Tuesday, December 22, 2015

Announcing the Formation of a National ME/CFS Advocacy Initiative

Today, a group of patient advocates announced the formation of a national advocacy initiative. 

With the recent announcement that NIH funding is to be increased, this could not have come at a better time. 

The doors are open to anybody who wants to join.


More than ever before, 2015 has been a year that has brought fresh hope to Myalgic Encephalomyelitis (ME) patients. The Institute of Medicine (IOM) and NIH Pathways to Prevention (P2P) reports confirmed the neglect and disbelief that have held the disease hostage for decades and strongly recommended action to improve patient care. Publications from Stanford, Columbia and Haukeland (Norway) Universities brought new insights into the biology. World-renowned scientists have joined the fight. Stories about severely ill patients like Ron Davis’s son have created more public awareness. And the Tuller series brought greater exposure to the concerns with the PACE trial and psychogenic theories.

For the first time, there’s a sense that we have huge opportunities to change the future for ME patients. And just as importantly, there’s a sense that if we want to turn those opportunities into reality, then we need to find new ways to work together across the community to increase the impact of our voices.

To that end, a number of organizations, bloggers and independent advocates, listed below, have started having discussions to identify those areas where they can agree on goals and work together to achieve what is needed for patients.

Thus far, we have identified common goals to focus on, including the need to dramatically increase funding, to advance the research agenda, to resolve the definitional challenges, and to improve clinical care through quality medical education. We expect that this will lead to actions directed toward Congressional leaders, HHS and its agencies, and public awareness through the media.

To achieve these goals, we are going to need broad participation across the community. We will leverage the Groups feature on the MEAction.net platform to get input on these goals and to share proposals for joint actions. Because we are working as a loose collaboration, groups and individuals will be given the opportunity to opt in or opt out of specific actions.

Working in this way and at this scale is new for all of us and we will be learning as we go. We also know that we won’t all agree on every tactic or policy direction. But we believe there is power in numbers and coordination and are all committed to taking advantage of every opportunity that we can to regain our future.

Please join us and share your ideas and enthusiasm. If you are interested in participating and providing input, you can join in the discussion on MEAction Groups here: http://www.meaction.net/us-action-working-groups/


Patient Organizations

Connecticut CFIDS Association, Inc.
ImmuneDysfunction.org dba The Vermont CFIDS Association, Inc
Massachusetts CFIDS/ME & FM Association
The Myalgic Encephalomyelitis Action Network (#MEAction)
Open Medicine Foundation (OMF)
New Jersey ME/CFS Association, Inc.
Pandora Org
Phoenix Rising
Simmaron Research
Solve ME/CFS Initiative
Wisconsin ME and CFS Association, Inc.

Patient blogs

Health Rising (Cort Johnson)
OccupyCFS (Jennifer Spotila)
Onward Through the Fog (Erica Verrillo)
Race to Solve ME/CFS (Claudia Goodell)
Speak Up About ME (Denise Lopez-Majano)

Independent Advocates

Lily Chu. MD, MSHS
Mary Dimmock
Sonya Heller Irey
Robert and Courtney Miller
Donna Pearson
Staci R. Stevens, MA
Steve Krafchick, MPH, JD
Rich Carson

Saturday, December 19, 2015

The PACE Wars Continue: A request for data, and a denial

The PACE wars are continuing, with James Coyne, David Tuller, Ronald W. Davis, Vincent R. Racaniello, Bruce Levin, and even a former editor of the BMJ on one side, and the authors of the PACE trial (along with their supporting institutions) on the other.

When the former editor of the British Medical Journal characterizes the refusal to release PACE data as "defending the indefensible," you know the tides are turning. (The BMJ published a long-term follow-up on PACE claiming continued benefits of CBT and GET.) Other researchers who, like James Coyne, are not directly connected to ME/CFS are also weighing in on the side of transparency.

In an effort to verify the claims made by PACE, four researchers have now asked for PACE data. Their request is based solely on the basis of getting to the truth. Nothing could be more reasonable.

A similar request by James Coyne was denied on the basis that the data might be "misused" and patients' rights violated. However, in the same denial, the authors conceded that they had indeed released data, but only to researchers who had validated their study.

In short, the PACE authors seem to be saying that as long as you validate their research, patient rights will be protected.

This can't end well for the PACE team.

You can sign a petition to retract the PACE trial HERE.


A request for data from the PACE trial

Virology Blog, 17 DECEMBER 2015

Mr. Paul Smallcombe
Records & Information Compliance Manager
Queen Mary University of London
Mile End Road
London E1 4NS

Dear Mr Smallcombe:

The PACE study of treatments for ME/CFS has been the source of much controversy since the first results were published in The Lancet in 2011. Patients have repeatedly raised objections to the study’s methodology and results. (Full title: “Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome: a randomized trial.”)

Recently, journalist and public health expert David Tuller documented that the trial suffered from many serious flaws that raise concerns about the validity and accuracy of the reported results. We cited some of these flaws in an open letter to The Lancet that urged the journal to conduct a fully independent review of the trial. (Dr. Tuller did not sign the open letter, but he is joining us in requesting the trial data.)

These flaws include, but are not limited to: major mid-trial changes in the primary outcomes that were not accompanied by the necessary sensitivity analyses; thresholds for “recovery” on the primary outcomes that indicated worse health than the study’s own entry criteria; publication of positive testimonials about trial outcomes and promotion of the therapies being investigated in a newsletter for participants; rejection of the study’s objective outcomes as irrelevant after they failed to support the claims of recovery; and the failure to inform participants about investigators’ significant conflicts of interest, and in particular financial ties to the insurance industry, contrary to the trial protocol’s promise to adhere to the Declaration of Helsinki, which mandates such disclosures.

Although the open letter was sent to The Lancet in mid-November, editor Richard Horton has not yet responded to our request for an independent review. We are therefore requesting that Queen Mary University of London to provide some of the raw trial data, fully anonymized, under the provisions of the U.K.’s Freedom of Information law.

In particular, we would like the raw data for all four arms of the trial for the following measures: the two primary outcomes of physical function and fatigue (both bimodal and Likert-style scoring), and the multiple criteria for “recovery” as defined in the protocol published in 2007 in BMC Neurology, not as defined in the 2013 paper published in Psychological Medicine. The anonymized, individual-level data for “recovery” should be linked across the four criteria so it is possible to determine how many people achieved “recovery” according to the protocol definition.

We are aware that previous requests for PACE-related data have been rejected as “vexatious.” This includes a recent request from psychologist James Coyne, a well-regarded researcher, for data related to a subsequent study about economic aspects of the illness published in PLoS One—a decision that represents a violation of the PLoS policies on data-sharing.

Our request clearly serves the public interest, given the methodological issues outlined above, and we do not believe any exemptions apply. We can assure Queen Mary University of London that the request is not “vexatious,” as defined in the Freedom of Information law, nor is it meant to harass. Our motive is easy to explain: We are extremely concerned that the PACE studies have made claims of success and “recovery” that appear to go beyond the evidence produced in the trial. We are seeking the trial data based solely on our desire to get at the truth of the matter.

We appreciate your prompt attention to this request.


Ronald W. Davis, PhD
Professor of Biochemistry and Genetics
Stanford University

Bruce Levin, PhD
Professor of Biostatistics
Columbia University

Vincent R. Racaniello, PhD
Professor of Microbiology and Immunology
Columbia University

David Tuller, DrPH
Lecturer in Public Health and Journalism
University of California, Berkeley

Sunday, December 13, 2015

Scientific Misconduct and the PACE Trial

Dr. James Coyne has been outspoken in his criticism of the PACE trial. He has publicly described the study as"bad science" using "voodoo statistics" to cover up faulty methodology.

Recently, Dr. Coyne requested a release of the PACE trial data from King's College London, one of the sponsors of the study.

The answer Dr. Coyne received from King's College London (see below) is surprisingly honest. Their concern (as stated in the highlighted portions) is that they may be criticized for their research. In fact, King's College states quite explicitly that anyone who might be critical cannot have access to the data. They also cited an "active campaign" to discredit the PACE trial as justification for denying a perfectly legitimate request for data.

