TWiVOn episode #375 of the science show This Week in Virology, the TWiVziks present everything you want to know about Zika virus, including association of infection with microcephaly and Guillain-Barré syndrome, transmission, epidemiology, and much more.

You can find TWiV #375 at microbe.tv/twiv.

FlavivirusCan Zika virus be sexually transmitted? Perhaps in very rare cases, but the main mode of transmission is certainly via mosquitoes. That’s why I’ve shamelessly stolen a quote on this topic from Dr. William Schaffner of Vanderbilt University:

Mosquito transmission is the highway, whereas sexual transmission is the byway. Sexual transmission cannot account for this sudden and widespread transmission of this virus.

If you just read the news headlines, which many people do, you will think that Zika virus spreads like HIV. But it does not.

Let’s make a clear distinction between sexually transmitted viruses (like HIV – sex is the main mode of transmission, along with contaminated blood), versus sexually transmissible viruses. The latter includes viruses that now and then might be sexually transmitted under certain circumstances, but which normally are transmitted by another route. Zika virus is transmitted among humans by mosquitoes. If sexual transmission occurs, it is very, very rare, given the large number of Zika virus infections that have been documented.

Is Zika virus sexually transmissible?

The first hint of sexual transmission of Zika virus came from the story of two American scientists working in Senegal in 2008, where they were sampling mosquitoes. Between 6-9 days after returning to their homes in Colorado, they developed a variety of symptoms of infection including fatigue, headache, chills, arthralgia, and a maculopapular rash. The wife of one patient had not traveled to Africa, yet she developed similar symptoms three days after her husband. Analysis of paired acute and convalescent sera from all three patients revealed antibodies against Zika virus. The authors of the study do not conclude that transmission from husband to wife was via sexual activity – they suggest it as a possiblity. Their data could not prove sexual transmission.

More recently infectious Zika virus was detected in semen of a French Polynesian male who had recovered from infection. The presence of virus in semen is compatible with sexual transmission, but the patient was not known to have transmitted infection to anyone.

The CDC has concluded that Zika virus was transmitted to an individual in Texas who had sex with a traveler returning from Venezuela. As of this writing I do not know exactly how the CDC came to this conclusion.

What would be needed to prove that Zika virus is sexually transmissible?

Polymerase chain reaction (PCR) is used to diagnose many viral diseases. This assay detects small fragments of viral nucleic acid and can be very specific. However as we are trying to establish for the first time that Zika virus can be transmitted sexually, more than PCR must be done – infectious virus should be recovered from the donor and recipient. A positive PCR result does not mean that infectious virus is present in the sample, only fragments of the genome, which of course would not be infectious. It is important to correlate the presence of infectious virus with sexual transmission.

Not only should infectious virus be recovered from both donor and recipient, but the viral genome sequences should be nearly identical, providing strong evidence for sexual transmission. If the viral genome sequences were substantially different, this result could imply that the infection was acquired from someone else.

Looking for anti-viral antibodies in serum is a good way to confirm virus infection when virus is no longer present. However it is not as specific as PCR or virus isolation, and does not provide information about the genome of the donor and recipient virus.

Sexual transmission of Ebolavirus still remains speculative. There are several suspected cases, and many examples of PCR positive semen samples from men who have recovered from the disease. It’s not easy to prove that a virus can be transmitted sexually, especially when it is a rare event.

Just as we are not sure that Zika virus causes microencephaly, we are not sure if it can be sexually transmitted.

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.

 

Last week, a commentary in Nature about the debate over data-sharing in science made some excellent points. Unfortunately, the authors lumped “hard-line opponents” of research into chronic fatigue syndrome with those who question climate change and the health effects of tobacco, among others—accusing them of engaging in “endless information requests, complaints to researchers’ universities, online harassment, distortion of scientific findings and even threats of violence.”

Whatever the merits of the overall argument, this charge—clearly a reference to the angry response of patients and advocates to the indefensible claims made by the PACE trial–unleashed a wave of online commentary and protest on ME/CFS forums. Psychologist James Coyne posted a fierce response, linking the issue specifically to the PACE authors’ efforts to block access to their data and citing the pivotal role of the Science Media Centre in the battle.

