Trial By Error, Continued: Did the PACE Study Really Adopt a ‘Strict Criterion’ for Recovery?

By David Tuller, DrPH

David Tuller is academic coordinator of the concurrent masters degree program in public health and journalism at the University of California, Berkeley.

First, some comments: When Virology Blog posted my very, very, very long investigation of the PACE trial two weeks ago, I hoped that the information would gradually leak out beyond the ME/CFS world. So I’ve been overwhelmed by the response, to say the least, and technologically unprepared for my viral moment. I didn’t even have a photo on my Twitter profile until yesterday.

Given the speed at which events are unfolding, I thought it made sense to share a few thoughts, prompted by some of the reactions and comments and subsequent developments.

I approached this story as a journalist, not an academic. I read as much as I could and talked to a lot of people. I did not set out to write the definitive story about the PACE trial, document every single one of its many oddities, or credit everyone involved in bringing these problems to light. My goal was to explain what I recognized as some truly indefensible flaws in a clear, readable way that would resonate with scientists, public health and medical professionals, and others not necessarily immersed in the complicated history of this terrible disease.

To do that most effectively and maximize the impact, I had to find a story arc, some sort of narrative, to carry readers through 14,000 words and many dense explanations of statistical and epidemiologic concepts. After a couple of false starts, I settled on a patient and advocate, Tom Kindlon, as my “protagonist”—someone readers could understand and empathize with. Tom is smart, articulate, and passionate about good science–and he knows the PACE saga inside out. He was a terrific choice whose presence in the story, I think, made reading it a lot more bearable.

That decision in no way implied that Tom was the only possible choice or even the best possible choice. I built my work on the work of others, including many that James Coyne recently referred to as “citizen-scientists.” Tom’s dedication to tracking and critiquing the research has been heroic, given his health struggles. But the same could be said, and should be said, of many others who have fought to raise awareness about the problems with PACE since the trial was announced in 2003.

The PACE study has generated many peer-reviewed publications and a healthy paper trail. My account of the story, notwithstanding its length, has significant gaps. I haven’t finished writing about PACE, so I hope to fill in some of them myself—as with today’s story on the 2011 Lancet commentary written by colleagues of Peter White, the lead PACE investigator. But I have no monopoly on this story, nor would I want one—the stakes are too high and too many years have already been wasted. Given the trial’s wealth of problems and its enormous influence and ramifications, there are plenty of PACE-related stories left for everyone to tackle.

I am, obviously, indebted to Tom—for his good humor, his willingness to trust me given so many unfair media portrayals of ME/CFS, and his patience when I peppered him with question after question via Facebook, Twitter, and e-mail.

I am also indebted to my friend Valerie Eliot Smith. We met when I began research on this project in July, 2014; since then, she has become an indispensible resource, offering transatlantic support across multiple domains. Valerie has given me invaluable legal counsel, making sure that what I was writing was verifiable and, just as important, defendable—especially in the U.K. (I don’t want to know how many billable hours she has invested!) She has provided keen strategic advice. She has been a terrific editor, whose input greatly improved the story’s flow and readability. She has done all this, I realize, at some risk to her own health. I am lucky she decided to join me on this unexpected journey.

I would like to thank, as well, Dr. Malcolm Hooper, Margaret Williams, Dr. Nigel Speight, Dr. William Weir, Natalie Boulton, Lois Addy, and the Countess of Mar for their help and hospitality while I was in England researching the story last year. I will always cherish the House of Lords plastic bag that I received from the Countess. (The bag was stuffed with PACE-related reports and documents.)

So far, Richard Horton, the editor of The Lancet, has not responded to the criticisms documented in my story. As for the PACE investigators, they provided their own response last Friday on Virology Blog, followed by my rebuttal.

In seeking that opportunity for the PACE investigators to respond, a public relations representative from Queen Mary University of London, or QMUL, had approached Virology Blog. In e-mails to Dr. Racaniello, the public relations representative had suggested that “misinformation” and “inaccuracies” in my article had triggered social media “abuse” and could cause “reputational damage.”

These are serious charges, not to be taken lightly. Last Friday’s exchange has hopefully put an end to such claims. It seems unlikely that calling rituximab an “anti-inflammatory” rather than an “immunomodulatory” drug would trigger social media abuse or cause reputational damage.

Last week, in an effort to expedite Virology Blog’s publication of the PACE investigators’ response, the QMUL public relations representative further charged that I had not sought their input before the article was posted. This accusation goes to the heart of my professional integrity as a journalist. It is also untrue—as the public relations representative would have known had he read my piece or talked to the PACE investigators themselves. (Whether earlier publication of their response would have helped their case is another question.)

Disseminating false information to achieve goals is not usually an effective PR strategy. I have asked the QMUL public relations representative for an explanation as to why he conveyed false information to Dr. Racaniello in his attempt to advance the interests of the PACE investigators. I have also asked for an apology.


 

Since 2011, the PACE investigators have released several papers, repeatedly generating enthusiastic news coverage about the possibility of “recovery”–coverage that has often drawn conclusions beyond what the publications themselves have reported.

The PACE researchers can’t control the media and don’t write headlines. But in at least one case, their actions appeared to stimulate inaccurate media accounts–and they made no apparent effort immediately afterwards to correct the resulting international coverage. The misinformation spread to medical and public health journals as well.

(I mentioned this episode, regarding the Lancet “comment” that accompanied the first PACE results in 2011, in my excruciatingly long series two weeks ago on Virology Blog. However, that series focused on the PACE study, and the comment itself raised additional issues that I did not have the chance to explore. Because the Lancet comment had such an impact on media coverage, and ultimately most likely on patient care, I felt it was important to return to it.)

The Lancet comment, written by Gils Bleijenberg and Hans Knoop from the Expert Centre for Chronic Fatigue at Radboud University Nijmegen in the Netherlan was called “Chronic fatigue syndrome: where to PACE from here?” It reported that 30 percent of those receiving the two rehabilitative interventions favored by the PACE investigators–cognitive behavior therapy and graded exercise therapy–had “recovered.” Moreover, these participants had “recovered” according to what the comment stated was the “strict criterion” used by the PACE study itself.