This letter exposes the increasingly obvious reason for refusing to release the PACE trial data. If the data were released, it would be revealed that the results were falsified. Considering that there were 19 institutions participating in the trial, a public examination of the results would be deeply embarrassing. An exposure of outright fraud would also open them up to censure. Rather than face that possibility, the institutions in question have closed ranks, shouted "harassment," and invoked conspiracy theories.

In the world of science, it is not only unacceptable to argue that withholding data is justified because it might be disproved, it is ludicrous. The hallmark of scientific inquiry is reproducibility. If the results of a study cannot be reproduced, its findings are called into question.

Taking that idea one step further, this type of secrecy could be interpreted as outright misconduct. In a post on the London School of Economics blog, Nicole Janz argues that given how few researchers are willing to share data, "classifying data secrecy as misconduct may be a harsh, but necessary step." She cites political science guidelines that state that “researchers have an ethical obligation to facilitate the evaluation of their evidence based knowledge claims through data access, production transparency, and analytic transparency.”  In like fashion, the American Psychological Association has stated that "sharing data within the larger scientific community encourages a culture of openness and accountability in scientific research." [Emphasis mine]

Between conflicts of interest and lack of reproducibility, scientific integrity has been badly damaged over the past decade - to the point that most research findings are demonstrably false. The only way to stem the tide of jerry-rigged results is to enact penalties. Any study that refuses to share its data should be subject to an inquiry. 

James Coyne has requested just that. He has asked that the PACE paper be "provisionally retracted" until the data are shared. Under the standards of good scientific conduct, nothing could be more reasonable.

You can sign the petition to retract the PACE trial here.

Read the original letter here.

Governance & Legal Services
Information Management and Compliance
Room 2.32
Franklin Wilkins Building
150 Stamford Street
Tel: 020 7848 7816

Email: legal-compliance@kcl.ac.uk

Professor James Coyne
By email only to: jcoynester@gmail.com

11 December 2015

Dear Professor Coyne,

Request for information under the Freedom of Information Act 2000 (“the Act”)

Further to your recent request for information held by King’s College London, I am writing to confirm that the requested information is held by the university. The university is withholding the information in accordance with section 14(1) of the Act – Vexatious Request.

Your request
You initially requested the information in accordance with the data sharing policies of the Public Library of Science (PLOS). The university has decided to treat this as a request under section 1(1) of the Act, as the information is held by the university. We received your information request on 13 November 2015.

You requested the following information.

“I have read with interest your 2012 article in PLOS One, "Adaptive Pacing, Cognitive Behaviour Therapy, Graded Exercise, and Specialist Medical Care for Chronic Fatigue Syndrome..." 

I am interested in reproducing your empirical results, as well as conducting some additional exploratory sensitivity analyses. 

Accordingly, and consistent with PLOS journals' data sharing policies, I ask you to kindly provide me with a copy of the dataset in order to allow me to verify the substantive claims of your article through reanalysis. I can read files in SPSS, XLS[x], or any reasonable ASCII format.”

Our response

We have given careful consideration to your request and have determined that section 14(1) of the Act applies to your request.

The university has considered, in particular, the following guidance and decisions in coming to this conclusion:

  • Information Commissioner v Devon County Council and Dransfield [2012] UKUT 440 (AAC) (Dransfield)
  • John Mitchell v Information Commissioner EA/2013/0019 (Mitchell)
  • Decision of the Information Commissioner: FS50558352 – 18 March 2015
  • Guidance issued by the Information Commissioner’s Office


The article referred to in the request is a cost-effectiveness analysis based on a medical paper titled “Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial”. This is more commonly known as the PACE trial. This is a collaborative project between researchers from Queen Mary University of London, Oxford University and King’s College London. This was a large scale randomised clinical trial testing treatments for chronic fatigue syndrome (CFS) also known as myalgic encephalomyelitis (ME).

The university considers itself to be a joint holder of the requested information with Queen Mary University of London.

It is acknowledged that the project has led to controversy. There have been significant efforts to publically discredit the trial following the release of the first article in the Lancet journal in 2011. Among other public campaigns, there is a Wikipedia page dedicated to criticisms of this project. The campaign has included deeply personal criticism to the researchers involved as well as significant comment around the decisions not to disclose data and information about the project.

This request

The university considers that there is a lack of value or serious purpose to your request. The university also considers that there is improper motive behind the request. The university considers that this request has caused and could further cause harassment and distress to staff.

The university considers that the motive and purpose behind this request is polemical. The university notes the view of the Information Commissioner in decision FS50558352 that the request in that case was ‘more focussed on attacking and attempting to discredit the trial than in obtaining useful information on the topic.’ The requested information relates to economic analysis undertaken by academic staff with considerable experience in this field. External sources were used as part of that analysis and the process took approximately one year to complete. We would expect any replication of data to be carried out by a trained Health Economist.

The university acknowledges the general principle that requests should be considered both applicant and motive ‘blind’. “However, the proper application of section 14 cannot side-step the question of the underlying rationale or justification for the request.” (Dransfield p9 para. 34). The university considers that it is entitled to take into account the wider dealings and publicity surrounding the project when considering the motive behind this request.

The active campaign to discredit the project has caused distress to the university’s researchers who hold legitimate concerns that they will be subject to public criticism and reputational damage. The researchers based at the university were aware of the criticism of the trial and of the comments that have been made publically. They were also aware of the numerous requests for information received by Queen Mary University of London. The researchers involved in this project are experienced and well-used to scrutiny of their work. However, since the receipt of the request, they have reported concern that they will targeted with the same criticisms as their colleagues at Queen Mary University of London.

The university adopts the comments made in the Mitchell case at paragraphs 31-34 in relation to the need to protect academic freedom and protect academic staff who put forward ‘new ideas and controversial or unpopular opinions.’

In conclusion, the university considers that when applying a holistic approach, this request can properly be considered to be vexatious.

This completes the university’s response to your information request.

Your right to complain

If you are unhappy with the service you have received in relation to your information request or feel that it has not been properly handled you have the right to complain or request a review of our decision by contacting the Head of Information Management and Compliance within 60 days of the date of this letter.

Further information about our internal complaints procedure is available at the link below:

In the event that you are not content with the outcome of your complaint you may apply to the Information Commissioner for a decision. Generally the Information Commissioner cannot make a decision unless you have exhausted the internal complaints procedure provided by King’s College London.

The Information Commissioner can be contacted at the following address:
The Information Commissioner’s Office
Wycliffe House
Water Lane

Yours sincerely
Ben Daley
Information Compliance Manager

Saturday, December 5, 2015

Our Two Minutes of Fame: Collins talks about ME/CFS on Charlie Rose

Francis Collins, head of the NIH, was interviewed on Charlie Rose on November 23, 2014. It was a long interview, and until now it was available only on Hulu. Some thoughtful person has made a clip of the roughly two minutes Collins talked about ME/CFS.

Two minutes may not seem like much air time, but it's exactly two minutes longer than any head of the NIH has afforded this disease in the last three decades. To his credit, Dr. Collins did not try to soft-pedal the illness.


Rose: I saw something, it may have been associated with NIH, about chronic fatigue.

Collins: I've been puzzled and frustrated about how little we understand about this condition. Chronic Fatigue Syndrome, people who have that diagnosis, it's a very heterogeneous collection of individuals, but the Institute of Medicine has just sort of defined what it is limited to: people who are profoundly affected by fatigue, oftentimes coming after an acute … you can't get out of bed. You are disabled, you are utterly unable to carry out daily activities. You have other things. Exertion seems to make you worse instead of better, and you have sleep disorders. Sleep is not refreshing as it should be. You may have postural hypotension, where you stand up and your blood pressure drops, and then you pass out. It's serious stuff, and it's particularly frustrating to see cases, and there are hundreds of thousands of them, of people who were healthy, and then have what appears to be a flu-like illness, but they go to bed and then they can't get up for months.

So we just announced that we are going to make a big push to try to get an answer here. Bring some of these new technologies, of genomics, and proteomincs, metabolomics and imaging and figure out what is going on in this condition. And if we understood that maybe we'd know what fatigue of other sorts is all about. Why do people on chemotherapy get fatigue? We don't really know. Wouldn't it be nice to have that answered?

Monday, November 30, 2015

Visual Stress: A Symptom of ME/CFS

A University of Leicester research team has discovered a vision-related abnormality that could help diagnose ME/CFS. 

