On episode #364 of the science show This Week in Virology, Vincent, Rich, and Kathy speak with Ralph Baric and Vineet Menachery about their research on the potential of SARS-like bat coronaviruses  to infect human cells and cause disease in mice.

You can find TWiV #364 at www.twiv.tv.

SARSA study on the potential of SARS-virus-like bat coronaviruses to cause human disease has reawakened the debate on the risks and benefits of engineering viruses. Let’s go over the science and then see if any of the criticisms have merit.

The SARS epidemic of 2003 was caused by a novel coronavirus (CoV) that originated in bats. Results of sequence analyses have shown that viruses related to SARS-CoV continue to circulate in bats, but their potential for infecting humans is not known. One can learn only so much from looking at viral sequences – eventually experiments need to be done.

To answer the question ‘do the SARS-CoV like viruses circulating in bats have the potential to infect humans’, a recombinant virus was created in which the gene encoding the spike glycoprotein of SARS virus was swapped with the gene from a bat virus called SHC014. The SARS-CoV that was used (called SARS-MA15) had been previously passaged from mouse to mouse until it was able to replicate in that host. The use of this mouse-adapted virus allows studies on viral disease and its prevention in a mammalian host.

The recombinant virus, called SHC014-MA15, replicated well in a human epithelial airway cell line and in primary human airway epithelial cell cultures. The recombinant virus replicated just as well as the Urbani strain of human SARS-CoV. This result was surprising because the part of the spike protein of SCH014 that binds the cell receptor, ACE2, is sufficiently different from the SARS-CoV spike, suggesting that the virus might not infect human cells.

First lesson learned: looking at a viral genome sequence alone does not answer all questions. The spike glycoprotein of a bat coronavirus can mediate virus entry into human cells.

Next the authors wanted to know if SHC014-MA15 could infect mice and cause respiratory disease. Ten week old mice were infected intranasally with either SCH014-MA15 or SARS-MA15. Animals infected with SARS-MA15 lost weight rapidly and died within 4 days. Mice infected with SCH014-MA15 lost weight but did not die. When older (12 month) mice were used (these are more susceptible to SARS-MA15 infection), both viruses caused weight loss, but SARS-MA15 killed all the mice while SCH014-MA15 was less virulent (20% of mice died).

Second lesson learned: a human SARS-CoV with a bat glycoprotein can infect mice but is attenuated compared to a human, mouse adapted strain.

The next question asked was whether monoclonal antibodies (think ZMAPP, used in some Ebolavirus infected patients) against SARS-CoV could protect cells from infection with SCH014-MA15. The answer is no.

Third lesson learned: anti-SARS-CoV monoclonal antibodies do not protect from infection with SCH014-MA15.

Could an inactivated SARS-CoV vaccine protect mice from infection with SCH014-MA15?  An inactivated SARS-CoV vaccine provided no protection against infection SCH-014-MA15. When mice were first infected with a high dose of SCH014-MA15, there was some protection against challenge with the same virus, but protection did not last. And the side effects, weight loss and some death, would not be acceptable for a vaccine.

Fourth lesson learned: an inactivated SARS-CoV vaccine does not protect against infection with SCH014-MA15, and the recombinant virus itself is barely protective but not a safe vaccine.

In the final experiment of the paper, the SCH014 virus was recovered from an infectious DNA clone made from the genome sequence. This virus infected primary human airway epithelial cell cultures but not as well as did SARS-CoV Urbani. In mice SCH014 did not cause weight loss and it replicated to lower titers than SARS-CoV Urbani.

Fifth lesson learned: At least one circulating SARS-like bat CoV can infect human cells, but causes only mild disease in mice. Additional changes in the viral genome would likely be needed to cause a SARS-like epidemic.

Let’s now take a look at some of the public statements that have been made about this work.

Richard Ebright says that ‘The only impact of this work is the creation, in a lab, of a new, non-natural risk”. He could not be more wrong. For Ebright’s benefit, I submit my summary above of what we have learned from this work. Furthermore, I suggest that Ebright has not read the paper, or if he had, he has not put it in the context of the gaps in our knowledge of bat coronavirus potential to infect humans. This type of negative quote is easily picked up by the press, but it’s completely inaccurate.

Simon Wain-Hobson says that a novel virus was created that ‘grows remarkably well’ in human cells; ‘if the virus escaped, nobody could predict the trajectory’.

I do agree that we cannot predict what would happen if SCH014-MA15 were released into the human population. In my opinion the risk of release and spread of this virus in humans is very low. The attenuated virulence of the SCH014-MA15 virus in mice suggests (but does not prove) that the recombinant virus is not optimized for replication in mammals. Recall that the virus used to produce the recombinant, SARS-MA15 is mouse-adapted and may very well have lost some virulence for humans. In a broader sense, virologists have been manipulating viruses for years and none have gone on to cause an epidemic in humans. While there have been recent lapses in high-containment biological facilities, none have resulted in harm, and work has gone on for years in many other facilities without harm. I understand that none of these arguments tell us what will happen in the future, but these are the data that we have to calculate risk. Bottom line: the risk of these experiments is very low.