Yet the PACE investigators themselves did not make this claim in their paper. Rather, they reported that participants in the two rehabilitative arms were more likely to improve and to be within what they referred to as “the normal range” for physical function and fatigue, the study’s two primary outcome measures. (“Normal range” is a statistical concept that has no inherent connection to “normal functioning” or “recovery.” More on that below.)

In addition, the comment did not mention that 15 percent of those receiving only the baseline condition of “specialist medical care” also “recovered” according to the same criterion. Thus, only half of this 30 percent “recovery” rate could actually be attributed to the interventions.

The PACE investigators themselves reviewed the comment before publication.

Thanks to this inaccurate account of the PACE study’s reported findings, the claim of a 30 percent “recovery” rate dominated much of the news coverage. Trudie Chalder, one of the key PACE investigators, reinforced the message of the Lancet comment when she declared at the press conference announcing the PACE results that participants in the two rehabilitative interventions got “back to normal.”

Just as the PACE paper did not report that anyone had “recovered,” it also did not report that anyone got “back to normal.”

Three months later, the PACE authors acknowledged in correspondence in The Lancet that the paper did not discuss “recovery” at all and that they would be presenting “recovery” data in a subsequent paper. They did not explain, however, why they had not taken earlier steps to correct the apparently inaccurate news coverage about how patients in the trial had “recovered” and gotten “back to normal.”

*****

It is not unusual for journals, when they publish studies of significance, to also commission commentaries or editorials that discuss the implications of the findings. It is also not unusual for colleagues of a study’s authors to be asked to write such commentaries. In this case, Bleijenberg and Knoop were colleagues of Peter White, the lead PACE investigator.  In 2007, the three had published, along with two other colleagues, a paper called “Is a full recovery possible after cognitive behavior therapy for chronic fatigue syndrome?” in the journal Psychotherapy and Psychosomatics.

(In their response last Friday to my Virology Blog story, the PACE investigators noted that they had published a “correction” to clarify that the 2011 Lancet paper was not about “recovery”; presumably, they were referring to the Lancet correspondence three months later. In their response to Virology Blog, they blamed the misconception on an “editorial…written by others.” But they did not mention that those “others” were White’s colleagues. In their response, they also did not explain why they did not “correct” this “recovery” claim during their pre-publication review of the comment, nor why Chalder spoke at the press conference of participants getting “back to normal.”)

In the Lancet comment, Bleijenberg and Knoop hailed the PACE team for its work. And here’s what they wrote about the trial’s primary outcome measures for physical function and fatigue: “PACE used a strict criterion for recovery: a score on both fatigue and physical function within the range of the mean plus (or minus) one standard deviation of a healthy person’s score.”

This statement was problematic for a number of reasons. Given that the PACE paper itself made no claims for “recovery,” Bleijenberg and Knoop’s assertion that it “used” any criterion for “recovery” at all was false. The PACE study protocol had outlined four specific criteria that constituted what the investigators referred to as “recovery.” Two of them were thresholds on the physical function and fatigue measures, but the Lancet paper did not present data for the other criteria and so could not report “recovery” rates.

Instead, the Lancet paper reported the rates of participants in all the groups who finished the study within what the researchers referred to as “the normal ranges” for physical function and fatigue. But as noted immediately by some in the patient community, these “normal ranges” featured a bizarre paradox: the thresholds for being “within the normal range” on both the physical function and fatigue scales indicated worse health than the entry thresholds required to demonstrate enough disability to qualify for the trial in the first place.

*****

To many patients and other readers, for the Lancet comment to refer to “normal range” scales in which entry and outcome criteria overlapped as a “strict criterion for recovery” defied logic and common sense. (According to data not included in the Lancet paper but obtained later by a patient through a freedom-of-information request, 13 percent of the total sample was already “within normal range” for physical function, fatigue or both at baseline, before any treatment began.)

In the Lancet comment, Bleijenberg and Knoop also noted that these “normal ranges” were based on “a healthy person’s score.” In other words, the “normal ranges” were purportedly derived from responses to the physical function and fatigue questionnaires by population-based samples of healthy people.

But this statement was also at odds with the fact. The source for the fatigue scale was a population of attendees at a medical practice—a population that could easily have had more health issues than a sample from the general population. And as the PACE authors themselves acknowledged in the Lancet correspondence several months after the initial publication, the SF-36 population-based scores they used to determine the physical function “normal range” were from an “adult” population, not the healthier, working-age population they had inaccurately referred to in The Lancet. (An “adult” population includes the elderly.)

The Lancet has never corrected this factual mistake in the PACE paper itself. The authors had described—inaccurately–how they derived a key outcome for one of their two primary measures. This error indisputably made the results appear better than they were, but only those who scrutinized the correspondence were aware of this discrepancy.

The Lancet comment, like the Lancet paper itself, has also never been corrected to indicate that the source population for the SF-36 responses was not a “healthy” population after all, but an “adult” one that included many elderly. The comment’s parallel claim that the source population for the fatigue scale “normal range” was “healthy” as well has also not been corrected.

Richard Horton, the editor of The Lancet, did not respond to a request for an interview to discuss whether he agreed that the “normal range” thresholds represented “a strict criterion for recovery.” Peter White, Trudie Chalder and Michael Sharpe, the lead PACE investigators, and Gils Bleijenberg, the lead author of the Lancet comment, also did not respond to requests for interviews for this story.

*****

How did the PACE study end up with “normal ranges” in which participants could get worse and still be counted as having achieved the designated thresholds?

Here’s how: The investigators committed a major statistical error in determining the PACE “normal ranges.” They used a standard statistical formula designed for normally distributed populations — that is, populations in which most people score somewhere in the middle, with the rest falling off evenly on each side. When normally distributed populations are graphed, they form the classic bell curve. In PACE, however, the data they were analyzing was far from normally distributed. The population-based responses to the physical function and fatigue questionnaires were skewed—that is, clustered toward the healthy end rather than symmetrically spread around a mean value.