The Nature commentary demonstrated the degree to which this narrative—that the PACE authors have been subjected to a wave of threats and unfair campaigning against their work and reputations—has been accepted as fact by the UK medical and academic establishment. Despite the study’s unacceptable methodological lapses and the lack of any corroborating public evidence from law enforcement about such threats, the authors have wielded these claims to great effect. Wrapping themselves in victimhood, they have even managed to extend their definition of harassment to include any questioning of their science and the filing of requests for data—a tactic that has shielded their work from legitimate and much-needed scrutiny.

Until recently, complaining about harassment worked remarkably well for the PACE team. Maybe that’s why they tried claiming victimhood again last October, when Virology Blog ran “Trial By Error,” my in-depth investigation of PACE. The series was the first major critique of the trial’s many indefensible flaws from outside the ME/CFS patient and advocacy community. Afterwards, the investigators complained that “misinformation” and “inaccuracies” in my stories had subjected them to “abuse” on social media and could cause them “a considerable amount of reputational damage.”

These claims were ridiculous—an attempt to deploy their standard strategy for dismissing valid criticisms. The PACE authors amplified this error in December, when they rejected Dr. Coyne’s request for data from a PACE paper published in PLoS One as “vexatious.” They had called previous requests from patients “vexatious” without attracting negative comment or attention—except from other patients. But applying the term to a respected researcher backfired, drawing howls from others in the scientific community with no knowledge of ME/CFS—the PACE team’s action was “unforgivable,” according to Columbia stats professor Andrew Gelman, and “absurd,” according to Retraction Watch.

(In fact, the PLoS One data, when ultimately released, will show that the paper’s main claim—that the PACE-endorsed treatments are cost-effective—is based on a false statement about sensitivity analyses, as I reported on Virology Blog.)

How did this theme of harassment and “vexatiousness” become part of the conversation in the first place? Starting in 2011, a few months after The Lancet published the first PACE results, top news organizations began reporting on an alarming phenomenon: Possibly dangerous chronic fatigue syndrome patients were threatening prominent psychiatrists and psychologists who were researching the illness. These reports appeared in, among other outlets, the BMJ, the Guardian, and The Sunday Times of London. The Times headline, a profile of Sir Simon Wessely, a longtime colleague of the PACE authors, was typical: “This man faced death threats and abuse. His crime? He suggested that ME was a mental illness.”

One patient had supposedly appeared at a PACE author’s lecture with a knife. Other CFS researchers had received death threats. Sir Wessely famously said that he felt safer in Afghanistan and Iraq than in the UK doing research into the disease—a preposterous statement that the press appeared to take at face value. News accounts compared the patients to radical animal terrorists.

According to the news reports, the patients objected to the involvement of these mental health experts because they were anti-psychiatry and resented being perceived as suffering from a psychological disorder. Editorials in medical journals and other publications followed the news accounts, all of them defending “science” against these unwarranted and frightening attacks.

In fact, the Science Media Centre orchestrated the story in the first place—not surprising, given its longtime association with the PACE team and its uncritical promotion of the various PACE papers. According to a 2013 SMC report reviewing the accomplishments of the first three years of its “mental health research function”: “Tom Feilden, science correspondent for BBC Radio 4’s Today programme, won the UK Press Gazette’s first ever specialist science writing award for breaking the story the SMC gave him about the harassment and intimidation of researchers working on CFS/ME. The SMC had nominated him for the award.”

It’s great that the SMC not only spoon-fed Feilden the story but was so pleased with the reporter’s hard work that it nominated him for a prestigious award. In a brochure prepared for SMC’s anniversary, Feilden himself thanked the centre for its help in organizing the scoop about the “vitriolic abuse” and the “campaign of intimidation.”

Of course, patients were attacking the PACE study not because they were anti-science or anti-psychiatry but because the study itself was so terrible, as I reported last October. Luckily, a growing number of scientists outside the field, like Dr. Coyne and the top researchers from Columbia, Stanford and Berkeley who signed an open letter to The Lancet demanding an independent review, have now recognized this. How are patients supposed to react when a study so completely ignores scientific norms, and no one else seems to notice or care, no matter how many times it is pointed out?

