and IL-beta was significantly lower in CFS. ” (Oxford “CFS”, which again should be called CF because new-onset prolonged debilitating fatigue is the only requirement)

http://www.ncbi.nlm.nih.gov/pubmed/7997849 Tirelli
http://www.ncbi.nlm.nih.gov/pubmed/15280416 Kennedy
http://www.ncbi.nlm.nih.gov/pubmed/20520837 Klimas (Fukuda modification with PEM required)
http://www.ncbi.nlm.nih.gov/pubmed/17693977 Milhaylova
PMID: 21619669 Brenu
PMID 20032425 Meeus
PMID 9824439 Ogawa
PMC267940 Klimas
PMID 2824604 Caligiuri

CD11b increased instead of decreased; studies finding increased apoptosis; multiple studies finding low NK cell function (lots more that I didn’t cite); various other immune abnormalities; together indicating a significant immune dysfunction and chronic or reactivating infection.

No neuro-immune disease = no increased incidence of XMRV (or MLV/ HGRV for that matter)

3 06 2011
Willow

So what will happen to people with ME/CFS now? If it is not XMRV, will all the interest go away, or will people like you continue to be interested in the disease?

Did you know that ME/CFS gets only $4-6 million in federal funds annually?

Do any of the following interest you?

Maes M, Twisk FN. “Why myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may kill you: disorders in the inflammatory and oxidative and nitrosative stress (IO&NS) pathways may explain cardiovascular disorders in ME/CFS.” Neuro Endocrinol Lett. 2009;30(6):677-93. Review. PMID: 20038921

Chia J, Chia A, Voeller M, Lee T, Chang R. “Acute enterovirus infection followed by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and viral persistence.” J Clin Pathol. 2010 Feb;63(2):165-8. Epub 2009 Oct 14. PMID: 19828908

Jammes Y, Steinberg JG, Delliaux S, Brégeon F. “Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses.” J Intern Med. 2009 Aug;266(2):196-206. Epub 2009 May 19. PMID: 19457057

Schutzer SE, Angel TE, Liu T, Schepmoes AA, Clauss TR, Adkins JN, Camp DG, Holland BK, Bergquist J, Coyle PK, Smith RD, Fallon BA, Natelson BH. “Distinct cerebrospinal fluid proteomes differentiate post-treatment lyme disease from chronic fatigue syndrome.” PLoS One. 2011 Feb 23;6(2):e17287. PMID: 21383843

Fletcher MA, Zeng XR, Maher K, Levis S, Hurwitz B, Antoni M, Broderick G, Klimas NG. “Biomarkers in chronic fatigue syndrome: evaluation of natural killer cell function and dipeptidyl peptidase IV/CD26.” PLoS One. 2010 May 25;5(5):e10817. PMID: 20520837

Peckerman A, LaManca JJ, Dahl KA, Chemitiganti R, Qureishi B, Natelson BH. “Abnormal impedance cardiography predicts symptom severity in chronic fatigue syndrome.” Am J Med Sci. 2003 Aug;326(2):55-60. PMID: 12920435

Hurwitz BE, Coryell VT, Parker M, Martin P, Laperriere A, Klimas NG, Sfakianakis GN, Bilsker MS. “Chronic fatigue syndrome: illness severity, sedentary lifestyle, blood volume and evidence of diminished cardiac function.” Clin Sci (Lond). 2009 Oct 19;118(2):125-35. PMID: 19469714

Whistler T, Jones JF, Unger ER, Vernon SD. “Exercise responsive genes measured in peripheral blood of women with chronic fatigue syndrome and matched control subjects.” BMC Physiol. 2005 Mar 24;5(1):5. PMID: 15790422

Zhang L, Gough J, Christmas D, Mattey DL, Richards SC, Main J, Enlander D, Honeybourne D, Ayres JG, Nutt DJ, Kerr JR. “Microbial infections in eight genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis.” J Clin Pathol. 2010 Feb;63(2):156-64. Epub 2009 Dec 2. PMID: 19955554

Twisk FN, Maes M. “A review on cognitive behavorial therapy (CBT) and graded exercise therapy (GET) in myalgic encephalomyelitis (ME) / chronic fatigue syndrome (CFS): CBT/GET is not only ineffective and not evidence-based, but also potentially harmful for many patients with ME/CFS.” Neuro Endocrinol Lett. 2009;30(3):284-99. Review. PMID: 19855350

VanNess, J, Snell, C, & Stevens, S. (2007) Diminished Cardiopulmonary Capacity During Post-Exertional Malaise. Journal of Chronic Fatigue Syndrome, 14(2): 77-85. (J CFS is Haworth Press and peer-reviewed)

3 06 2011
Willow

please note, the above is not a rhetorical question :)

5 06 2011
laikaspoetnik

Of course bloggers like me who blog about all kinds of topics will not cover anything that appears about CFS, but only really pioneering work, which looks very promising or which is controversial, that catch our eyes.