The abnormality, called "pattern glare," produces distortions, such as curving, wavering, and colors, when viewing stripes. Pattern glare has been associated with migraines and Irlen Syndrome (a visual processing disorder). It can lead to headaches, photophobia, and eyestrain. 

This is not the first study to find a correlation between visual disturbances and ME/CFS. In May 2014, an Australian group found a greater occurrence of  Irlen Syndrome in ME/CFS patients (Loew et al. "Symptoms of Meares-Irlen/Visual Stress Syndrome in subjects diagnosed with Chronic Fatigue Syndrome.") 

A previous Australian study found significant variations in blood lipids as well as urine amino and organic acids in ME/CFS patients with Irlen Syndrome. They proposed that ocular symptoms might be caused by activation of the immune system due to "some infective agent." (Robinson et al. "A biochemical analysis of people with chronic fatigue who have Irlen Syndrome: Speculation concerning immune system dysfunction.")

Coincidentally, I had an eye exam shortly before the University of Leicester study was published. On viewing a cross-hatch pattern, I remarked that it had blue horizontal stripes, and purple vertical stripes. "It's black and white," said the technician. 

Both of my children have pattern glare - one has migraines, and the other Irlen Syndrome. 

Visual stress could be a symptom of Chronic Fatigue Syndrome, research suggests

Press Release: University of Leicester, November 24, 2015. People suffering from Chronic Fatigue Syndrome (CFS) could experience higher levels of visual stress than those without the condition, according to new research from the University of Leicester.

CFS, also known as Myalgic Encephalomyelitis (ME), is a condition that causes persistent exhaustion that affects everyday life and doesn't go away with sleep or rest. Diagnosis of the condition is difficult as its symptoms are similar to other illnesses.

A research team from the University of Leicester led by Dr Claire Hutchinson from the Department of Neuroscience, Psychology and Behaviour has examined patients with and without CFS and has found that those suffering from the condition are more vulnerable to pattern-related visual stress, which causes discomfort and exhaustion when viewing repetitive striped patterns, such as when reading text.

The results of the study, which is published in the journal Perception, could help in the diagnosis of CFS, as the findings suggest that there are visual system abnormalities in people with ME/CFS that may represent an identifiable and easily measurable behavioural marker of the condition.

Dr Hutchinson explained: "Diagnosis of ME/CFS is controversial. With the exception of disabling fatigue, there are few definitive clinical features of the condition and its core symptoms, overlap with those often prevalent in other conditions. As a result, ME/CFS is often a diagnosis of exclusion, being made as a last resort and possibly after a patient has experienced a series of inappropriate treatments of misdiagnosed disorders.

"It is imperative therefore that research focuses on identifying significant clinical features of CFS/ME with a view to elucidating its underlying pathology and delineating it from other illnesses. Doing so will help researchers and healthcare professionals gain important insights into the condition, aid diagnosis and, in the longer term, inform evidence-based therapeutic interventions."

The study assessed vulnerability of ME/CFS patients to pattern-related visual stress using a standardised test called the pattern glare test, in which people report the number of visual distortions they experience when looking at three repetitive striped patterns of different levels of detail.

During the study twenty patients with CFS and twenty patients without the condition were recruited.

Participants viewed 3 patterns, the spatial frequencies (SF) of which were either 0.3 (low-SF), 2.3 (mid-SF) and 9.4 (high-SF) cycles per degree (c/deg). They then reported the number of distortions they experienced when viewing each pattern.

Patients with ME/CFS reported more distortions on the intermediate striped pattern (Pattern 2) than people without the condition.

Dr Hutchinson added: "The existence of pattern-related visual stress in ME/CFS may represent an identifiable and easily measurable behavioural marker of ME. This could, in conjunction with other diagnostic tests, help delineate it from other conditions."

The work was funded by ME Research UK who provided funding for a 1-year MPhil studentship, awarded to Rachel Wilson, who was supervised by Drs Claire Hutchinson and Kevin Paterson from the University of Leicester's Department of Neuroscience, Psychology and Behaviour.

Dr Neil Abbot, Research & Operations Director at ME Research UK, added: "Around three-quarters of people with ME/CFS report a range of eye and vision-related symptoms that interfere with their everyday lives, yet there has been very little scientific investigation of the problem.

"Dr Claire Hutchinson and her team have previously confirmed the existence of eye movement difficulties in ME/CFS patients, and that symptoms, including eye pain, can be severe. Her new report in Perception extends these findings and raises the possibility that vision anomalies, including pattern-related visual stress, may have a diagnostic role in the disease."

Citation: Wilson RL, Paterson KB, Hutchinson CV. Increased Vulnerability to Pattern-Related Visual Stress in Myalgic Encephalomyelitis. Perception 2015 Nov 3.


The objective of this study was to determine vulnerability to pattern-related visual stress in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A total of 20 ME/CFS patients and 20 matched (age, gender) controls were recruited to the study. Pattern-related visual stress was determined using the Pattern Glare Test. Participants viewed three patterns, the spatial frequencies (SF) of which were 0.3 (low-SF), 2.3 (mid-SF), and 9.4 (high-SF) cycles per degree (c/deg). They reported the number of distortions they experienced when viewing each pattern. ME/CFS patients exhibited significantly higher pattern glare scores than controls for the mid-SF pattern. Mid-high SF differences were also significantly higher in patients than controls. These findings provide evidence of altered visual perception in ME/CFS. Pattern-related visual stress may represent an identifiable clinical feature of ME/CFS that will prove useful in its diagnosis. However, further research is required to establish if these symptoms reflect ME/CFS-related changes in the functioning of sensory neural pathways.

Wednesday, November 25, 2015

Mady Hornig's Research Made Simple

Sudden Onset has produced another excellent video explaining the science of ME/CFS.

In ME/CFS: The Scientific Evidence -Episode 3 - "The SIGNATURE" Mady Hornig's research on immune abnormalities is elegantly explained using images and music. I would encourage everyone to watch this 15-minute video, as you will not find a more concise explanation anywhere.

Mady Hornig's cytokine study, Distinct plasma immune signatures in ME/CFS are present early in the course of illness, made headlines last February for a number of reasons. First, it showed significant immune system alterations between patients and healthy controls. Second, it revealed why many other studies have not found similar abnormalities.

The answer turned out to be something fairly simple. The immune systems of people who had ME/CFS for three years (or less) had a cytokine pattern (a "signature") that was markedly different from controls as well as from patients who had been ill more than three years.

Based on these findings, the researchers concluded that people with short-term ME/CFS have upregulated immune systems indicative of a viral infection, and patients with long-term ME/CFS suffer from "immune exhaustion."

What was remarkable about this study was that not just one, but ALL twenty-four cytokines were altered in both long- and short-term patients compared to controls.

The early phase (blue bars) of ME/CFS showed elevations of nearly all the interleukins (pro-inflammatory cytokines) which is typical of an immune system fighting off an infection. Strikingly, patients who had been ill for less than a year were 100 times more likely to have elevated interferon gamma, which is indicative of a viral infection. Short-term patients were also 50% more likely to have elevated IL-12 P40, which is a pro-inflammatory cytokine produced by microglial cells (among others). The microglia are activated in the brain when there is an infection in the central nervous system. Although an elevation of IL-12 P40 is not definitive proof of neuroinflammation, it supports a study published in 2014 by Nakatomi et al. which found evidence of microglial activation in the brains of patients with ME/CFS.

The chronic phase (red bars) showed elevations in eotaxin CCL11,  GMCSF (granulocyte macrophage colony-stimulating factor receptor), PDGF-BB (platelet-derived growth factor-BB ), and CD40L. Also of note was the depression of IL-17F in both phases. (In 2008, Metgzer et al. found a similar depression of IL-17F. The authors concluded that this cytokine may play a protective role against the disease. )

Because they perform so many roles, it is impossible to make generalizations about the function of individual cytokines. Nonetheless, three of the cytokines related to the chronic phase of ME/CFS stand out.

  • Eotaxin CCL 11 recruits eosinophils, white blood cells which are elevated in people with allergies. When administered to mice, eotaxin CCLL decreases their neurogenesis and cognitive performance.
  • GMCSF is found in high levels in joints with rheumatoid arthritis, an autoimmune disease.
  • CD40L leads to reactive oxygen species production, resulting in oxidative stress.
Oxidative stress, atopy (allergy), and autoimmunity are three immune processes implicated in long-term ME/CFS.