With a normally distributed set of data, a “normal range” using the standard formula used in PACE—taking the mean, plus/minus one standard deviation–contains 68 percent of the values. But when the values are clustered toward one end, as in the source populations for physical function and fatigue, a larger percentage ends up being included in a “normal range” calculated using this same formula. Other statistical methods can be used to calculate 68 percent of the values when a dataset does not form a normal distribution.

If the standard formula is used on a population-based survey with scores clustered toward the healthier end, the result is an expanded “normal range” that pushes the lower threshold even lower, as happened with the PACE physical function scale. And in PACE, the threshold wasn’t just low–it was lower than the score required for entry into the trial. This score, of course, already represented severe disability, not “recovery” or being “back to normal”—and certainly not a “strict criterion” for anything.

Bleijenberg and Knoop, the comment authors, were themselves aware of the challenges faced in calculating accurate “normal ranges,” since the issue was addressed in the 2007 paper they co-wrote with Peter White. In this paper, White, Bleijenberg, and Knoop discussed the concerns related to determining a “normal range” from population data that was heavily clustered toward the healthy end of the scale. The paper noted that using the standard formula “assumed a normal distribution of scores” and generated different results under the “violation of the assumptions of normality.”

*****

Despite the caveats the three scientists included in this 2007 paper, Bleijenberg and Knoop’s 2011 Lancet comment did not mention these concerns about distortion arising from applying the standard statistical formula to values that were not normally distributed. (White and his colleagues also did not mention this problem in the PACE study itself.)

Moreover, the 2007 paper from White, Bleijenberg, and Knoop had identified a score of 80 on the SF-36 as representing “recovery”—a much higher “recovery” threshold than the SF-36 score of 60 that Bleijenberg and Knoop now declared to be a “strict criterion” In the Lancet comment, the authors did not mention this major discrepancy, nor did they explain how and when they had changed their minds about whether an SF-36 score of 60 or 80 best represented “recovery.” (In 2011, White and his colleagues also did not mention this discrepancy between the score for “recovery” in the 2007 paper and the much lower “normal range” threshold in the PACE paper.)

Along with the PACE paper, The Lancet comment caused an uproar in the patient and advocacy communities–especially since the claim that 30 percent of participants in the rehabilitative arms “recovered” per a “strict criterion” was widely disseminated.

The comment apparently caused some internal consternation at The Lancet as well. In an e-mail to Margaret Williams, the pseudonym for a longtime clinical manager in the National Health Service who had complained about the Lancet comment, an editor at the journal, Zoe Mullan, agreed that the reference to “recovery” was problematic.

“Yes I do think we should correct the Bleijenberg and Knoop Comment, since White et al explicitly state that recovery will be reported in a separate report,” wrote Mullan in the e-mail. “I will let you know when we have done this.”

No correction was made, however.

*****

In 2012, to press the issue, the Countess of Mar pursued a complaint about the comment’s claim of “recovery” with the (now-defunct) Press Complaints Commission, a regulatory body established by the media industry that was authorized to investigate the conduct of news organizations. The countess, who frequently championed the cause of the ME/CFS patient community in Parliament’s House of Lords, had long questioned the scientific basis of support of cognitive behavior therapy and graded exercise therapy, and she believed the Lancet’s comment’s claims of “recovery” contradicted the study itself.

In defending itself to the Press Complaints Commission, The Lancet acknowledged the earlier suggestion by a journal editor that the comment should be corrected.

“I can confirm that our editor of our Correspondence section, Zoe Mullan, did offer her personal opinion at the time, in which she said that she thought that we should correct the Comment,” wrote Lancet deputy editor Astrid James to the Press Complaints Commission, in an e-mail.

“Zoe made a mistake in not discussing this approach with a more senior member of our editorial team,” continued James in the e-mail. “Now, however, we have discussed this case at length with all members of The Lancet’s senior editorial team, and with Zoe, and we do not agree that there is a need to publish a correction.”

The Lancet now rejected the notion that the comment was inaccurate. Despite the explicit language in the comment identifying the “normal range” thresholds as the PACE trial’s own “strict criterion for recovery,” The Lancet argued in its response to the Press Complaints Commission that the authors were only expressing their personal opinion about what constituted “recovery.”

In other words, according to The Lancet, Bleijenberg and Knoop were not describing—wrongly–the conclusions of the PACE paper itself. They were describing their own interpretation of the findings. Therefore, the comment was not inaccurate and did not need to be corrected.

(In its response to the Press Complaints Commission, The Lancet did not explain why thresholds that purportedly represented a “strict criterion for recovery” overlapped with the entry criteria for disability.)

*****

The Press Complaints Commission issued its findings in early 2013. The commission agreed with the Countess of Mar that the statement about “recovery” in the Lancet comment was inaccurate. But the commission gave a slightly different reason. The commission accepted the Lancet’s argument that Bleijenberg and Knoop were trying to express their own opinion. The problem, the commission ruled, was that the comment itself didn’t make that point clear.

“The authors of the comment piece were clearly entitled to take a view on how “recovery” should be defined among the patients in the trial,” wrote the commission. However, continued the decision: “The authors of the comment had failed to make clear that the 30 per cent figure for ‘recovery’ reflected their view that function within “normal range’ was an appropriate way of ‘operationalising’ recovery–rather than statistical analysis by the researchers based on the definition for recovery provided. This was a distinction of significance, particularly in the context of a comment on a clinical trial published in a medical journal. The comment was misleading on this point and raised a breach of Clause 1 (Accuracy) of the Code.”

However, this determination seemed based on a msreading of what Bleijenberg and Knoop had actually written: “PACE used a strict criterion for recovery.” That phrasing did not suggest that the authors were expressing their own opinion about “recovery.” Rather, it was a statement about how the PACE study itself purportedly defined “recovery.” And the statement was demonstrably untrue.