The paper of Mikovits, first caught my eye because it seemed groundbreaking. But the paper was seriosly flawed and could not be reproduced. And the attitude of Mikovits plus their involvement in the diagnostic test firm made me seriously doubt their findings.

Thus no, I don’t think I will blog a lot about CFS anymore. And certainly not about small studies that show a minor link. Of the above studies the potential harmful effects of CBT seems most interesting to me.

But there may be recent articles that may be interesting to review. Like the ones suggested to me by @zenmonkey on Twitter:

But generally speaking I fear that the XMRV/CFS debacle will have negative consequences for the attention for CFS in general.

5 06 2011
Willow

If you’re interested in the GET controversy, you may like to read Prof. Hooper’s dialog with Prof. White regarding the PACE trial which can be accessed here:
http://www.meactionuk.org.uk/Comments-on-PDW-letter-re-PACE.htm

Regarding the other studies, how are studies about ME/CFS ever going to be anything other than small, with essentially no funding at all? How are the studies going to show a clear effect, when the official inclusion criteria are muddy and do not require anything specific to the disease (some require only fatigue, some have fatigue plus a polythetic list of other symptoms, but none [except the Canadian, which is rarely used] has any requirement for anything specific to this particular disease, such as post-exertional malaise)?

That’s the problem I’m talking about. You have about 1 million extremely sick, debilitated people in America, and about 17 million of them around the world. Many of these people have no appropriate medical intervention. Instead they are laughed at, patronized, given harmful interventions such as graded exercise, and generally abused by their own physicians, their own relatives, and society at large.

We have some excellent indications what’s wrong and where research funds would be best directed. We have essentially no research funds.

And the band plays on.

6 06 2011
laikaspoetnik

Observational studies can be done with larger populations. And I’m never interested in very small links (<2 times higher chance of getting a rare disease). Like the link described in the paper: Evidence for a Heritable Predisposition to Chronic Fatigue Syndrome (http://www.biomedcentral.com/1471-2377/11/62/abstract).

But anyway, we were only discussing to which extent I would find new ME/CFS findings interesting enough to BLOG about. Since my blog is not about XMRV or ME/CFS I only pick up the most remarkable papers.

That doesn't mean research that what I don't blog about isn't important.
I understand your point, the difficulty of getting research done, the difficulty of getting research funded. I 'm in a somewhat similar situation, because no one is interested in the disease I'm having and it is therefore very difficult to find finances for new research that would improve quality of life or for a simple small esky to take the emergency ampules along on vacation. (Compare that to what is done for diabetes patients). However, the cause is found and can be treated. Yours is not.

5 06 2011
Willow

I did forget to say, thanks in advance for your interest in the cerebralspinal fluid study and the Light study–I thought thouse were both fascinating, too. :)

6 06 2011
Willow

I don’t know what disease you have that doesn’t get enough funding. I do understand there are a few of those out there. I didn’t quite understand what problem this creates, but I hope it’s able to be solved.

The Light studies I found interesting were these:

Light AR, et al, “Moderate Exercise Increases Expression for Sensory, Adrenergic, and Immune Genes in Chronic Fatigue Syndrome Patients But Not in Normal Subjects,” J Pain, 2009 Oct;10(10):1099-112. Epub 2009 Jul 31. PMID: 19647494

Light AR, Bateman L, Jo D, Hughen RW, Vanhaitsma TA, White AT, Light KC. “Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome, and Fibromyalgia Syndrome.” J Intern Med. 2011. PMID: 21615807

What I was trying to ask you, and apparently not being very clear about, is, would you please continue to speak up for ME/CFS, regardless of whether you see any very compelling studies to blog about, purely on humanitarian grounds?

6 06 2011
laikaspoetnik

Thanks for the clarification. yes I will try to do so, but in balance with the other topics. CFS patients can help me (like you did) by alerting me to new science they find promising or highly interesting.