At this point, a replication of this study is crucial. We can only hope that the NIH will undertake funding for similar immune system research.

It would also be enormously helpful if the authors of previous immune system (and other) studies went back over their data to see if there are patterns associated with short- and long-term patients which may have been lost when the results were averaged. Among the 5000+ studies that have been performed on ME/CFS patients there is a wealth of data that have yet to be explored.

Some of those "hiding in plain sight" data may lead to a biomarker.

Monday, November 23, 2015

David Tuller Exposes Conflicts of Interest on PACE Team

David Tuller is on the warpath.

After the authors of the PACE trial brushed off Tuller's observation that conflicts of interest were not reported to trial participants, he did some research. Predictably, he found that not only were three of the four principal researchers hired as consultants for insurance companies, but that decisions made by those companies had direct bearing on PACE findings and on recommendations made by PACE authors.

Corporate Collusion?

Conflicts of interest have become a major problem in the medical field. With pharmaceutical and insurance companies hiring physicians and researchers to conduct and evaluate basic research, the results of those studies have become increasingly unreliable.

It was the editor of The Lancet, Richard Horton, who observed that  half of the research published was false. In a May 2015 editorial he stated that:

“The case against science is straightforward: much of the scientific literature, perhaps half, may simply be untrue. Afflicted by studies with small sample sizes, tiny effects, invalid exploratory analyses, and flagrant conflicts of interest, together with an obsession for pursuing fashionable trends of dubious importance, science has taken a turn towards darkness.” [Emphasis mine]

The irony of this statement cannot be lost on those who have followed the PACE trial.

Some of the main players in the push to have ME/CFS labeled as a psychiatric illness have advised insurance companies. These companies have consistently used this medical advice and "research" to turn down disability and medical claims. (For an excellent article on this topic as it relates to ME/CFS, read Corporate Collusion?)

Michael Sharpe, a principal investigator for PACE, provided expert testimony and advice to several insurance companies, including UNUM Provident, Windsor Life, Bupa, Reassure, and Aegon UK.

Dr. Peter Manu, a psychiatrist employed as a consultant with Metlife, was instrumental in securing denials of disability payments to patients with CFS. In a chapter published in Disability and Chronic Fatigue Syndrome he argued that patients with CFS are really suffering from psychiatric illnesses, but are misdiagnosed by physicians who express "strong convictions" that CFS is produced by an immune dysfunction, a virus, or "other physical cause."

Dr. Manu went on to write a book, The Psychopathology of Functional Somatic Syndromes: Neurobiology and Illness Behavior in Chronic Fatigue Syndrome, Fibromyalgia, Gulf War Illness, Irritable Bowel, and Premenstrual Dysphoria, in which he argues that all of the aformentioned are psychosomatic. (Manu drew liberally upon Sharpe to defend his statement that "most physicians have understood [these conditions] to be mental illnesses.") His recommendation was to treat the illnesses with antidepressants and CBT.

ME/CFS is not the only illness that has been the object of insurance company manipulation. As a case in point, the existence of Chronic Lyme disease has been consistently denied by the IDSA (Infectious Diseases Society of America), an organization whose ties to industry led to an investigation by the Connecticut Attorney General. The investigation concluded that "The conflicts of interest of the IDSA guidelines panel members were significant and represent the type of ties to industry and patents that are common to key academic researchers in the field."

David Tuller has done an excellent job of exposing some of the industry ties that formed the rationale for, and determined the results of, the PACE trial. It is up to us to insist on an investigation.

You can sign the petition to retract the PACE trial HERE.

You can sign the petition demanding an HHS investigation of the PACE trial HERE.



Trial by Error, Continued: PACE Team’s Work for Insurance Companies Is “Not Related” to PACE. Really?

By David Tuller, Wednesday, November 18, 2015 at 06:45 AM EST

In my initial story on Virology Blog, I charged the PACE investigators with violating the Declaration of Helsinki, developed in the 1950s by the World Medical Association to protect human research subjects. The declaration mandates that scientists disclose "institutional affiliations" and "any possible conflicts of interest" to prospective trial participants as part of the process of obtaining informed consent.

The investigators promised in their protocol to adhere to this foundational human rights document, among other ethical codes. Despite this promise, they did not tell prospective participants about their financial and consulting links with insurance companies, including those in the disability sector. That ethical breach raises serious concerns about whether the "informed consent" they obtained from all 641 of their trial participants was truly "informed," and therefore legitimate.

The PACE investigators do not agree that the lack of disclosure is an ethical breach. In their response to my Virology Blog story, they did not even mention the Declaration of Helsinki or explain why they violated it in seeking informed consent. Instead, they defended their actions by noting that they had disclosed their financial and consulting links in the published articles, and had informed participants about who funded the research--responses that did not address the central concern.

"I find their statement that they disclosed to The Lancet but not to potential subjects bemusing," said Jon Merz, a professor of medical ethics at the University of Pennsylvania. "The issue is coming clean to all who would rely on their objectivity and fairness in conducting their science. Disclosure is the least we require of scientists, as it puts those who should be able to trust them on notice that they may be serving two masters."

In their Virology Blog response, the PACE team also stated that no insurance companies were involved in the research, that only three of the 19 investigators "have done consultancy work at various times for insurance companies," and that this work "was not related to the research." The first statement was true, but direct involvement in a study is of course only one possible form of conflict of interest. The second statement was false. According to the PACE team's conflict of interest disclosures in The Lancet, the actual number of researchers with insurance industry ties was four—along with the three principal investigators, physiotherapist Jessica Bavington acknowledged such links.

But here, I'll focus on the third claim--that their consulting work "was not related to the research." In particular, I'll examine an online article posted by Swiss Re, a large reinsurance company. The article describes a "web-based discussion group" held with Peter White, the lead PACE investigator, and reveals some of the claims-assessing recommendations arising from that presentation. White included consulting work with Swiss Re in his Lancet disclosure.

The Lancet published the PACE results in February, 2011; the undated Swiss Re article was published sometime within the following year or so. The headline: "Managing claims for chronic fatigue the active way." (Note that this headline uses "chronic fatigue" rather than "chronic fatigue syndrome," although chronic fatigue is a symptom common to many illnesses and is quite distinct from the disease known as chronic fatigue syndrome. Understanding the difference between the two would likely be helpful in making decisions about insurance claims.)

The Swiss Re article noted that the illness "can be an emotive subject" and then focused on the implications of the PACE study for assessing insurance claims. It started with a summary account of the findings from the study, reporting that the "active rehabilitation" arms of cognitive behavioral therapy and graded exercise therapy "resulted in greater reduction of patients' fatigue and larger improvement in physical functioning" than either adaptive pacing therapy or specialist medical care, the baseline condition. (The three intervention arms also received specialist medical care.)

The trial's "key message," declared the article, was that "pushing the limits in a therapeutic setting using well described treatment modalities is more effective in alleviating fatigue and dysfunction than staying within the limits imposed by the illness traditionally advocated by ‘pacing.'"

Added the article: "If a CFS patient does not gradually increase their activity, supported by an appropriate therapist, then their recovery will be slower. This seems a simple message but it is an important one as many believe that ‘pacing' is the most beneficial treatment."

This understanding of the PACE research—presumably based on information from Peter White's web-based discussion—was wrong. Pacing is not and has never been a "treatment." It is also not one of the "four most commonly used therapies," as the newsletter article declared, since it has never been a "therapy" either. It is a self-help method practiced by many patients seeking the best way to manage their limited energy reserves.

The PACE investigators did not test pacing. Instead, the intervention they dubbed "adaptive pacing therapy" was an operationalized version of "pacing" developed specifically for the study. Many patients objected to the trial's form of pacing as overly prescriptive, demanding and unlike the version they practiced on their own. Transforming an intuitive, self-directed approach into a "treatment" administered by a "therapist" was not a true test of whether the self-help approach is effective, they argued--with significant justification. Yet the Swiss Re article presented "adaptive pacing therapy" as if it were identical to "pacing."

The Swiss Re article did not mention that the reported improvements from "active rehabilitation" were based on subjective outcomes and were not supported by the study's objective data. Nor did it report any of the major flaws of the PACE study or offer any reasons to doubt the integrity of the findings.