Compounding the confusion, the Press Complaints Commission decision noted that the Lancet comment had been discussed with the PACE investigators prior to publication. Since the phrase “strict criterion for recovery” had thus apparently been vetted by the PACE team itself, it remained unclear why the commission determined that Bleijenberg and Knoop were only expressing their own opinion.

The commission’s response left other questions unanswered. The commission noted that the Countess had pointed out that the “recovery” score for physical function cited by the commenters was lower than the score required for entry. Despite this obvious anomaly, the commission did not indicate whether it had asked The Lancet or Bleijenberg and Knoop to explain how such a nonsensical scale could be used to assess “recovery.”.

*****

Notwithstanding the inaccuracy of the Lancet comment’s “recovery” claim, the commission also found that the journal had already taken “sufficient remedial action” to rectify the problem. The commission noted that the correspondence published after the trial had provided a prominent forum to debate concerns over the definition of “recovery.” The decision also noted that the PACE authors themselves had clarified in the correspondence that the actual “recovery” findings would be published in a subsequent paper.

In ruling that “sufficient remedial action” had already been taken, however, the commission did not mention the potential damage that already might have been caused by this inaccurate “recovery” claim. Given the comment’s declaration that 30 percent of participants in the cognitive behavior and graded exercise therapy arms had “recovered” according to a “strict criterion,” the message received worldwide dissemination—even though the PACE paper itself made no such claim.

Medical and public health journals, conflating the Lancet comment and the PACE study itself, also transmitted the 30 percent “recovery” rate directly to clinicians and others who treat or otherwise deal with ME/CFS patients.

The BMJ referred to the approximately 30 percent of patients who met the “normal range” thresholds as “cured.” A study in BMC Health Services Research cited PACE as having demonstrated “a recovery rate of 30-40%”—months after the PACE authors had issued their “correction” that their paper did not report on “recovery” at all. (Another mystery about the BMC Health Services Research report is the source of the 40 percent figure for “recovery.”) A 2013 paper in PLoS One similarly cited the PACE study—not the Lancet comment—and noted that 30 percent achieved a “full recovery.”

Given that relapsing after too much exertion is a core symptom of the illness, it is impossible to calculate the possible harms that could have arisen from this widespread dissemination of misinformation to health care professionals—all based on the flawed claim from the comment that 30 percent of participants had recovered according to the PACE study’s “strict criterion for recovery.”

And that “strict criterion,” it should be remembered, allowed participants to get worse and still be counted as better.

Comments on this entry are closed.

  • eafw

    Thank you very much for writing this series. I hope that your investigations will be brought to a wider audience as there is much in there that deserves a full airing.

    You are probably aware that the PACE/SMC media machine and propaganda has stepped up a gear or two, as the truth of this deeply flawed trial and the way it has been misrepresented is now being written about by others apart from ME sufferers

    The Telegraph and Spectator articles, the support from Lancet Psych, Wessely’s fairytale piece in mentalelf today, the pressure being put on you, the ducking and diving around who said what (as you have documented here) – all part of their campaign.

    Ironically we, ME sufferers, are dismissed as the “abusive” ones for questioning this ongoing fraud, and the harm done by it. Again thank you very much for speaking out.

  • Sasha

    Thank you again, David Tuller, for your hard work on covering this extraordinary story. Since your last blog was published – and no doubt inspired by the wave of public attention that you had managed to bring at last to PACE’s flaws – a petition was set up.

    It asks The Lancet and Psychological Medicine to retract the claims of improvement and recovery that you write about that were based on the ludicrous “normal ranges” for fatigue and physical function. It also asks for publication of the real recovery results using the per-protocol analyses.

    The petition has smashed all records for the ME community and has gained over 7,000 signatures in less than seven days.

    I hope everyone here will sign the petition and help spread the word about it:

    http://my.meaction.net/petitions/pace-trial-needs-review-now

    The petition’s background pages clearly and simply explain the issues, for those unfamiliar with the story.

    The target is 10,000 signatures. Please help us reach it.

  • Alison Orr

    I’m not actually well enough to properly absorb all the information in your articles, nor the responses from the PACE researchers. I am well enough, however, to understand that the PACE trial has been a debacle that the researchers should be ashamed of. I am immensely grateful to you for the depth of research you’ve undertaken and your persistance in answering criticisms, trying to clarify the doublethink of the Wessely school. Their persistance and lack of humility has me tearing my hair out. We will have our day, if I live long enough, and in large part due to people of integrity like you. Thank you.

  • Sasha

    David, as you’ll know, although the PACE authors didn’t claim in the Lancet paper that their absurd “normal ranges” represented recovery – though they did in their later Psychological Medicine paper – they did nevertheless make a strong claim on the basis of it.

    This is an excerpt from the PACE petition’s “What’s wrong in the Lancet?” page:

    ****

    But the authors treated the “normal ranges” as though being within them was evidence of good enough health to reflect effective treatment. They wrote:

    “No more than 30% of participants were within normal ranges for both outcomes and only 41% rated themselves as much better or very much better in their overall health. We suggest that these findings show that either CBT or GET, when added to SMC, is an effective treatment for chronic fatigue syndrome, and that the size of this effect is moderate.​”

    ****

    http://www.meaction.net/whats-wrong-in-the-lancet/

    So it’s disappointing that all the disapprobation gets directed at the editorial while plenty should also be directed at the PACE authors for this meaningless and inflated claim.

    Again, I hope that people will sign the petition.

  • Laura Vitale

    Thank you, David Tuller, for your willingness and perseverance to bring the truth to light regarding the deeply flawed PACE study. Your work on this awesome.

  • Erik Johnson

    See the problem here?
    Those of us who stumble over lowering the inflammatory response can exercise.
    Our “anomaly” seemingly supports the psychs view that it can be enforced.