The PACE study’s missteps rendered the results meaningless. Let’s recap briefly. The investigators changed their primary outcomes in ways that made it easier to report success, included outcome measures for improvement that were lower than the entry criteria for disability, and published a newsletter in which they promoted the therapies under investigation. They rejected as irrelevant their own pre-selected objective outcomes when the results failed to uphold their claims, and used an overly broad definition for the illness that identified people without it. Finally, despite an explicit promise in their protocol to inform participants of “any possible conflicts of interest,” they did not tell them of their work advising disability insurers on how to handle claimants with ME/CFS.

Patients and advocates have raised these and other legitimate concerns, in every possible academic, scientific and popular forum. This effort has been framed by the investigators, The Lancet and the Science Media Centre as a vicious and anti-scientific “campaign” against PACE. The news reports adopted this viewpoint and utterly failed to examine the scientific mistakes at the root of patients’ complaints.

Moreover, the reports did not present any independent evidence of the purported threats, other than claims made by the researchers. There were no statements from law enforcement authorities confirming the claims. No mention of any arrests made or charges having been filed. And little information from actual patients, much less these extremist, dangerous patients who supposedly hated psychiatry [see correction below]. In short, these news reports failed to pass any reasonable test of independent judgment and editorial skepticism.

Despite their questionable scientific methods and unreliable results, the PACE authors have widespread support among the UK medical and academic establishment. So does the Science Media Centre. Media reports, including last week’s Nature commentary, have presented without question the PACE authors’ perspective on patient response to the study. The reality is that patients have been protesting a study they know to be deeply flawed. Sometimes they have protested very, very loudly. That’s what people do when they are desperate for help, and no one is listening. To call it harassment is disgraceful.

Update 2/3/16: After reading some of the comments, I thought it was important to make clear that I don’t doubt the PACE investigators and some of their colleagues might have received very raw and nasty e-mails or phone calls. Perhaps some of these felt threatening, and perhaps they called in the police. (I’ve worked as a reporter for many years and have also received many, many raw and nasty e-mails, so I know it’s not enjoyable—but pissing people off is also part of the job.) The news accounts, however, provided no independent verification of the investigators’ charges. And the point is that, whether or not they have been the recipient of some unpleasant communications, the investigators have repeatedly used these claims to justify blocking legitimate inquiry into the PACE trial.

Correction: I reviewed the three major articles I linked to, not every single article about the issue, so my description of the coverage applies to those three. I originally wrote that the articles contained “no” interviews with actual patients. However, the Sunday Times article did include a short interview with one ME/CFS patient–a convicted child-molester who blamed his crime on fall-out from his illness. I apologize for the mistake, although I leave it to readers to decide if interviewing this person represented a sincere effort on the reporter’s part to present patients’ legitimate concerns.

I also wrote that the articles included no statements from law enforcement confirming the claims of threats. The Guardian article contained this sentence: “According to the police, the militants are now considered to be as dangerous and uncompromising as animal rights extremists.” This statement is vague, anonymous and impossible to verify with anyone in particular, so I don’t view it as an authoritative statement from law enforcement.

TWiV 374: Discordance in B

TWiVOn episode #374 of the science show This Week in Virology, the TWiVniks consider the role of a cell enzyme that removes a protein linked to the 5′-end of the picornavirus genome, and the connection between malaria, Epstein-Barr virus, and endemic Burkitt’s lymphoma.

You can find TWiV #374 at microbe.tv/twiv.

Zika virus

FlavivirusThe rapid spread of Zika virus through the Americas, together with the association of infection with microcephaly and Guillain-Barré syndrome, have propelled this previously ignored virus into the limelight. What is this virus and where did it come from?

History
Zika virus was first identified in 1947 in a sentinel monkey that was being used to monitor for the presence of yellow fever virus in the Zika Forest of Uganda. At this time cell lines were not available for studying viruses, so serum from the febrile monkey was inoculated intracerebrally into mice. All the mice became sick, and the virus isolated from their brains was called Zika virus. The same virus was subsequently isolated from Aedes africanus mosquitoes in the Zika forest.

Serological studies done in the 1950s showed that humans carried antibodies against Zika virus, and the virus was isolated from humans in Nigeria in 1968. Subsequent serological studies revealed evidence of infection in other African countries, including Uganda, Tanzania, Egypt, Central African Republic, Sierra Leone, and Gabon, as well as Asia (India, Malaysia, Philippines, Thailand, Vietnam, Indonesia).