The article next asked, "What can insurers and reinsurers do to assist the recovery and return to work of CFS claimants?" It then described the conclusions to be drawn from the discussion with White about the PACE trial—the "key takeaways for claims management."

First, Swiss Re advised its employees, question the diagnosis, because "misdiagnosis is not uncommon."

The second point was this: "It is likely that input will be required to change a claimant's beliefs about his or her condition and the effectiveness of active rehabilitation...Funding for these CFS treatments is not expensive (in the UK, around £2,000) so insurers may well want to consider funding this for the right claimants."

Translation: Patients who believe they have a medical disease are wrong, and they need to be persuaded that they are wrong and that they can get better with therapy. Insurers can avoid large payouts by covering the minimal costs of these treatments for patients vulnerable to such persuasion, given the right "input."

Finally, the article warned that private therapists might not provide the kinds of "input" required to convince patients they were wrong. Instead of appropriately "active" approaches like cognitive behavior therapy and graded exercise therapy, these therapists might instead pursue treatments that could reinforce claimants' misguided beliefs about being seriously ill, the article suggested.

"Check that private practitioners are delivering active rehabilitation therapies, such as those described in this article, as opposed to sick role adaptation," the Swiss RE article advised. (The PACE investigators, drawing on the concept known as "the sick role" in medical sociology, have long expressed concern that advocacy groups enabled patients' condition by bolstering their conviction that they suffered from a "medical disease," as Michael Sharpe, another key PACE investigator, noted in a 2002 UNUMProvident report. This conviction encouraged patients to demand social benefits and health care resources rather than focus on improving through therapy, Sharpe wrote.)

Lastly, the Swiss Re article addressed "a final point specific to claims assessment." A diagnosis of chronic fatigue syndrome, stated the article, provided an opportunity in some cases to apply a mental health exclusion, depending upon the wording of the policy. In contrast, a diagnosis of myalgic encephalomyelitis did not.

The World Health Organization's International Classification for Diseases, or ICD, which clinicians and insurance companies use for coding purposes, categorizes myalgic encephalomyelitis as a neurological disorder that is synonymous with the terms "post-viral fatigue syndrome" and "chronic fatigue syndrome." But the Swiss Re article stated that, according to the ICD, "chronic fatigue syndrome" can also "alternatively be defined as neurasthenia which is in the mental health chapter."

The PACE investigators have repeatedly advanced this questionable idea. In the ICD's mental health section, neurasthenia is defined as "a mental disorder characterized by chronic fatigue and concomitant physiologic symptoms," but there is no mention of "chronic fatigue syndrome" as a discrete entity. The PACE investigators (and Swiss Re newsletter writers) believe that the neurasthenia entry encompasses the illness known as "chronic fatigue syndrome," not just the common symptom of "chronic fatigue."

This interpretation, however, appears to be at odds with an ICD rule that illnesses cannot be listed in two separate places—a rule confirmed in an e-mail from a WHO official to an advocate who had questioned the PACE investigators' argument. "It is not permitted for the same condition to be classified to more than one rubric as this would mean that the individual categories and subcategories were no longer mutually exclusive," wrote the official to Margaret Weston, the pseudonym for a longtime clinical manager in the U.K. National Health Service.

Presumably, after White disseminated the good news about the PACE results at the web-based discussion, Swiss Re's claims managers felt better equipped to help ME/CFS claimants. And presumably that help included coverage for cognitive behavior therapy and graded exercise therapy so that claimants could receive the critical "input" they needed in order to recognize and accept that they didn't have a medical disease after all.

In sum, contrary to the investigators' argument in their response to Virology Blog, the PACE research and findings appear to be very much "related to" insurance industry consulting work. The claim that these relationships did not represent "possible conflicts of interest" and "institutional affiliations" requiring disclosure under the Declaration of Helsinki cannot be taken seriously.

Update 11/17/15 12:22 PM: I should have mentioned in the story that, in the PACE trial, participants in the cognitive behavior therapy and graded exercise therapy arms were no more likely to have increased their hours of employment than those in the other arms. In other words, there was no evidence for the claims presented in the Swiss Re article, based on Peter White's presentation, that these treatments were any more effective in getting people back to work.

The PACE investigators published this employment data in a 2012 paper in PLoS One. It is unclear whether Peter White already knew these results at the time of his Swiss Re presentation on the PACE results.

Tuesday, November 17, 2015

Why Was the FINE Study Disappeared?

David Tuller has posted another wonderful article in his series on the PACE trial. In this article he asks the important question, Whatever happened to the FINE study?

The FINE study was published shortly before the PACE trial. (You can read the FINE study here.) 

It used similar treatment strategies as well as a similar timeline as PACE, but unlike the PACE trial the authors concluded at the end of 70-week study that patients had not significantly benefited from "pragmatic care" (supportive listening, and gradually increasing activity). 

Tuller's question is perfectly valid. Why does everyone cite the PACE trial, with its dubious claims of "recovery," while ignoring the FINE trial, which made no claims that patients had gotten better, let alone recovered?

Please feel free to express what you think of the PACE Trial.

You can send an email to the Lancet's editor, Richard Horton: richard.horton@lancet.com. 

Refer to: "Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial" published by The Lancet, Volume 377, No. 9768, p 823–836, 5 March 2011. (You can read the full study here.)

You can sign a petition asking the Lancet to retract their publication of the PACE trial HERE.

Reprinted with the kind permission of David Tuller. This article first appeared on Dr. Vincent Racaniello's Virology Blog.


Trial By Error, Continued: Why has the PACE Study’s “Sister Trial” been “Disappeared” and Forgotten?

By David Tuller, DrPH, 9 NOVEMBER 2015

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

In 2010, the BMJ published the results of the Fatigue Intervention by Nurses Evaluation, or FINE. The investigators for this companion trial to PACE, also funded by the Medical Research Council, reported no benefits to ME/CFS patients from the interventions tested.

In medical research, null findings often get ignored in favor or more exciting “positive” results. In this vein, the FINE trial seems to have vanished from the public discussion over the controversial findings from the PACE study. I thought it was important to re-focus some attention on this related effort to prove that “deconditioning” is the cause of the devastating symptoms of ME/CFS. (This piece is also too long but hopefully not quite as dense.)

An update on something else: I want to thank the public relations manager from Queen Mary University of London for clarifying his previous assertion that I did not seek comment from the PACE investigators before Virology Blog posted my story. In an e-mail, he explained that he did not mean to suggest that I hadn’t contacted them for interviews. He only meant, he wrote, that I hadn’t sent them my draft posts for comment before publication. He apologized for the misunderstanding.

I accept his apology, so that’s the end of the matter. In my return e-mail, however, I did let him know I was surprised at the expectation that I might have shared the draft with the PACE investigators before publication. I would not have done that whether or not they had granted me interviews. This is journalism, not peer-review. Different rules.


In 2003, with much fanfare, the U.K. Medical Research Council announced that it would fund two major studies of non-pharmacological treatments for chronic fatigue syndrome. In addition to PACE, the agency decided to back a second, smaller study called “Fatigue Intervention by Nurses Evaluation,” or FINE. Because the PACE trial was targeting patients well enough to attend sessions at a medical clinic, the complementary FINE study was designed to test treatments for more severely ill patients.

(Chronic fatigue syndrome is also known as myalgic encephalomyelitis, CFS/ME, and ME/CFS, which has now been adopted by U.S. government agencies. The British investigators of FINE and PACE prefer to call it chronic fatigue syndrome, or sometimes CFS/ME.)

Alison Wearden, a psychologist at the University of Manchester, was the lead FINE investigator. She also sat on the PACE Trial Steering Committee and wrote an article about FINE for one of the PACE trial’s participant newsletters. The Medical Research Council and the PACE team referred to FINE as PACE’s “sister” trial. The two studies included the same two primary outcome measures, self-reported fatigue and physical function, and used the same scales to assess them.

The FINE results were published in BMJ in April, 2010. Yet when the first PACE results were published in The Lancet the following year, the investigators did not mention the FINE trial in the text. The trial has also been virtually ignored in the subsequent public debate over the results of the PACE trial and the effectiveness, or lack thereof, of the PACE approach.

What happened? Why has the FINE trial been “disappeared”?