6 06 2011
Willow

You’re a gem! Thank you.

3 06 2011
KAL

An excellent professional piece as always and a pleasure to read as it is not laced with profanity. You are correct as always – there was no fraud here, just doubt. Will this unusual retraction set a precedent in unrelated work?

In another article Dr. McClure says she is furious about the money wasted on further studies. This is slightly disingenuous. No one held a gun to her head or that of any other researcher forcing them to spend money just because another group stood by their findings – no matter how flawed they turned out to be.

If at any time researchers felt there were sufficient negative studies they could have stopped spending money. Lombardi et al continues to stand by their ever changing study, but that doesn’t necessarily mean more studies need to be done. Nor are negative studies necessarily a waste of money.

As well, Dr. McClure was among the first to publish and there were variables such as patient definition (possibly studying peaches and calling them apples), differing protocols etc that her group did not address. Variables that subsequent studies ruled out – Switzer et al even did a second paper that did address variables they did not account for in their first paper because it was a legitimate scientific concern.

Would it have saved money if Dr. McClure and some of the early papers had addressed these variables to begin with? Maybe, and of course finger pointing is free no matter whose finger it is including mine.

What some commentators noted and authors from several of the most recent negative studies said was best summed up by Chin et al:

“It is also vital to state that there is still a wealth of prior data… to encourage further research into the involvement of other infectious agents in CFS, and these efforts must continue.

Dr. Racaniello, whose popular peer review based blog has covered every twist and turn – teaching as he went, also said that the lack of XMRV involvement does not mean CFS is not an infectious disease.

I would be astonished if Lipkin’s study or the study of the Blood Working group definitively link XMRV to CFS, but Lipkin is also working on a metagenomics study which includes carefully defined CFS patients. And infectious disease specialist Dr. Jose Montoya at the Stanford University in the U.S. is also working on a study looking at multiple pathogens or combinations of pathogens in carefully defined patients.

Positive or negative, the best science (and even flawed science) often results in many avenues for future work and occasionally opens up new fields of inquiry. That is priceless.

4 06 2011
Keith Grimaldi

Yet another nice post on this subject from you (and thanks for the link and kind words!).

I agree with your line on the call for retraction – it’s too late mate, the editor cannot say now that we don’t want the paper because it looks like it was wrong (that would apply to how many research reports??).

We have to accept, despite its shortcomings and lack of certain disclosures that the original work was reported in good faith so it is not correct or fair to ask for a retraction now having accepted it for publication – it would set a very uncomfortable precedent.

The expression of doubt is OK – but it could have had a few lines about why and how it got accepted in the first place – some mild “nostra culpa” would have been reasonable. This sentence towards the end was an understatement about the unfortunate consequences:

“The study by Lombardi et al. (1) attracted considerable
attention, and its publication in Science has had a far-reaching
impact on the community of CFS patients and beyond”

By coincidence we had a debate last week on the excellent Italian blog MyGenomix (http://bit.ly/k02XmF – with link to google translated english version, quite readable!) about when and where to publish (prompted by a previous post on the RNA editing story, also in Science – along with longevity genes and arsenic!) – publishing in Science does have consequences. Yes they don’t want to miss a groundbreaking study but it is better to miss 10 of them than publish one that is wrong. These sort of studies, where there are any doubts about methods, controls etc have a place in the literature – rapid publication, minimal peer review, to accellerate the discovery process without making major claims and to get your priority established if it turns out right. PLosONE is excellent for this type of work.

Also press releases pimping upcoming content should be banned, the abstracts should speak for themselves – luckily in this case the damage appears to have been contained and it avoided becoming like the MMR vaccine tragedy (and remember that was press released, press conferenced, and published in extremely high impact journal the Lancet, yet it was a report of a study based on just 12 cases).

4 06 2011
ERV

We have to accept, despite its shortcomings and lack of certain disclosures that the original work was reported in good faith so it is not correct or fair to ask for a retraction now having accepted it for publication – it would set a very uncomfortable precedent.
I would argue that this scenareo will absolutely be part of setting a new precedent.

When scientists publish a paper in good faith, and it turns out the foundation of the paper and all the conclusions it contains were the result of lab contamination/artifact, the authors retract the paper on their own accord.