Zika virus moved outside of Africa and Asia in 2007 and 2013 with outbreaks in Yap Island and French Polynesia, respectively. The first cases in the Americas were detected in Brazil in May 2015. The virus circulating in Brazil is an Asian genotype, possibly imported during the World Cup of 2014. As of this writing Zika virus has spread to 23 countries in the Americas.

The virus
Zika virus is a member of the flavivirus family, which also includes yellow fever virus, dengue virus, Japanese encephalitis virus, and West Nile virus. The genome is a ~10.8 kilobase, positive strand RNA enclosed in a capsid and surrounded by a membrane (illustrated; image copyright ASM Press, 2015). The envelope (E) glycoprotein, embedded in the membrane, allows attachment of the virus particle to the host cell receptor to initiate infection. As for other flaviviruses, antibodies against the E glycoprotein are likely important for protection against infection.

Transmission
Zika virus is transmitted among humans by mosquito bites. The virus has been found in various mosquitoes of the Aedes genus, including Aedes africanus, Aedes apicoargenteus, Aedes leuteocephalus, Aedes aegypti, Aedes vitattus, and Aedes furcifer. Aedes albopictus was identified as the primary vector for Zika virus transmission in the Gabon outbreak of 2007. Whether there are non-human reservoirs for Zika virus has not been established.

Signs and Symptoms
Most individuals infected with Zika virus experience mild or no symptoms. About 25% of infected people develop symptoms 2-10 days after infection, including rash, fever, joint pain, red eyes, and headache. Recovery is usually complete and fatalities are rare.

Two conditions associated with Zika virus infection have made the outbreak potentially more serious. The first is development of Guillain-Barré syndrome, which is progressive muscle weakness due to damage of the peripheral nervous system. The association of Guillain-Barré was first noted in French Polynesia during a 2013 outbreak.

Congenital microcephaly has been associated with Zika virus infection in Brazil. While there are other causes of microcephaly, there has been a surge in the number of cases during the Zika virus outbreak in that country. Whether or not Zika virus infection is responsible for this birth defect is not known. One report has questioned the surge in microcephaly, suggesting that it is largely attributed to an ‘awareness’ effect.  Current epidemiological data are insufficient to prove a link of microcephaly with Zika virus infection. Needed are studies in which pregnant women are monitored to see if Zika virus infection leads to microcephaly.

Given the serious nature of Guillain-Barré and microcephaly, it is prudent for pregnant women to either avoid travel to areas that are endemic for Zika virus infection, or to take measures to reduce exposure to mosquitoes.

Control
There are currently no antiviral drugs or vaccines that can be used to treat or prevent infection with Zika virus. We do have a safe and effective vaccine against another flavivirus, yellow fever virus. Substituting the gene encoding the yellow fever E glycoprotein with that from Zika virus might be a good approach to quickly making a Zika vaccine. However testing of such a vaccine candidate might require several years.

Mosquito control is the only option for restricting Zika virus infection. Measures such as wearing clothes that cover much of the body, sleeping under a bed net, and making sure that breeding sites for mosquitoes (standing water in pots and used tires) are eliminated are examples. Reducing mosquito populations with insecticides may also help to reduce the risk of infection.

Closing thoughts
It is not surprising that Zika virus has spread extensively throughout the Americas. This area not only harbors mosquito species that can transmit the virus, but there is little population immunity to infection. Infections are likely to continue in these areas, hence it is important to determine whether or not Zika virus infection has serious consequences.

Recently Zika virus was identified in multiple states, including Texas, New York, and New Jersey, in international travelers returning to the US . Such isolations are likely to continue as long as infections occur elsewhere. Whether or not the virus becomes established in the US is a matter of conjecture. West Nile virus, which is spread by culecine mosquitoes, entered the US in 1999 and rapidly spread across the country. In contrast, Dengue virus, which is spread by Aedes mosquitoes, has not become endemic in the US.

We recently discussed Zika virus on episode #368 of the science show This Week in Virology. You can be sure that we will revisit this topic very soon.

Added 1/28/16 9:30 PM: The letter below to TWiV provides more detail on the situation in Brazil.

Esper writes:

Hi TWIVomics

I hope this email finds you all well and free of pathogenic viruses.