The main goal of the FINE trial was to test a treatment for homebound patients that adapted and combined elements of cognitive behavior therapy and graded exercise therapy, the two rehabilitative therapies being tested in PACE. The approach, called “pragmatic rehabilitation,” had been successfully tested in a small previous study. In FINE, the investigators planned to compare “pragmatic rehabilitation” with another intervention and with standard care from a general practitioner.

Here’s what the Medical Research Council wrote about the main intervention in an article in its newsletter, MRC Network, in the summer of 2003: “Pragmatic rehabilitation…is delivered by specially trained nurses, who give patients a detailed physiological explanation of symptom patterns. This is followed by a treatment programme focussing on graded exercise, sleep and relaxation.”

The second intervention arm featured a treatment called “supportive listening,” a patient-centered and non-directive counseling approach. This treatment presumed that patients might improve if they felt that the therapist empathized with them, took their concerns seriously, and allowed them to find their own approach to addressing the illness.

The Medical Research Council committed 1.3 million pounds to the FINE trial. The study was conducted in northwest England, with 296 patients recruited from primary care. Each intervention took place over 18 weeks and consisted of ten sessions–five home visits lasting up to 90 minutes alternating with five telephone conversations of up to 30 minutes.

As in the PACE trial, patients were selected using the Oxford criteria for chronic fatigue syndrome, defined as the presence of six months of medically unexplained fatigue, with no other symptoms required. The Oxford criteria have been widely criticized for yielding heterogeneous samples, anda report commissioned by the National Institutes of Health this year recommended by the case definition be “retired” for that reason.

More specific case definitions for the illness require the presence of core symptoms like post-exertional malaise, cognitive problems and sleep disorders, rather than just fatigue per se. Because the symptom called post-exertional malaise means that patients can suffer severe relapses after minimal exertion, many patients and advocacy organizations consider increases in activity to be potentially dangerous.

To be eligible for the FINE trial, participants needed to score 70 or less out of 100 on the physical function scale, the Medical Outcomes Study 36-Item Short Form Health Survey, known as the SF-36. They also needed to score a 4 or more out of 11 on the 11-item Chalder Fatigue Scale, with each item scored as either 0 or 1. On the fatigue scale, a higher score indicated greater fatigue.

Among other measures, the trial also included a key objective outcome–the “time to take 20 steps, (or number of steps
taken, if this is not achieved) and maximum heart rate reached on a step-test.”

Participants were to be assessed on these measures at 20 weeks, which as right after the end of the treatment period, and again at 70 weeks, which was one year after the end of treatment. According to the FINE trial protocol, published in the journal BMC Medicine in 2006, “short-term assessments of outcome in a chronic health condition such as CFS/ME can be misleading” and declared the 70-week assessment to be the “primary outcome point.”


The theoretical model behind the FINE trial and pragmatic rehabilitation paralleled the PACE concept. The physical symptoms were presumed to be the result not of a pathological disease process but of “deconditioning” or “dysregulation” caused by sedentary behavior, accompanied by disrupted sleep cycles and stress. The sedentary behavior was itself presumed to be triggered by patients’ “unhelpful’ conviction that they suffered from a progressive medical illness. Counteracting the deconditioning involved re-establishing normal sleep cycles, reducing anxiety levels and gently increasing physical exertion, even if patients remained homebound.

“The treatment [pragmatic rehabilitation] is based on a model proposing that CFS/ME is best understood as a consequence of physiological dysregulation associated with inactivity and disturbance of sleep and circadian rhythms,” stated the FINE trial protocol. “We have argued that these conditions…are often maintained by illness beliefs that lead to exercise-avoidance. The essential feature of the treatment is the provision of a detailed explanation for patients’ symptoms, couched in terms of the physiological dysregulation model, from which flows the rationale for a graded return to activity.”

On the FINE trial website, a 2004 presentation about pragmatic rehabilitation explained the illness in somewhat simpler terms, comparing it to “very severe jetlag.” After explaining how and why pragmatic rehabilitation led to physical improvement, the presentation offered this hopeful message, in boldface: “There is no disease–you have a right to full health. This is a good news diagnosis. Carefully built up exercise can reverse the condition. Go for 100% recovery.”

In contrast, patients, advcoates and many leading scientists have completely rejected the PACE and FINE approach. They believe the evidence overwhelmingly points to an immunological and neurological disorder triggered by an initial infection or some other physiological insult. Last month, the National Institutes of Health ratified this perspective when it announced a major new push to seek biomedical answers to the disease, which it refers to as ME/CFS.

As in PACE, patients in the FINE trial were issued different treatment manuals depending upon their assigned study arm. The treatment manual for pragmatic rehabilitation repeatedly informed participants that the therapy could help them get better—even though the trial itself was designed to test the effectiveness of the therapy. (In the PACE trial, the manuals for the cognitive behavior and graded therapy arms also included many statements promoting the idea that the therapies could successfully treat the illness.)

“This booklet has been written with the help of patients who have made a full recovery from Chronic Fatigue Syndrome,” stated the FINE pragmatic rehabilitation manual on its second page. “Facts and information which were important to them in making this recovery have been included.” The manual noted that the patients who helped write it had been treated at the Royal Liverpool University Hospital but did not include more specific details about their “full recovery” from the illness.

Among the “facts and information” included in the manual were assertions that the trial participants, contrary to what they might themselves believe, had no persistent viral infection and “no underlying serious disease.” The manual promised them that pragmatic rehabilitation could help them overcome the illness and the deconditioning perpetuating it. “Instead of CFS controlling you, you can start to regain control of your body and your life,” stated the manual.

Finally, as in PACE, participants were encouraged to change their beliefs about their condition by “building the right thoughts for your recovery.” Participants were warned that “unhelpful thoughts”—such as the idea that continued symptoms indicated the presence of an organic disease and could not be attributed to deconditioning—“can put you off parts of the treatment programme and so delay or prevent recovery.”

The supportive listening manual did not similarly promote the idea that “recovery” from the illness was possible. During the sessions, the manual explained, “The listener, your therapist, will provide support and encourage you to find ways to cope by using your own resources to change, manage or adapt to difficulties…She will not tell you what to do, advise, coach or direct you.”


A qualitative study about the challenges of the FINE research process, published by the investigators in the journal Implementation Science in 2011, shed light on how much the theoretical framework and the treatment approaches frustrated and angered trial participants. According to the interviews with some of the nurses, nurse supervisors, and participants involved in FINE, the home visits often bristled with tension over the different perceptions of what caused the illness and which interventions could help.

“At times, this lack of agreement over the nature of the condition and lack of acceptance as to the rationale behind the treatment led to conflict,” noted the FINE investigators in the qualitative paper. “A particularly difficult challenge of interacting with patients for the nurses and their supervisors was managing patients’ resistance to the treatment.”

One participant in the pragmatic rehabilitation arm, who apparently found it difficult to do what was apparently expected, attributed this resistance to the insistence that deconditioning caused the symptoms and that activity would reverse them. “If all that was standing between me and recovery was the reconditioning I could work it out and do it, but what I have got is not just a reconditioning problem,” the participant said. “I have got something where there is damage and a complete lack of strength actually getting into the muscles and you can’t work with what you haven’t got in terms of energy.”

Another participant in the pragmatic rehabilitation arm was more blunt. “I kept arguing with her [the nurse administering the treatment] all the time because I didn’t agree with what she said,” said the participant, who ended up dropping out of the trial.

Some participants in the supportive listening arm also questioned the value of the treatment they were receiving, according to the study. “I mostly believe it was more physical than anything else, and I didn’t see how talking could truthfully, you know, if it was physical, do anything,” said one.

In fact, the theoretical orientation also alienated some prospective participants as well, according to interviews the investigators conducted with some patients who declined to enter the trial. ‘It [the PR intervention] insisted that physiologically there was nothing wrong,” said one such patient. “There was nothing wrong with my glands, there was nothing wrong, that it was just deconditioned muscles. And I didn’t believe that…I can’t get well with treatment you don’t believe in.”

When patients challenged or criticized the therapeutic interventions, the study found, nurses sometimes felt their authority and expertise to be under threat. “They are testing you all the time,” said one nurse. Another reported: “That anger…it’s very wearing and demoralizing.”

One nurse remembered the difficulties she faced with a particular participant. “I used to go there and she would totally block me, she would sit with her arms folded, total silence in the house,” said the nurse. “It was tortuous for both of us.”