    MEActionUK · Welcome to the home of UK ME Campaigning

    Re: FW: [CO-CURE] RES: Transcriptional Control of Complement Activation
    in an Exercise Model of Chronic Fatigue Syndrome

    Sat Nov 22, 2008 8:41 am

    Message #45885 of 70405

    — In MEActionUK@yahoogroups.com,
    “Tom Kindlon”

    wrote:

    >

    > “By contrast, expression of several complement genes remained at

    higher level in CFS subjects before and post-exercise indicating a

    lack of acute phase transcriptional response by these genes which may

    lead to localized and uncontrollable inflammation mediated tissue

    damage (37).”

    >

    Tom.

    During the 1985 Incline Village epidemic, I literally “stumbled” over

    a strange “effect” that I attempted to have investigated.

    There was ONE peculiar circumstance under which I could predictably

    exercise without paying a high post-exertional price and relapsing.

    When I was absolutely free of all neurotoxic inflammatory “triggers”

    prior to and during the exercise, the exercise seemed to help rather

    than hurt.

    The inflammatory response made the critically important difference

    between crashing or not.

    I asked Dr Cheney and Dr Peterson to help me research

    this “effect”, but they couldn’t bring themselves to believe it.

    As you know, I have been absolutely slamdunked out of CFS groups for

    trying to talk about this effect and the substance which controlled

    it. This is so bizarre that I can scarcely believe it myself.

    I know… it sounds crazy, but the substance was mold.

    -Erik Johnson

    “Mold Warriors” by Dr Ritchie Shoemaker.

    Chapt 23 “Mold at Ground Zero for CFS”

    “Answers from Abroad: Vindication for Erik” page 447.

    Dr Shoemaker writes: “Making me fall to the floor, he (Dr DeMeirleir)

    said “Oh, yes, we know a lot about mold exposure in the original

    cohort in Incline Village.

    The source of activation of the endopeptidase that cleaves RNase L is

    increased response of a cytokine, alpha interferon.”

    CFSFMExperimental Message #

    Search:

    Advanced

    my results from Fibro and fatigue center Message List

    Reply | Forward | Delete Jun 11 2005 Message #78224 of 125110

    Living at higher altitudes was Re: my results from Fibro and fatigue

    center/Erik

    Quote: Erik said:

    > Even if the Vascular Endothelial Growth Factor (VEGF) remains

    elevated by reprogramming, the EPO pulse does NOT and is only

    temporarily released in a “pulse” by hypoxia. Any beneficial effects

    are quickly overcome by re-exposure to biotoxins.

    >

    >

    >

    D Queries:

    > ***This in contrast to the quote by Dr Shoemaker pulled by Rich

    Vankonynenbergfrom “Mold Warriors” which we just read yesterday a few

    posts back.

    In it, Shoemaker indicates adequate VEGF as a result of EPO(as

    Procrit) alone can develop capillary beds, sustainably ameliorating

    and abating some key CFS biotoxic symptoms. Aside other protocol

    aspects, you seem to be saying that creating EPO pulsing as you do

    it is what is effective, not this Procrit therapy. Correct?

    >

    Erik responds: The quote from Dr Shoemaker was:

    “There is more good news about epo. Since the genes for VEGF and

    epo are both linked, that means that production of both is linked.

    When we see simultaneously normal levels of epo in blood and low

    VEGF, there is a gene transcription problem. Why does this matter?

    For some patients, the use of epo as a supplement can override what

    is called, ‘transcription block,’ can boost VEGF as well. For these

    patients, a short course of epo ‘resets’ the genes, defeats the

    block and there is no fall in VEGF after the epo pulse therapy is

    over. Those patients return to health and maintain that

    improvement.”

    So you see there is no contrast in my statement.

    The EPO is pulsed, the VEGF reprogramming is the result.

    But the process can be overcome by re-exposure to the offending

    irritant that incites the inflammatory response.

    Dr Shoemaker uses Actos to calm down this response to keep the

    inflammatory response modulated in order for the EPO reprogramming

    to be effective while the Cholestyramine to furthers this by

    adsorbing the recirculating toxins released by the shift in leptin

    signalling.

    Jonathan and I accomplish this artificially by removing all traces

    of the inflammatory irritant BEFORE inducing an EPO pulse by

    whatever amount of exercise begins to push the anaerobic threshold,

    and maintain this state WITHOUT going completely anaerobic.

    I believe this is why GET is moderately effective in some people and

    completely destructive in others – it all depends on the level of

    inflammatory response BEFORE an attempt to induce EPO is made.

    It’s the luck of the draw. People who are in an area of lesser

    toxins are allowed to reprogram VEGF while those in an inflammatory

    state demolish their Krebs cycle and crash.

    Jonathan took the chance out of the equation by monitoring the

    inflammatory response during GET and it paid off.

    I offered to make explain this to Peter Denton White and he shot me

    down cold. No surprise, but at least I can say I made the effort.

    -Erik

    ———————————————

    > —–Original Message—–

    > From: ME/CFS and Fibromyalgia Information Exchange Forum

    > [mailto:CO-CURE@…] On Behalf Of Fred Springfield

    > Sent: 19 November 2008 20:40

    > To: CO-CURE@…

    > Subject: [CO-CURE] RES: Transcriptional Control of Complement

    Activation in

    > an Exercise Model of Chronic Fatigue Syndrome

    >

    > Transcriptional Control of Complement Activation in an Exercise

    Model

    > of Chronic Fatigue Syndrome.

    >

    > Journal: Mol Med. 2008 Nov 16. [Epub ahead of print]

    >

    > Authors: Sorensen B, Jones JF, Vernon SD, Rajeevan MS.

    >

    > Affiliation: Division of Viral and Rickettsial Diseases, National

    > Center for Zoonotic, Vector-borne and Enteric Diseases, Centers for

    > Disease Control and Prevention, Atlanta, GA, USA 30333;

    >

    > NLM Citation: PMID: 19015737

    >

    >

    > Complement activation resulting in significant increase of C4a split

    > product may be a marker of post-exertional malaise in chronic

    fatigue

    > syndrome (CFS) subjects. This study was focused to identify the

    > transcriptional control that may contribute to the increased C4a in

    > CFS subjects post-exercise.