My name is Esper Kallas, an ID specialist and Professor at the Division of Clinical Immunology and Allergy, University of São Paulo, Brazil.

I have been addicted to TWIV since a friend from U. Wisconsin participated in the GBV-C episode (David O’Connor, episode #260). Since then, never missed one episode. After long silent listening, I decided to write for the first time, motivated by the ongoing events in my country, potentially related to the Zika virus.

In the last episode, Emma wrote about events taking place in the small town of Itapetim, State of Pernambuco, Northeastern Brazil, which I will describe a bit later in this email. Before, let me bring some background information on the current situation.

Most believed Zika was a largely benign virus, causing a self-limited disease, clearly described in episode #368. Its circulation was documented after an outbreak became noticed in the State of Bahia (NE Brazil) by a group led by Guilherme Ribeiro, a talented young Infectious Diseases Scientist from Fiocruz (PMID: 26584464, Emerg Infect Dis. 2015 Dec;21(12):2274-6, free access)

However, things started to get awkward around October 2015, when a single hospital in Recife (NE Brazil) and some other practicing Obstetricians and Pediatricians from the region started reporting a mounting number of microcephaly cases in newborns, later confirmed by the national registry of newborns. The numbers are astonishing. The graph below depicts the number of cases per year prior to the surge in 2015. Only this year, 2,975 cases were reported by December 26, the vast majority in the second semester of the year. Cases are concentrated in the Northeast (map), with 2,608 cases, including 40 stillbirths or short living newborns.

Microcephaly, Brazil

In response to the situation, the Brazilian Ministry of Health has declared a national public health emergency (http://portalsaude.saude.gov.br/index.php/cidadao/principal/agenciasaude/20629-ministerio-da-saude-investiga-aumento-de-casos-de-microcefalia-em-pernambuco).

The Brazilian Ministry of Health has been presenting updates every week (see link: http://portalsaude.saude.gov.br/index.php/o-ministerio/principal/leia-mais-o-ministerio/197-secretaria-svs/20799-microcefalia). It is important to observe some imperfections in these numbers: 1. There may be an over reporting after the news made to the big media, suggesting an association between microcephaly and Zika virus. 2. The criterion to consider a microcephaly case has been changed after the current epidemic from 33cm to 32cm; this is because 33cm of head circumference is sitting in the 10th percentile of newborns at 40 weeks of pregnancy and the adjustment would bring the limit to the 3rd percentile, increasing the specificity to detect a true microcephaly case (this may result in an over reporting in the beginning of the epidemic).

The association between Zika virus infection and microcephaly was suspected since the beginning, when Brazilian health authorities ruled out other potential causes, together with the fact that the microcephaly epidemic followed Zika virus spread. Further evidences were the two positive RT-PCR for Zika RNA in two amniotic fluids obtained from two pregnancies of microcephalic fetuses and a stillborn microcephaly case with positive tissues for Zika RNA. In fact, French Polynesia went back to their records and also noticed an increase of microcephaly case reporting, following their epidemic by the same virus strain in 2013 and 2014.

Now, Zika virus transmission has been detected in several countries in the Americas (http://www.paho.org/hq/index.php?option=com_topics&view=article&id=427&Itemid=41484&lang=en).

Although strong epidemiological data suggest the association between Zika virus and the microcephaly epidemic, a causal link between the virus and the disease is still lacking and is limited to few case reports. Many questions still remain. Does the virus damage embryonic neural tissue? What is the percentage of fetuses getting infected when the mother acquires Zika virus during pregnancy? Does the stage of pregnancy interfere with virus ability to be transmitted to the fetus and the development of neurologic effects? Are there other neurological defects related to Zika virus infection? Is there another cofactor involved, such as malnutrition or other concurrent infection? All these questions are exceedingly important to provide counseling to pregnant women and those who are planning to become pregnant, especially in Northeastern Brazil. In fact, Brazilian authorities have been recommending avoiding pregnancy until this situation is further clarified.

The microcephaly epidemic impact is unimaginable. It is a tragedy. These children are compromised for life and the impact on their families is beyond any prediction.