That ‘Science’ had to issue their statement, and that the authors are declining to retract is novel, but only because the authors behaviors are so non-standard. We have never had to deal with scientists who refuse to retract an unsalvageably wrong paper of their own volition (the only one I can think of is Andrew Wakefield himself, the other authors pulled voluntarily).

So now the field has to determine what to do when this happens.

Its certainly uncomfortable, but its not because of other scientists behavior or the scientific process as a whole. its because of Lombardi et als strange behavior, and no one knows what to do about it.

5 06 2011
laikaspoetnik

That ‘Science’ had to issue their statement, and that the authors are declining to retract is novel, but only because the authors behaviors are so non-standard.

Since when is this [authors behaviors] sufficient reason to retract a paper?

I would not be surprised if the paper ends up retracted, – and I would be the last to object to it- once it is really clear it is completely false, but lets await the final results of the ongoing studies. Or in other words, don’t retract till it is 100% sure the data are false.

It would not be desirable to set a precedent that papers are retracted because of (serious) doubt only. Furthermore if one paper with false positive data is retracted, others should follow.

(by the way from a librarian standpoint I wonder whether mere retraction doesn’t affect the retrieval of such a paper. One should always be able to access the erroneous data. So I would rather see a red stamp: retracted).

But my main point wasn’t that the paper doesn’t deserve retraction. It is more that I’m wary of Science real intentions.

Like @eurogene explains so well: Yes they [science] don’t want to miss a groundbreaking study but it is better to miss 10 of them than publish one that is wrong. . So I found they had should have done a better job to peer review the paper and not just go for the glory. The same is true for PNAS that doesn’t “accept several XMRV negative papers also of high caliber science”, but only high sensationalist positive papers. (your last post – & I agree).

My main point thus is that I find Science editors are chickening out of the situation, they have created thenselves. (approving sensationalist paper without appropriate peer review.)

5 06 2011
ERV

Since when is this [authors behaviors] sufficient reason to retract a paper?
I dont mean their questionable recreational activities (as non-standard as they are). I mean their refusal to retract an unsalvageable paper is non-standard– the entirety of the data and the entirety of their conclusions are based on a contamination. A lab artifact. A normal scientist would voluntarily retract a paper if this happened to them– it sucks, but shit happens. This has happened before, and it will happen again. Could happen to me tomorrow *shrug*

But these authors refuse to retract.

I dont think that has ever happened before.

5 06 2011
laikaspoetnik

Ok. Thanks. Oh, yes it is quite extra-ordinary for authors to adhere to their data, that are crumbling day by day. I don’t understand their attitude either. I even doubted myself when my data were right. I used to drive my supervisor mad with all my “buts” and “perhaps”. It is so U-N-S-C-I-E-N-T-I-F-I-C not to doubt your data when no one can reproduce them and there is clear indication why you are wrong. It is so U-N-S-C-I-E-N-T-I-F-I-C NOT to take the doubts serious. Still I remain with my point of view, that the attitude of Science is not of a very high standard. They’re taking the easy way out.

10 06 2011
RRM

I think it is different in that the Lombardi et al. authors are implicitly using ScienceMag’s reputability to keep advancing their views. Even in her reply to Bruce Alberts, Mikovits only really centered on the original study and its seemingly infallible methodology.

If someone would use my name (luckily nobody will ;-) ) to argue “I am right, I am right, it’s in RRM’s magazine and therfore I am right” on a finding that is very probably false, I would also act on it in some way. Not because of politics, but because my (purely hypothetical) reputability would be on the line. It wouldn’t really matter if I would have made a mistake earlier or not.

P.S. Her reply to Alberts is grounds for retraction in itself, IMO, as she basically admits that the protocols that the Science authors originally described will not yield the results that were originally reported.

P.P.S. Despite the above, I still feel it’s a good decision not to retract as of now. It would potentially endanger the Lipkin study, which is still useful, if only to convince.

4 06 2011
Jack

A newbie I am afraid, but a very fine read nonetheless Laika.

All this information is usually so scattered, that I find it particuarly helpful these days, to have it presented so succinctly.

Many thanks

5 06 2011
laikaspoetnik

Thanks, nice to hear you found the paper helpful.

5 06 2011
Keith Grimaldi

@ERV

Yes you have a reasonable point which I accept. But has it been shown beyond doubt that the Lombardi results are were due to contamination/artifact? I don’t know, I’m not up on all the literature, you certainly are – I am going mainly on Laikas’ points (e.g “And why doesn’t Science await the results from the official confirmation studies meant to finally settle whether XMRV exist in our blood supply and/or CFS”).