At times, nurses themselves responded to these difficult interactions with bouts of anger directed at the participants, according to a supervisor.

“Their frustration has reached the point where they sort of boiled over,” said the supervisor. “There is sort of feeling that the patient should be grateful and follow your advice, and in actual fact, what happens is the patient is quite resistant and there is this thing like you know, ‘The bastards don’t want to get better.’”


BMJ published the FINE results in 2010. The FINE investigators found no statistically significant benefits to either pragmatic rehabilitation or supportive listening at 70 weeks. Despite these null findings one year after the end of the 18-week course of treatment, the mean scores of those in the pragmatic rehabilitative arm demonstrated at 20 weeks a “clinically modest” but statistically significant reduction in fatigue—a drop of one point (plus a little) on the 11-point fatigue scale. The slight improvement still meant that participants were much more fatigued than the initial entry threshold for disability, and any benefits were no longer statistically significant by the final assessment.

Despite the null findings at 70 weeks, the authors put a positive gloss on the results, reporting first in the abstract that fatigue was “significantly improved” at 20 weeks. Given the very modest one-point change in average fatigue scores, perhaps the FINE investigators intended to report instead that there was a “statistically significant improvement” at 20 weeks—an accurate phrase with a somewhat different meaning.

The abstract included another interesting linguistic element. While the trial protocol had designated the 70-week assessment as “the primary outcome point,” the abstract of the paper itself now stated that “the primary clinical outcomes were fatigue and physical functioning at the end of treatment (20 weeks) and 70 weeks from recruitment.”

After redefining their primary outcome points to include the 20-week as well as the 70-week assessment, the abstract promoted the positive effects found at the earlier point as the study’s main finding. Only after communicating the initial benefits did they note that these advantages for pragmatic rehabilitation later wore off. The FINE paper cited no oversight committee approval for this expanded interpretation of the trial’s primary outcome points to include the 20-week assessment, nor did it mention the protocol’s caveat about the “misleading” nature of short-term assessments in chronic health conditions.

In fact, within the text of the paper, the investigators noted that the “pre-designated outcome point” was 70 weeks. But they did not explain why they then decided to highlight most in the abstract what was not the pre-designated but instead a post-hoc “primary” outcome point—the 20-week assessment.

A BMJ editorial that accompanied the FINE trial also accentuated the positive results at 20 weeks rather than the bad news at 70 weeks. According to the editorial’s subhead, pragmatic rehabilitation “has a short term benefit, but supportive listening does not.” The editorial did not note that this was not the pre-designated primary outcome point. The null results for that outcome point—the 70-week assessment—were not mentioned until later in the editorial.


Patients and advocates soon began criticizing the study in the “rapid response” section of the BMJ website, citing its theoretical framework, the use of the broad Oxford criteria as a case definition, and the failure to provide the step-test outcomes, among other issues.

“The data provide strong evidence that the anxiety and deconditioning model of CFS/ME on which the trial is predicated is either wrong or, at best, incomplete,” wrote one patient. “These results are immensely important because they demonstrate that if a cure for CFS/ME is to be found, one must look beyond the psycho-behavioural paradigm.”

Another patient wrote that the study was “a wake-up call to the whole
of the medical establishment” to take the illness seriously. One predicted “that there will those who say that the this trial failed because
the patients were not trying hard enough.”

A physician from Australia sought to defend the interests not of patients but of the English language, decrying the lack of hyphens in the paper’s full title: “Nurse led, home based self help treatment for patients in primary care with chronic fatigue syndrome: randomised controlled trial.”

“The hyphen is a coupling 
between carriages of words to ensure unambiguous
 transmission of thought,” wrote the doctor. “Surely this should read ‘Nurse-led, home-based, self-

“Lest English sink further into the Great Despond of 
ambiguity and non-sense [hyphen included in the original comment], may I implore the co-editors of
the BMJ to be the vigilant watchdogs of our mother tongue
 which at the hands of a younger ‘texting’ generation is heading towards anarchy.” [The original comment did not include the expected comma between ‘tongue’ and ‘which.’]


In a response on the BMJ website a month after publishing the study, the FINE investigators reported that they had conducted a post-hoc analysis with a different kind of scoring for the Chalder Fatigue Scale.

Instead of scoring the answers as 0 or 1 using what was called a bimodal scale, they rescored them using what was called a continuous scale, with values ranging from 0 to 3. The full range of possible scores now ran from 0 to 33, rather than 0 to 11. (As collected, the data for the Chalder Fatigue Scale allowed for either scoring system; however, the original entry criteria of 4 on the bimodal scale would translate into a range from 4 to as high as 19 on the revised scale.)

With the revised scoring, they now reported a “clinically modest, but statistically significant effect” of pragmatic rehabilitation at 70 weeks—a reduction from baseline of about 2.5 points on the 0 to 33 scale. This final score represented some increase in fatigue from the 20-week interim assessment point.

In their comment on the website, the FINE investigators now reaffirmed that the 70-week assessment was “our primary outcome point.” This statement conformed to the protocol but differed from the suggestion in the BMJ paper that the 20-week results also represented “primary” outcomes. Given that the post-hoc rescoring allowed the investigators to report statistically significant results at the 70-week endpoint, this zig-zag back to the protocol language was perhaps not surprising.

In their comment, the FINE investigators also explained that they did not report their step-test results—their one objective measure of physical capacity–“due to a significant amount of missing data.” They did not provide an explanation for the missing data. (One obvious possible reason for missing data on an objective fitness test is that participants were too disabled to perform it at all.)

The FINE investigators did not address the question of whether the title of their paper should have included hyphens.

In the rapid comments, Tom Kindlon, a patient and advocate from a Dublin suburb, responded to the FINE investigators’ decision to report their new post-hoc analysis of the fatigue scale. He noted that the investigators themselves had chosen the bimodal scoring system for their study rather than the continuous method.

 sure many pharmacological and non-pharmacological studies could look
 different if investigators decided to use a different scoring method or
scale at the end, if the results weren’t as impressive as they’d hoped,” he wrote. “But that is not normally how medicine works. So, while it is interesting
 that the researchers have shared this data, I think the data in the main
paper should be seen as the main data.”


The FINE investigators have published a number of other papers arising from their study. In a 2013 paper on mediators of the effects of pragmatic rehabilitation, they reported that there were no differences between the three groups on the objective measure of physical capacity, the step test, despite their earlier decision not to publish the data in the BMJ paper.

Wearden herself presented the trial as a high point of her professional career in a 2013 interviewfor the website of the University of Manchester’s School of Psychological Sciences. “I suppose the thing I did that I’m most proud of is I ran a large treatment trial of pragmatic rehabilitation treatment for patients with chronic fatigue syndrome,” she said in the interview. “We successfully carried that trial out and found a treatment that improved patients’ fatigue, so that’s probably the thing that I’m most proud of.”

The interview did not mention that the improvement at 20 weeks was transient until the investigators performed a post-hoc-analysis and rescored the fatigue scale.


The Science Media Centre, a self-styled “independent” purveyor of information about science and scientific research to journalists, has consistently shown an interest in research on what it calls CFS/ME. It held a press briefing for the first PACE results published in The Lancet in 2011, and has helped publicize the release of subsequent studies from the PACE team.

However, the Science Media Centre does not appear to have done anything to publicize the 2010 release of the FINE trial, despite its interest in the topic. A search of the center’s website for the lead FINE investigator, Alison Wearden, yielded no results. And a search for CFS/ME indicated that the first study embraced by the center’s publicity machine was the 2011 Lancet paper.

That might help explain why the FINE trial was virtually ignored by the media. A search on the LexisNexis database for “PACE trial” and “chronic fatigue syndrome” yielded 21 “newspaper” articles (I use the “apostrophes” here because I don’t know if that number includes articles on newspaper websites that did not appear in the print product; the accuracy of the number is also in question because the list did not include two PACE-related articles that I wrote for The New York Times).

Searches on the database combining “chronic fatigue syndrome” with either “FINE trial” or “pragmatic rehabilitation” yielded no results. (I used the version of LexisNexis Academic available to me through the University of California library system.)

Other researchers have also paid scant attention to the FINE trial, especially when compared to the PACE study. According to Google Scholar, the 2011 PACE paper in The Lancet has been cited 355 times. In contrast, the 2010 FINE paper in BMJ has only been cited 39 times.