Back to the story sent by Emma. A small town in the North of Pernambuco State, named Itapetim, has almost 14 thousand inhabitants and has reported 11 cases of microcephaly in the past 3 months. This very same town has been suffering from a prolonged drought, since September 2013 when the last reservoir went dry. Perhaps the storage of clean water or the limited resources has led to the best environment for arbovirus spread and the development of microcephaly.

But the Zika virus’s impact may be reaching further. An increase in Guillain-Barré syndrome cases has also been noticed in the Northeast of Brazil, possibly related to the epidemic.

Several groups have been trying to establish animal models to study the interaction of Zika virus with neural tissue. The forthcoming developments are critical to better understand the virus immunopathology and confirm (or refute) the association between the virus infection and neurologic damage in fetuses and in the infected host developing Guillain-Barré syndrome. Many things still shrouded in mystery.

Keep on the good work. I will keep on listening!

Esper

Do you want to learn virology? Every spring I teach a virology course at Columbia University, and this year’s version has just started. I record every lecture and put the videos on YouTube. Here is a link to the playlist: Virology Lectures 2016. Lecture #1, What is a Virus, is embedded below as a teaser.

I strongly believe that the best approach to teaching introductory virology is by emphasizing shared principles. Studying the phases of the viral reproductive cycle, illustrated with a set of representative viruses, provides an overview of the steps required to maintain these infectious agents in nature. Such knowledge cannot be acquired by learning a collection of facts about individual viruses. Consequently, the major goal of my virology course is to define and illustrate the basic principles of animal virus biology.

You can find the complete course syllabus, pdf files of the slides, and reading at virology.ws/course.

My goal is to be Earth’s virology professor, and this is my virology course for the planet.

On episode #373 of the science show This Week in Virology, Vincent speaks with Julius about his long career in virology, including his crucial work as part of the team at the University of Pittsburgh that developed the Salk inactivated poliovirus vaccine.

You can find TWiV #373 at microbe.tv/twiv. Or you can watch the video below.



On 17 December 2015, Ron Davis, Bruce Levin, David Tuller and I requested trial data from the PACE study of treatments for ME/CFS published in The Lancet in 2011. Below is the response to our request from the Records & Compliance Manager of Queen Mary University of London. The bolded portion of our request, noted in the letter, is the following: “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.”


Dear Prof. Racaniello

Thank you for your email of 17th December 2015. I have bolded your request below, made under the Freedom of Information Act 2000.

You have requested raw data, linked at an individual level, from the PACE trial. I can confirm that QMUL holds this data but I am afraid that I cannot supply it. Over the last five years QMUL has received a number of similar requests for data relating to the PACE trial. One of the resultant refusals, relating to Decision Notice FS50565190, is due to be tested at the First-tier Tribunal (Information Rights) during 2016. We believe that the information requested is similarly exempt from release in to the public domain. At this time, we are not in a position to speculate when this ongoing legal action will be concluded.

Any release of information under FOIA is a release to the world at large without limits. The data consists of (sensitive) personal data which was disclosed in the context of a confidential relationship, under a clear obligation of confidence. This is not only in the form of explicit guarantees to participants but also since this is data provided in the context of medical treatment, under the traditional obligation of confidence imposed on medical practitioners. See generally, General Medical Council, ‘Confidentiality’ (2009) available at http://www.gmc-uk.org/guidance/ethical_guidance/confidentiality.asp The information has the necessary quality of confidence and release to the public would lead to an actionable breach.

As such, we believe it is exempt from disclosure under s.41 of FOIA. This is an absolute exemption.

The primary outcomes requested are also exempt under s.22A of FOIA in that these data form part of an ongoing programme of research.

This exemption is subject to the public interest test. While there is a public interest in public authorities being transparent generally and we acknowledge that there is ongoing debate around PACE and research in to CFS/ME, which might favour disclosure, this is outweighed at this time by the prejudice to the programme of research and the interests of participants. This is because participants may be less willing to participate in a planned feasibility follow up study, since we have promised to keep their data confidential and planned papers from PACE, whether from QMUL or other collaborators, may be affected.

On balance we believe that the public interest in withholding this information outweighs the public interest in disclosing it.

In accordance with s.17, please accept this as a refusal notice.

For your information, the PACE PIs and their associated organisations are currently reviewing a data sharing policy.