    >

    > Differential expression of genes in the classical and lectin

    pathways

    > were evaluated in peripheral blood mononuclear cells (PBMCs) using

    > quantitative reverse transcription PCR. Calibrated expression values

    > were normalized to internal (peptidylpropyl isomerase B [PPIB]) or

    > external (ribulose-1,5-bisphosphate carboxylase/oxygenase large

    > subunit [rbcL]) reference genes or geometric mean (GM) of genes

    > ribosomal protein, large, P0 (RPLP0) and phosphoglycerate kinase 1

    (PGK1).

    >

    > All nine genes tested, except mannose-binding lectin 2 (MBL2), were

    > expressed in PBMCs. At 1 hr post-exercise, C4, mannan-binding lectin

    > serine protease 2 (MASP2) and ficolin 1(FCN1 ) transcripts were

    > detected at higher levels (>/= 2-fold) in at least 50% (4 out of 8)

    > of CFS subjects that increased to 88% (7 out of 8) CFS subjects when

    > subjects with over-expression of either C4 or MASP2 were combined.

    > Only increase in MASP2 transcript was statistically significant

    > [PPIB, p=0.001; GM, p=0.047; rbcL, p=0.045]). This may be due to the

    > significant but transient down-regulation of MASP2 in control

    > subjects (PPIB, p = 0.023; rbcL, p = 0.027). By 6 hrs post-exercise,

    > MASP2 expression was similar in both groups.

    >

    > In conclusion, lectin pathway responded to exercise differentially

    > between CFS and controls subjects. MASP2 down-regulation may act as

    > an anti-inflammatory acute-phase response in healthy subjects,

    > whereas its elevated level may account for increased C4a and

    > inflammation mediated post-exertional malaise in CFS subjects.

    >

    MEActionUK · Welcome to the home of UK ME Campaigning

    #48366 of 72861

    Sat Jan 31, 2009 3:04 pm |

    Remember the significance of the VO2 Max test…. the variable level

    of oxygen uptake, and also remember Immune Complement Activation Factor

    C4A.

    It might prove handy later.

    -Erik

  • Erik Johnson

    I wonder how many people lowered their inflammation by getting outside, away from toxic irritants, and were able to exercise?
    But go back inside again and crash, after seemingly “disproving” their own illness.

    It’s like a self-defeating tautology.

  • Sasha

    Erik, I don’t know if you’re aware but your comment is literally five feet long (on my laptop monitor at least). I’m not joking – I measured it. And it seems to bear no relation to David Tuller’s article.

    I wonder if you’d consider putting this comment on a site of your own and perhaps providing a short link to it from here, if you feel it’s relevant?

    I’m sure you’d want to be fair to other people who are posting comments. With such a huge comment, others can’t be seen.

  • Brent

    Thank you very much for your hard work and effort in bringing out the truth.

  • Sandra

    Spot on. Thank you, David.

  • fractal

    > Why does almost everything about this disease end up in linguistic controversies?

    This group of psychiatrists have long decided that CFS is all in the mind, and that patients should not be told the truth “for their own good”. I suspect it has just as much to do with the fact that the idea of psychosomatic illness has no scientific basis and a long history of being discredited. So this not telling patients also serves self protection.

    The end result is vague language that is meant to conceal while suggesting at the same time, without ever outright saying it, or even denying it, and also being so vague to allow them to claim misunderstanding if needed.

  • Simone

    Thank you for yet another well-researched piece, David.

  • J.Elston

    Thank you David Tuller for your hard work for someone like me, who for over 30yrs of this illness, has no power, or the energy, any more, to fight the ‘big boys’ . Thank you for dissecting, and writing, what you see and have found, in a truthfully and honest article. Thank you again.

  • Mary Posa

    Dear David Tuller. First, I would like to thank you for your profound argument. Due to their length, I was not able to read your texts and the study authors’ answer in detail. Scanning them, however, I found no comment on one, in my opinion the most obvious, error in the
    PACE trial: The use of the Oxford Diagnostic Criteria. In case you included
    this point in his argument, then it should be made much stronger!

    In German media, the PACE trial is also an issue — there, too, without reference to the diagnostic criteria used for the patients included in the study – namely, as I understand, all patients whiche are chronically exhausted, which is NOT the same as suffering from ME/CFS .Why is this point so broadly ingnored?

    ( I posted a similiar question also under the study’s authors’ reaction, hoping that anyone will answer.)

  • A.M.

    Thank you David Tuller for once again covering these issues. I would like to add the following points about the denial of the erroneous interpretation of the normal range as “recovery”. The Lancet, with Bleijenberg and Knoop, *strongly* defended the comment. According to correspondence from the Countess of Mar to Peter White and Simon Wessely: [1]

    [The Deputy Editor goes on to state about my complaint to the Press Complaints Commission concerning the Comment: “We would like to reject this complaint in the strongest possible terms. We believe there are no inaccuracies….We have shared the complaint with Dr Bleijenberg and Dr Knoop and they stand by the content of their published Comment….They stand by their use of the term ‘recovery’….We stand by our publication of the Comment by Dr Bleijenberg and Dr Knoop, and have found no inaccuracy that warrants a correction. We hope that our response is clear”.]

    Such a strong defence for an obvious error is difficult to fathom, and not just because 60 points for SF-36 physical function is worse than the PACE trial entry threshold for significant disability; Bleijenberg and Knoop have both co-authored papers, before and after 2011, which consider 60 points to reflect either substantial or “severe” impairment. [2-5]

    In April 2011 Richard Horton (chief editor of the Lancet) launched a scathing attack on the critics of the trial and claimed that the criticisms of the trial were a “mirage”. He invited critics to submit letters for publication, as a test “of this particular section of the patient community to engage in a proper scientific discussion”. [6] Out of the eight letters to the editor formally published in the Lancet in May 2011, three address the normal range or its components. [7-9] An accompanying editorial authored by the Lancet proposed that there is an “an active campaign to discredit the research”. [10]