I think the statments by Ebright and Wain-Hobson are simply meant to scare the public and push us towards regulation of what they believe are ‘dangerous’ experiments. They are misleading because they ignore the substantial advances of the work. The experiments in this paper were well thought out, and the conclusions (listed above) are substantial. Creation of the recombinant virus SCH014-MA15 was needed to show that the spike glycoprotein could mediate entry into human cells. Only after that result was obtained did it make sense to recover the SCH014 bat virus. We now understand that at least one circulating bat SARS-like CoV can infect human cells and the mouse respiratory tract. More importantly, infection cannot be prevented with current SARS monoclonal antibodies or vaccines.

This information means that we should embark on a program to understand the different SARS-like spike glyocoproteins on bat CoVs, and try to develop therapeutics to prevent a possible second spillover into humans. This work will require further studies of the type reported in this paper.

My conclusion: these are low risk, high benefit experiments. You may disagree with my assessment of risk, but you cannot deny the benefits of this work. If you do, you simply haven’t read and understood the paper.

As you might imagine, the press has had a field day with this work. But many of these articles are misleading. For example, the headline of the Motherboard article touts “Ethical Questions Arise After Scientists Brew Super Powerful ‘SARS 2.0’ Virus”. As I pointed out above, both SCH014-MA15 and SCH104 are less virulent in mice than SARS-CoV, so this headline is completely wrong. An article in Sputnik International has the headline “Uncaging the Animal: Concerns Rise Over Scientists Tests on SARS 2.0” and the sub-headline is “‘SARS 2.0’ is closer than you might think as scientists are continuing medical tests that could create a whole new virus outbreak.” The article claims that the experiments are ‘science for the sake of science’. If the author had read the Nature article, he or she could not have reached that conclusion. Both articles feature scary quotations by Ebright and Wain-Hobson. The most egregious may be an article in the Daily Mail, which claims that “New SARS-like virus can jump directly from bats to humans without mutating, sparking fears of a future epidemic”. This statement is also wrong – there are no data in the paper which show that the virus can jump from bats to humans!

Perhaps at fault for much of this hyperbole is the press release on this work issued by the University of North Carolina, the home of the paper’s authors. The headline of the press release is: “New SARS-like virus can jump directly from bats to humans, no treatment available”. Exactly the same as the Daily Mail! Other errors in the press release emphasize that researchers need to work more closely with publicity departments to ensure that the correct message is conveyed to writers.



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.

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.

Update 11/18/15 6:54 AM: I also forgot to mention in the story that the three principal PACE investigators did not respond to an e-mail seeking comment about their insurance industry work. Lancet editor Richard Horton also did not respond to an e-mail seeking comment.


TWiV 363: Eat flu and dyad

15 November 2015

On episode #363 of the science show This Week in Virology, The TWiVers reveal influenza virus replication in the ferret mammary gland and spread to a nursing infant, and selection of transmissible influenza viruses in the soft palate.

You can find TWiV #363 at www.twiv.tv.

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


Ferret mother-infantDuring breastfeeding, mothers provide the infant with nutrients, beneficial bacteria, and immune protection. Fluids from the infant may also enter the mammary gland through retrograde flux of the nipple. Studies in a ferret model reveal that influenza virus replicates in the mammary gland, is shed in breast milk and transmitted to the infant. Virus may also travel in the opposite direction, from infant to mother.

The role of the mammary gland in influenza virus transmission was studied using a ferret model comprising lactating mothers and nursing infants. Intranasal inoculation of nursing mother ferrets with the 2009 H1N1 influenza virus lead to viral replication and development of influenza in both mother and infant. When the study design was reversed, and 4 week old nursing ferrets were inoculated intranasally with the same virus, viral replication and disease ensued first in the infants, and then in the mothers. Infectious virus was recovered both in the mammary glands and in the nipples at day 4 post infant inoculation, and in mother’s milk from 3-5 days post infant inoculation. Histopathological examination of sections of mammary glands from infected mothers revealed destruction of the mammary architecture.

These results show that nursing infants may pass influenza virus to mothers. It seems clear that influenza virus replicates in the mammary gland and that infectious virus is present in milk. How does this virus infect the mother? One possibility is that infection is transmitted by respiratory contact with virus-containing milk, or by inhalation of aerosols produced by nursing. How influenza virus in the mammary gland would reach the mother’s lung via the blood to cause respiratory disease is more difficult to envision and seems unlikely.

When influenza virus was inoculated into the mammary gland of lactating mothers via the lactiferous ducts, both mother and breast feeding infant developed serious influenza. Infectious virus was detected first in the nasal wash of infants, then later in the nasal wash of mothers. Breast milk contained infectious virus starting on day 2 after inoculation. Histopathological examination of sections from infected mammary glands revealed destruction of glandular architecture and cessation of milk production. This observation is consistent with the results of gene expression analysis of RNA from virus infected mammary glands, which revealed reduction in transcripts of genes associated with milk production.