If you are dissatisfied with this response, you may ask QMUL to conduct a review of this decision.  To do this, please contact the College in writing (including by fax, letter or email), describe the original request, explain your grounds for dissatisfaction, and include an address for correspondence.  You have 40 working days from receipt of this communication to submit a review request.  When the review process has been completed, if you are still dissatisfied, you may ask the Information Commissioner to intervene. Please see www.ico.org.uk for details.

Yours sincerely

Paul Smallcombe
Records & Information Compliance Manager

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.

 

The PACE authors have long demonstrated great facility in evading questions they don’t want to answer. They did this in their response to correspondence about the original 2011 Lancet paper. They did it again in the correspondence about the 2013 recovery paper, and in their response to my Virology Blog series. Now they have done it in their answer to critics of their most recent paper on follow-up data, published last October in The Lancet Psychiatry.

(They published the paper just a week after my investigation ran. Wasn’t that a lucky coincidence?)

The Lancet Psychiatry follow-up had null findings: Two years or more after randomization,  there were no differences in reported levels of fatigue and physical function between those assigned to any of the groups. The results showed that cognitive behavior therapy and graded exercise therapy provided no long-term benefits because those in the other two groups reported improvement during the year or more after the trial was over. Yet the authors, once again, attempted to spin this mess as a success.

In their letters, James Coyne, Keith Laws, Frank Twist, and Charles Shepherd all provide sharp and effective critiques of the follow-up study. I’ll let others tackle the PACE team’s counter-claims about study design and statistical analysis. I want to focus once more on the issue of the PACE participant newsletter, which they again defend in their Lancet Psychiatry response.

Here’s what they write: “One of these newsletters included positive quotes from participants. Since these participants were from all four treatment arms (which were not named) these quotes were [not]…a source of bias.”

Let’s recap what I wrote about this newsletter in my investigation. The newsletter was published in December 2008, with at least a third of the study’s sample still undergoing assessment. The newsletter included six glowing testimonials from participants about their positive experiences with the trial, as well as a seventh statement from one participant’s primary care doctor. None of the seven statements recounted any negative outcomes, presumably conveying to remaining participants that the trial was producing a 100 % satisfaction rate. The authors argue that the absence of the specific names of the study arms means that these quotes could not be “a source of bias.”

This is a preposterous claim. The PACE authors apparently believe that it is not a problem to influence all of your participants in a positive direction, and that this does not constitute bias. They have repeated this argument multiple times. I find it hard to believe they take it seriously, but perhaps they actually do. In any case, no one else should. As I have written before, they have no idea how the testimonials might have affected anyone in any of the four groups—so they have no basis for claiming that this uncontrolled co-intervention did not alter their results.

Moreover, the authors now ignore the other significant effort in that newsletter to influence participant opinion: publication of an article noting that a federal clinical guidelines committee had selected cognitive behavior therapy and graded exercise therapy as effective treatments “based on the best available evidence.” Given that the trial itself was supposed to be assessing the efficacy of these treatments, informing participants that they have already been deemed to be effective would appear likely to impact participants’ responses. The PACE authors apparently disagree.

It is worth remembering what top experts have said about the publication of this newsletter and its impact on the trial results. “To let participants know that interventions have been selected by a government committee ‘based on the best available evidence’ strikes me as the height of clinical trial amateurism,” Bruce Levin, a biostatistician at Columbia University, told me.

My Berkeley colleague, epidemiologist Arthur Reingold, said he was flabbergasted to see that the researchers had distributed material promoting the interventions being investigated, whether they were named or not. This fact alone, he noted, made him wonder if other aspects of the trial would also raise methodological or ethical concerns.

“Given the subjective nature of the primary outcomes, broadcasting testimonials from those who had received interventions under study would seem to violate a basic tenet of research design, and potentially introduce substantial reporting and information bias,” he said. “I am hard-pressed to recall a precedent for such an approach in other therapeutic trials. Under the circumstances, an independent review of the trial conducted by experts not involved in the design or conduct of the study would seem to be very much in order.”

TWiVOn episode #372 of the science show This Week in Virology, the TWiV-osphere introduces influenza D virus, virus-like particles encoded in the wasp genome which protect its eggs from caterpillar immunity, and a cytomegalovirus protein which counters a host restriction protein that prevents establishment of latency.

You can find TWiV #372 at microbe.tv/twiv