The PACE investigators likely exacerbated this virtual disappearance of the FINE trial by their decision not to mention it in their Lancet paper, despite its longstanding status as a “sister trial” and the relevance of the findings to their own study of cognitive behavior therapy and graded exercise therapy. The PACE investigators have not explained their reasons for ignoring the FINE trial. (I wrote about this lapse in my Virology Blog story, but in their response the PACE investigators did not mention it.)

This absence is particularly striking in light of the decision made by the PACE investigators to drop their protocol method of assessing the Chalder Fatigue Scale. In the protocol, their primary fatigue outcome was based on bimodal scoring on the 11-item fatigue scale. The protocol included continuous scoring on the fatigue scale, with the 0 to 33 scale, as a secondary outcome.

In the PACE paper itself, the investigators announced that they had dropped the bimodal scoring in favor of the continuous scoring “to more sensitively test our hypotheses of effectiveness.” They did not explain why they simply didn’t provide the findings under both scoring methods, since the data as collected allowed for both analyses. They also did not cite any references to support this mid-trial decision, nor did they explain what prompted it.

They certainly did not mention that PACE’s “sister” study, the FINE trial, had reported null results at the 70-week endpoint—that is, until the investigators rescored the data using a continuous scale rather than the bimodal scale used in the original paper.

The three main PACE investigators—psychiatrist Peter White and Michael Sharpe, and behavioral psychologist Trudie Chalder—did not respond to an e-mail request for comment on why their Lancet paper did not mention the FINE study, especially in reference to their post-hoc decision to change the method of scoring the fatigue scale. Lancet editor Richard Horton also did not respond to an e-mail request for an interview on whether he believed the Lancet paper should have included information about the FINE trial and its results.

Friday, November 13, 2015

Researchers Urge Independent Review of PACE Trial

The PACE Trial has been very much in the news lately with the virtually simultaneous exposé of the flaws of the trial by investigative journalist David Tuller and the publication of the PACE follow-up. (You can read David Tuller's articles here. The PACE follow-up is here.)

Given the many methodological flaws of the PACE trial, and its consistent refusal to release data from the trial for independent review, it is a wonder that it was ever published. However, not only was the trial rushed to publication, there is evidence that the editor of The Lancet, Richard Horton, was himself biased. In an interview on Australian radio in 2011, Horton claimed that criticisms about PACE are "attack" made by  "highly organised, very vocal and very damaging group of individuals who have, I would say, actually hijacked this agenda and distorted the debate." 

Ironically, Richard Horton recently issued a statement that a lot of published research is incorrect.  “The case against science is straightforward: much of the scientific literature, perhaps half, may simply be untrue," he said. With even deeper irony, he pointed to "tiny effects, invalid exploratory analyses, and flagrant conflicts of interest, together with an obsession for pursuing fashionable trends of dubious importance." Science has, to quote Horton again, "taken a turn towards darkness.” And Horton himself did much to turn it.

Calling for a review the PACE trial in an open letter, six prominent researchers have urged Dr. Horton to live up to his own words. According to the researchers, the reviewers should be "completely independent of, and have no conflicts of interests involving, the PACE investigators and the funders of the trial."

If you would like to express what you think of the PACE Trial, you can send an email to the Lancet's editor, Richard Horton: richard.horton@lancet.com. Refer to: "Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial" published by The Lancet, Volume 377, No. 9768, p 823–836, 5 March 2011. (You can read the full study here.)

You can sign a petition asking the Lancet to retract their publication of the PACE trial HERE.


An open letter to Dr. Richard Horton and The Lancet

Virology Blog, 13 NOVEMBER 2015

Dr. Richard Horton
The Lancet
125 London Wall
London, EC2Y 5AS, UK

Dear Dr. Horton:

In February, 2011, The Lancet published an article called “Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomized trial.” The article reported that two “rehabilitative” approaches, cognitive behavior therapy and graded exercise therapy, were effective in treating chronic fatigue syndrome, also known as myalgic encephalomyelitis, ME/CFS and CFS/ME. The study received international attention and has had widespread influence on research, treatment options and public attitudes.

The PACE study was an unblinded clinical trial with subjective primary outcomes, a design that requires strict vigilance in order to prevent the possibility of bias. Yet the study suffered from major flaws that have raised serious concerns about the validity, reliability and integrity of the findings. The patient and advocacy communities have known this for years, but a recent in-depth report on this site, which included statements from five of us, has brought the extent of the problems to the attention of a broader public. The PACE investigators have replied to many of the criticisms, but their responses have not addressed or answered key concerns.

The major flaws documented at length in the recent report include, but are not limited to, the following:

*The Lancet paper included an analysis in which the outcome thresholds for being “within the normal range” on the two primary measures of fatigue and physical function demonstrated worse health than the criteria for entry, which already indicated serious disability. In fact, 13 percent of the study participants were already “within the normal range” on one or both outcome measures at baseline, but the investigators did not disclose this salient fact in the Lancet paper. In an accompanying Lancet commentary, colleagues of the PACE team defined participants who met these expansive “normal ranges” as having achieved a “strict criterion for recovery.” The PACE authors reviewed this commentary before publication.

*During the trial, the authors published a newsletter for participants that included positive testimonials from earlier participants about the benefits of the “therapy” and “treatment.” The same newsletter included an article that cited the two rehabilitative interventions pioneered by the researchers and being tested in the PACE trial as having been recommended by a U.K. clinical guidelines committee “based on the best available evidence.” The newsletter did not mention that a key PACE investigator also served on the clinical guidelines committee. At the time of the newsletter, two hundred or more participants—about a third of the total sample–were still undergoing assessments.

*Mid-trial, the PACE investigators changed their protocol methods of assessing their primary outcome measures of fatigue and physical function. This is of particular concern in an unblinded trial like PACE, in which outcome trends are often apparent long before outcome data are seen. The investigators provided no sensitivity analyses to assess the impact of the changes and have refused requests to provide the results per the methods outlined in their protocol.

*The PACE investigators based their claims of treatment success solely on their subjective outcomes. In the Lancet paper, the results of a six-minute walking test—described in the protocol as “an objective measure of physical capacity”–did not support such claims, notwithstanding the minimal gains in one arm. In subsequent comments in another journal, the investigators dismissed the walking-test results as irrelevant, non-objective and fraught with limitations. All the other objective measures in PACE, presented in other journals, also failed. The results of one objective measure, the fitness step-test, were provided in a 2015 paper in The Lancet Psychiatry, but only in the form of a tiny graph. A request for the step-test data used to create the graph was rejected as “vexatious.”

*The investigators violated their promise in the PACE protocol to adhere to the Declaration of Helsinki, which mandates that prospective participants be “adequately informed” about researchers’ “possible conflicts of interest.” The main investigators have had financial and consulting relationships with disability insurance companies, advising them that rehabilitative therapies like those tested in PACE could help ME/CFS claimants get off benefits and back to work. They disclosed these insurance industry links in The Lancet but did not inform trial participants, contrary to their protocol commitment. This serious ethical breach raises concerns about whether the consent obtained from the 641 trial participants is legitimate.

Such flaws have no place in published research. This is of particular concern in the case of the PACE trial because of its significant impact on government policy, public health practice, clinical care, and decisions about disability insurance and other social benefits. Under the circumstances, it is incumbent upon The Lancet to address this matter as soon as possible.

We therefore urge The Lancet to seek an independent re-analysis of the individual-level PACE trial data, with appropriate sensitivity analyses, from highly respected reviewers with extensive expertise in statistics and study design. The reviewers should be from outside the U.K. and outside the domains of psychiatry and psychological medicine. They should also be completely independent of, and have no conflicts of interests involving, the PACE investigators and the funders of the trial.

Thank you very much for your quick attention to this matter.


Ronald W. Davis, PhD
Professor of Biochemistry and Genetics
Stanford University

Jonathan C.W. Edwards, MD
Emeritus Professor of Medicine
University College London

Leonard A. Jason, PhD
Professor of Psychology
DePaul University

Bruce Levin, PhD
Professor of Biostatistics
Columbia University

Vincent R. Racaniello, PhD
Professor of Microbiology and Immunology
Columbia University

Arthur L. Reingold, MD
Professor of Epidemiology
University of California, Berkeley
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