    Later in defence of the PACE trial, van der Meer & Lloyd (2012), who are both proponents of CBT and GET, falsely accused those letter writers of “unscientific and sometimes personal attacks”. [11] Although no apology was ever issued to the three letter writers who commented on the normal range, Lloyd & van der Meer (2015) have since conceded that the recovery criteria in the PACE trial was unduly liberal and based on overly generous thresholds. [12]

    Professor White and/or Queen Mary University of London have recently asserted that complaints to the Lancet and BMJ Rapid Responses are significant examples of harassment. [14] In April 2015 Horton published a general commentary about problems facing science, which identified “invalid exploratory analyses” as one of the factors why “science has taken a turn towards darkness”. [15]

    1. http://www.meactionuk.org.uk/Reply-to-PDW-and-Sir-Simon.htm

    2. http://www.ncbi.nlm.nih.gov/pubmed/17426416

    3. http://www.ncbi.nlm.nih.gov/pubmed/19689970

    4. http://www.ncbi.nlm.nih.gov/pubmed/22354999

    5. http://www.ncbi.nlm.nih.gov/pubmed/22865100

    6. http://www.abc.net.au/radionational/programs/healthreport/comparison-of-treatments-for-chronic-fatigue/2993296#transcript

    7. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60683-1/fulltext

    8. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60681-8/fulltext

    9. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60688-0/fulltext

    10. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2960696-X/fulltext

    11. http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2011.02468.x/full

    12. http://www.bmj.com/content/350/bmj.h2087

    13. http://www.bmj.com/content/350/bmj.h227/rr-16

    14. https://ico.org.uk/media/action-weve-taken/decision-notices/2015/1043579/fs_50558352.pdf

    15. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2815%2960696-1/fulltext

  • A.M.

    Before posting the last comment I deleted a paragraph but forgot to delete reference 13.

  • marmite234

    Claims about recovery have played a key role in the UK media’s understanding of the PACE trial’s results. That so many of this claims are indefensible is a bit of a problem.

  • Jo Best

    Excellent David, thanks much for your exceptional work on this.

  • John Leslie Whiting

    Dear David,

    Your commentaries have been and will continue to be an invaluable landmark to the scientific community, and as you have said yourself, by necessity you have conducted a lengthy enquiry in order to disclose deep flaws in the PACE study that might, at first glance, have been missed, that the PACE study’s authors and its publisher need to made aware of.

    I thank you for your diligence in clarifying these issues.

    Furthermore, the results of the PACE study were at odds with my own 27 year highly focused clinical experience with Chronic Fatigue Syndrome. The results of the PACE study did not resonate as either likely or true, based on a patient base larger than the PACE study, involving many patients who I have continued to see for 20 years or more. Your exposé explains in detail issues I have held firmly to, in the highest quality manner.

    For the record, I have never seen functional “recovery” in any of my thousands of patients. I have seen many patients improve with a variety of interventions, none of which would be considered permanent without ongoing treatment and support. Indeed, a few of my patients who did feel well enough, after many years of such management, elected to trial a withdrawal of therapy, but all relapsed within a period of 3 to 6 months, and the prior gains were invariably lost. Thus, cure was not achieved in such individuals.

    The concept of “cure” does not exist in my mind in the setting of CFS/ME at this point in time. Cure assumes that all that needs to be known to explain CFS/ME in pathophysiological terms, is not known and that they can be fully reversed or undone, and that the same illness will not return at some future date.

    The application of the term “cure”, given our present knowledge of CFS/ME, cannot be evenly loosely applied. To do so is scientifically erroneous except, if and only if, the primary and sole assumption is that this illness is a psychosomatic one. There is much objective evidence to indicate that this is not the case.

    Thus, cure must entail a full reversal of these biological underpinnings. The PACE study supporters cannot claim that they have achieved this.

    Various definitions for CFS and ME exist, none of which can be claimed to be 100% specific. Thus, “recovery” might be expected in some small percentage of selected patients, that would not be representative of a study group as a whole. Some of these individuals might be GET or CBT responsive.

    The PACE study looked at mild to moderately affected subjects. Those with severer disease were unable to participate. The latter, had they been included in the study, would have lessened the percentage of so called recovery cases. In addition, by focusing on those who did not recover, it would seem that, conservatively speaking, OVER 70% of patients did NOT benefit from GET and CBT. This is a sizeable figure, given that millions of people worldwide suffer from this condition.

    If the assumption that CFS is entirely psychosomatic had been correct, I believe that the figures for “recovery” would have been much higher in the PACE study, and that the claim for true recovery or cure would have been more justifiably applied. It is my belief that the author used “recovery” and “cure” terminology on the basis that their assumptions of a psychosomatic explanation were already correct.

    Their is no scientific basis to apply truth to their assumption, which is an hypothesis at best, and is not standing the test of time, as more and more evidence of a biological basis from a large variety of quarters accumulates.

    I support and would strongly approve the withdrawal of errors made or proper amendments to the PACE paper so that its implications and misleading conclusions are annulled. It interferes with public funding, proper scientific enquiry by the less versed and read elements of the scientific community, and is used to set a government standard for appropriate management of CFS/ME, presumably world wide, that includes for example Australia, where I practice.

    Again, Dr Tuller, I applaud you.

    Sincerely

    Dr John L Whiting
    Infectious Diseases & Internal Medicine
    Brisbane, Australia

  • John Leslie Whiting

    Dear David,

    Your commentaries have been and will continue to be an invaluable landmark to the scientific community, and as you have said yourself, by necessity you have conducted a lengthy enquiry in order to disclose deep flaws in the PACE study that might, at first glance, have been missed, that the PACE study’s authors and its publisher need to made aware of.

    I thank you for your diligence in clarifying these issues.

    Furthermore, the results of the PACE study were at odds with my own 27 year highly focused clinical experience with Chronic Fatigue Syndrome. The results of the PACE study did not resonate as either likely or true, based on a patient base larger than the PACE study, involving many patients who I have continued to see for 20 years or more. Your exposé explains in detail issues I have held firmly to, in the highest quality manner.