To determine if human breast cells can be infected with influenza virus, three different human epithelial breast cell lines were infected with the 2009 H1N1 virus strain. Virus-induced cell killing was observed and infectious virus was produced.

Even if we assume that influenza virus can replicate in the human breast, the implications for influenza transmission and disease severity are not clear. Transmission of HIV-1 from mother to infant by breast milk has been well documented. In contrast to influenza virus, HIV-1 is present in the blood from where it spreads to the breast. Most human influenza virus strains do not enter the blood so it seems unlikely that virus would spread to the breast of a mother infected via the respiratory route. However, viral RNA has been detected in the blood of humans infected with the 2009 H1N1 strain, the virus used in these ferret studies. Therefore we cannot rule out the possibility that some strains of influenza virus spread from lung via the blood to the breast, allowing infection of a nursing infant. Some answers might be provided by determining if influenza virus can be detected in the breast milk of humans with influenza.

What would be the implication of a nursing infant infecting the mother’s breast with influenza virus? As I mentioned above, it seems unlikely that this virus would enter the blood, and even if it could, how would the virus infect the apical side of the respiratory epithelium? What does seem clear is that viral replication in the breast could lead to a decrease in milk production which could be detrimental to the infant. If the mother had multiple births, then influenza virus might be transmitted to siblings nursing on the infected mother.

Are you wondering how an infant drinking influenza virus-laded breast milk acquires a respiratory infection? Recently it has been shown that influenza virus replicates in the soft palate of ferrets. The soft palate has mucosal surfaces that face both the oral cavity and the nasopharynx. Ingested virus could first replicate in the soft palate, then spread to the nasopharynx and the lung. A simpler explanation is that nursing produces virus-containing aerosols which are inhaled by the infant.


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.

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, and a 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 interview for 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.


Update 11/9/15 10:46 PM: According to a list of published and in-process papers on the FINE trial website, the main FINE study was rejected by The Lancet before being accepted by BMJ, suggesting that the journal was at least aware of the trial well before it published the PACE study. That raises further questions about the absence of any mention of FINE and its null findings in the text of the PACE paper.


On episode #362 of the science show This Week in Virology, the virus virtuosos, with their usual verve, illuminate a new method to identify all the viral nucleic acids in a sample, and regulation of viral gene expression by codon usage.

You can find TWiV #362 at www.twiv.tv.

HIV-1 mutation rateThe high mutation rate of RNA viruses enables them to evolve in the face of different selection pressures, such as entering a new host or countering host defenses. It has always been thought that the sources of such mutations are the enzymes that copy viral RNA genomes: they make random errors which they cannot correct. Now it appears that a cell enzyme makes an even greater contribution the mutation rate of an RNA virus.

Deep sequencing was used to determine the mutation rate of HIV-1 in the blood of AIDS patients by searching for premature stop codons in open reading frames of viral RNA. Because stop codons terminate protein synthesis, they do not allow production of infectious viruses. Therefore they can be used to calculate the mutation rate in the absence of selection. The mutation rate calculated in this way, 0.000093 mutations per base per cell, was slightly higher than previously calculated from studies in cell culture.

When HIV-1 infects a cell, the enzyme reverse transcriptase converts its RNA genome to DNA, which then integrates into the host cell genome. Identification of stop codons in integrated viral DNA should provide an even better estimate of the mutation rate of reverse transcriptase, because mutations that block the production of infectious virus have not yet been removed by selection. The mutation rate calculated by this approach was 0.0041 mutations per base per cell, or one mutation every 250 bases. This mutation rate is 44 times higher than the value calculated from viral RNA in patient plasma (illustrated).

Sequencing of integrated viral DNA from many patients revealed that the vast majority of mutations leading to insertion of stop codons – 98% – were the consequence of editing by the cellular enzyme APOBEC3G. This enzyme is a deaminase that changes dC to dU in the first strand of viral DNA synthesized by reverse transcriptase. APOBEC3G constitutes an intrinsic defense against HIV-1 infection, because extensive mutation of the viral DNA reduces viral infectivity. Indeed, most integrated HIV proviruses are not infectious as a consequence of APOBEC3G-induced mutations. That infection proceeds at all is due to incorporation of the viral protein vif in the virus particles. Vif binds APOBEC3G, leading to its degradation in cells.

The mutation rate of integrated HIV-1 DNA calculated by this method is much higher than that of other RNA viruses. This high mutation rate is driven by the cellular enzyme, APOBEC3G. At least half of the mutations observed in plasma viral RNAs are also contributed by this enzyme.

It has always been thought that error-prone viral RNA polymerases are largely responsible for the high mutation rates of RNA viruses. The results of this study add a new driver of viral variation, a cellular enzyme. APOBEC enzymes are known to introduce mutations in the genomes of other viruses, including hepatitis B virus, papillomaviruses, and herpesviruses. Furthermore, the cellular adenosine deaminase enzyme can edit the genomes of RNA viruses such as measles virus, parainfluenza virus, and respiratory syncytial virus. Cellular enzymes may therefore play a much greater role in the generation of viral diversity than previously imagined.


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.