Maybe they are becoming somewhat “Wakefieldesque” – but I agree with you, if it shown that they are definitley wrong then they should retract. But it fairness is must be demonstrated with a high level of evidence that artifact/contamination is the cause before demanding retraction. Shouldn’t have been published in the first place, not in Science, but retraction has to be handled with care

5 06 2011
wingfingers

To start to review this article, I have to state that is made up of English words that are strung together in an order which lets them appear to make sense. However the article is made up of so many untruths and pure conjectures that it is difficult to know where to start.
Even in the first sentence, it mentions that the seminal article in “Science” has been “debunked”. Nothing could be further from the truth. The authors of that article were asked to retract it from “Scence” but have completely refused to do so, quite rightly too.
The second sentence claims that the original article “falsely concluded” that the virus was “responsible”. In fact the authors claimed only that the virus was “associated” with ME(CFS) and never claimed causality.
Third sentence, an “Editorial Expression of Concern” is normally only used when there has been evidence of outright fraud. It is deprecatory to the magazine’s reputation to issue one, and very unusual in respect of an article where the field is still wide open and there are many more investigations in the pipeline. It was a huge mistake for the Editor to take this action.
Second para, second sentence – yes, anti-retroviral drugs have been prescribed to a small number of people. The drugs are normally used for AIDS but are safe enough, under medical supervision, to be given to uninfected people as a preventative (usually family members or healthy partners of gays). Most of these patients have been on the drugs for a year or more and are showing massive and steady improvements. You see, one way to prove that the disease – any disease – is caused by say a retrovirus, is to give a patient the appropriate treatment – it’s called “trial therapy” – if the drug works, you have the diagnosis in one.
Third para – not only do the recent studies fail to prove that XMRV doesn’t cause, or is associated with, ME(CFS), but the mudslinging rumour about “contamination” is pure speculation and totally wrong on all levels. Neither was the original study “severely botched”. In fact, Science was reluctant to publish it in the first place, being that the WPI was new to Science as the Institute had just been established, so they made the WPI run many extra tests to prove to everyone’s satisfaction that there was no contamination. The XMRV virus is not a mouse virus – it can’t multiply in lab mice; the WPI had no mice nor mouse tissues in its lab; and all their reagents, like the heparin used to prevent blood clotting, were also carefully scanned for contamination.
The trouble is that the XMRV virus is not only very small, it is very elusive, only found in very small numbers in the blood as it hides away in deeper organs. It is fragile and easily damaged by repeat freezing or wrong blood anticoagulants. If it were easy to find, we could have found it years ago. The techniques that the WPI needed to develop to find it, took them 8 months to develop, to tweak, hone and polish. They didn’t just use the basic PCR test, which was all that the negative studies used, but they amplified the virus by multiplying it in a special human cell line; they used a complicated “nested PCR” test for identification; they sequenced its genome; they took electron micrographs of it; and they found that many of the patients’ samples contained antibodies to it, something that would be impossible if it were due to sample or laboratory contamination. XMRV is now being found around the word, Spain, Germany and I think Japan.
One of the hallmarks of an XMRV Denier is that, as opposed to honest but confused scientists, they try to suggest that patients don’t even try antiretrovirals, on the grounds that they may be dangerous (they may be no worse, if at all, than some antibiotics). These deniers don’t want the work on XMRV to continue, they’re trying to put a block on it, to sweep it under the carpet. Their panic reaction in producing all the negative XMRV papers, gives their game away – what they mean is that they actually believe that XMRV might be the cause of ME(CFS) but they don’t want it to “get out”, as these people have many vested interests. (That itself is another long & complicated story).

5 06 2011
laikaspoetnik

@wingfingers Sorry I started to review your response, but failed to understand which article you are discussing. “Even in the first sentence, it mentions that the seminal article in “Science” has been “debunked”. That is not the first sentence of my post and not the first sentence of Science’s issue of concern. Please discuss either my post or specify what you are referring to….

7 06 2011
To Retract or Not to Retract… That’s the Question « Laika's MedLibLog

[...] Retract or Not to Retract… That’s the Question 7 06 2011 In the previous post I discussed [1] that editors of Science asked for the retraction of a paper linking XMRV retrovirus to [...]

4 10 2011
May

Thank you for this useful information!!!

from mba-degree-program.blogspot dot com

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