    For the record, I have never seen functional “recovery” in any of my thousands of patients. I have seen many patients improve with a variety of interventions, none of which would be considered permanent without ongoing treatment and support. Indeed, a few of my patients who did feel well enough, after many years of such management, elected to trial a withdrawal of therapy, but all relapsed within a period of 3 to 6 months, and the prior gains were invariably lost. Thus, cure was not achieved in such individuals.

    The concept of “cure” does not exist in my mind in the setting of CFS/ME at this point in time. Cure assumes that all that needs to be known to explain CFS/ME in pathophysiological terms, is now known and that they can be fully reversed or undone, and that the same illness will not return at some future date.

    The application of the term “cure”, given our present knowledge of CFS/ME, cannot be evenly loosely applied. To do so is scientifically erroneous except, if and only if, the primary and sole assumption is that this illness is a psychosomatic one. There is much objective evidence to indicate that this is not the case.

    Thus, cure must entail a full reversal of these biological underpinnings. The PACE study supporters cannot claim that they have achieved this.

    Various definitions for CFS and ME exist, none of which can be claimed to be 100% specific. Thus, “recovery” might be expected in some small percentage of selected patients, that would not be representative of a study group as a whole. Some of these individuals might be GET or CBT responsive.

    The PACE study looked at mild to moderately affected subjects. Those with severer disease were unable to participate. The latter, had they been included in the study, would have lessened the percentage of so called recovery cases. In addition, by focusing on those who did not recover, it would seem that, conservatively speaking, OVER 70% of patients did NOT benefit from GET and CBT. This is a sizeable figure, given that millions of people worldwide suffer from this condition.

    If the assumption that CFS is entirely psychosomatic had been correct, I believe that the figures for “recovery” would have been much higher in the PACE study, and that the claim for true recovery or cure would have been more justifiably applied. It is my belief that the author used “recovery” and “cure” terminology on the basis that their assumptions of a psychosomatic explanation were already correct.

    Their is no scientific basis to apply truth to their assumption, which is an hypothesis at best, and is not standing the test of time, as more and more evidence of a biological basis from a large variety of quarters accumulates.

    I support and would strongly approve the withdrawal of errors made or proper amendments to the PACE paper so that its implications and misleading conclusions are annulled. It interferes with public funding, proper scientific enquiry by the less versed and read elements of the scientific community, and is used to set a government standard for appropriate management of CFS/ME, presumably world wide, that includes for example Australia, where I practice.

    Again, Dr Tuller, I applaud you.

    Sincerely

    Dr John L Whiting
    Infectious Diseases & Internal Medicine
    Brisbane, Australia

  • Firestormm

    Thank you David Tuller for an excellent addition to your original articles and to Professor Racaniello for hosting.

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  • Karen Robins

    All illnesses deserve proper medical services and support. Cancer touches everyone these days. Whether it be Cancer, mental, genetic or environmental, acute or chronic disease/illness absolutely everyone deserve best medical treatment and support. ME/CFS and Fibro are not the only condition under funded by a mile. However given the high ratio of those affected it must be bottom of the pile. Not least the biggest deliberate cover-up in medical history. Two years ago I witnessed the Royal Free conduct biochemistry analysts on a close relative days away from death with an autoimmune disease. The treatment whilst requiring surgery also included nutritional supplements. All of which were intravenously infused into her body. The response was incredible over two weeks. So important was the biochemistry finding, and responding treatments, weighing 6.7 stones this person was eventually strong enough to withstand 7 hour surgery to fix blood vessels in abdomen. My point is the NHS Already knows the importance of biochemistry in treating immune diseases. Yet it is only CFS/ME patients whom are not offered biochemistry testing. Why? despite the progressive damage being shown through research and patient data for decades now! Many specialist doctors and research teams have self/patient charity funded their research and studies. Yet still medical authorities not only refuse to support by funding further investigation in the face of ever mounting evidence from around the world, they point blank do not allow the same level of existing tests awarded other conditions. The only rational conclusion being absolutely & intentionally, Gov led medical authorities/agencies are deliberately promoting and distributing (feeding media false reports) derogatory and misleading pace trial results, IOM finding and psychobabble studies. Completely blanking all the worldwide research, we as suffers know to be true. I know not one CFS/ME suffer whom begrudges treatment of any other condition. It is utterly unfair to even suggest otherwise. Our lives are being deliberately tossed aside by the very bodies whom swear an oath to do their utmost to protect life. The level of ridicule, harm of this disservice reaches way beyond ourselves, but to those we love most, partners, children, parents, brothers and sisters and not least our friends. We lose our careers, our homes, our financial security and way to many our lives. Medical Studies use comparison too. So yes with such huge demographics involved we can not be expected to put on blinkers (especially in the face of such adversity) to the differing medical care we see with other conditions. You see my close relative whom nearly lost her life to a chronic autoimmune disease. She had a flare up, the NHS pulled out all stops, including biochemistry testing and not only saved her life but returned her well being. She has watched my health, life and support being increasingly withdrawn. She has witnessed the daily struggles I have endured like us all. Without antiviral medicines being made available to me. She witness the ever increasing list of conditions impacting my body. Her diagnosis is extremely rare. Less than 5% of numbers of serious ME suffers. Yet the medical reviews and support she receives is ten times more consideration than I. My point is we CFS/ME suffers are being deliberately denied even our basic human rights. Those medical specialists who do work with our best intentions are deliberately professionally undermined and ridiculed. I have only been unwell for 8 years. I weep for those whom suffering has gone on for decades. To me our condition is the Medical equivalence of the holocaust !! We have every right to speak out.

  • Shane Carlson

    A very heart-felt “thank you” to both David Tuller and Vincent Raconiello.

    What an egregious and cynical case of privatizing profits (SwissRe and their lackeys, the PACE authors) and socializing costs with the blessing (financial assistance) of the NHS and the indifference of CDC.

    Bureaucrats benefit in the short term (for a time at least) but society is fleeced and medicine/journals/editors sell their credibility, all on the backs of patients who have been bullied by the experts who claim to simply be “trying to help.”

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