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By David Tuller, DrPH

And now again with BMJ Open. I have written many, many posts about my efforts to get this supposedly reputable journal to acknowledge the issues with Professor Crawley’s school absence study. I won’t recap that unfortunate matter in this post, except to note that I am still waiting for the results from a Bristol University investigation of that and a number of other papers from Professor Crawley’s team.

In any event, last week I sent Professor Trudie Chalder a letter about a mistake in the PRINCE trial protocol, which BMJ Open published in July. Today I sent a follow-up letter to Adrian Aldcroft, the editor-in-chief of the journal.

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Dear Mr Aldcroft–

Last week, I sent a letter to Professor Trudie Chalder on which I cc’d you and several others. That letter concerned a major factual error in the first paragraph of the PRINCE trial protocol, which BMJ Open published in July. Specifically, the protocol falsely claimed that the estimated costs of treating so-called “medically unexplained symptoms” among the English working-age population accounted for around 10% of the total National Health Service budget. Instead, according to the cited study, Bermingham et al, these estimated costs accounted for around 10% of the amount the NHS spent on that specific age group.

I have not heard back as of yet from Professor Chalder. I am appealing to you directly, as editor-in-chief of BMJ Open, to ask how long it will take to correct this substantive error. Bermingham et al is not ambiguous. After I raised questions earlier this year with the British Journal of General Practice about the exact same untrue assertion in a 2017 editorial on MUS, the journal corrected it. This BJGP correction was posted before publication of the PRINCE protocol.

It is somewhat perplexing that none of the 13 protocol authors, nor any of those who reviewed it, noticed this prominent mistake. After all, Bermingham et al is a seminal study in the field, so one might expect those who present themselves as experts in MUS to be familiar with the core findings. Such an elemental misreading of key data should certainly raise concerns for you, as an editor, that perhaps the PRINCE investigators have made other protocol claims that are also not reliably based on the research being cited.

Mr Aldcroft, you are the editor-in-chief of BMJ Open. Ensuring that documented mistakes are corrected in a timely manner falls squarely within the scope of your responsibilities as a guardian of the integrity and accuracy of the medical literature. This factual error is not a matter for “letters to the editor” or for debate with the authors in published correspondence. To be blunt, you need to do your job and fix the problem, with or without the assent and participation of Professor Chalder and her colleagues. .

I have cc’d Professor Chalder and Sarah Bermingham, the lead author of Bermingham et al, as well as Dr Fiona Godlee, editorial director of BMJ. Given the implications of MUS research on the treatment available to patients diagnosed with CFS, CFS/ME, ME/CFS or ME, I am cc-ing as well other individuals cc-d on my letter to Professor Chalder–several involved with the NICE committee investigating new ME/CFS guidelines and three members of Parliament concerned about the poor quality of research into the illness. I am also cc-ing Professor Chris Ponting, vice-chair of the CFS/ME Research Collaborative.

I look forward to your quick response.

Best–David

David Tuller, DrPH
Senior Fellow in Public Health and Journalism
Center for Global Public Health
School of Public Health
University of California, Berkeley

By David Tuller, DrPH

In its efforts to save money, the National Health Service has been expanding the program known as Improving Access to Psychological Therapies (IAPT) by encouraging physicians to refer over all those with so-called “medically unexplained symptoms” (MUS). Under IAPT, the illness referred to as “chronic fatigue syndrome” falls into the MUS category. The program essentially provides CBT and related “rehabilitative” interventions.

Key PACE investigators have been among the leaders in the MUS field, and their trial served as scientific “evidence” to justify the IAPT expansion. Although citing PACE in any kind of authoritative way has become much more problematic in the last couple of years, that hasn’t stopped people like Professor Trudie Chalder from conducting additional problematic trials. The PRINCE trial proposes to investigate whether trained GPs can provide an effective rehabilitative approach to “persistent physical symptoms” (PPS), another term used to describe the phenomenon under examination.

In late July, BMJ Open published the protocol for this trial. And sure enough, smack in the first paragraph of the text, is a major factual error about the cost of MUS to the NHS. Since the beginning of this year, I have repeatedly documented how this same error has appeared in multiple papers over the last decade. I had hoped that raising awareness about it would prevent further repetitions. I was wrong.

It is important to remember that BMJ Open is the journal that obfuscated, dissembled and presented false information when confronted with the indisputable fact that it published Professor Esther Crawley’s school absence study without ethical review under the false premise that it was service evaluation. And Professor Chalder is the researcher who claimed at the PACE press conference that twice as many who received CBT and GET got “back to normal”–and has never explained or apologized for that egregious misstatement. So expecting forthright admission of error and prompt corrective action from either BMJ Open or Professor Chalder would, I think, be unwise.

In any event, I sent the following letter to Professor Chalder late last week. I cc’d several other people.

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Dear Professor Chalder—

You are the senior and corresponding author of “Persistent physical symptoms reduction intervention: a system change and evaluation (PRINCE)—integrated GP care for persistent physical symptoms: protocol for a feasibility and cluster randomised waiting list, controlled trial.” This protocol was recently published by BMJ Open. I am writing to point out a factual error in the first paragraph of the text.

The sentence in questions reads: “The National Health Service (NHS) in England is estimated to spend approximately £3 billion each year attempting to diagnose and treat MUS, which represented ~10% of the total NHS expenditure in 2008–2009.” This statement is incorrect. The study cited, Bermingham et al, is clear: the amount estimated to have been spent on MUS among the working-age population in England was 10% of the total amount spent on that population, not of “total NHS expenditure.” This false assertion dramatically overstates the supposed impact of MUS on the NHS budget.

I have additional issues with this protocol, but I will leave those for another time. My immediate interest is that you and your co-authors correct this misinformation in short order. As I have noted in multiple posts on Virology Blog, leaders in this domain of scientific inquiry have repeatedly managed to mangle this data point in their efforts to promote public health policy, including the expansion of the Improving Access to Psychological Therapies program. In fact, the British Journal of General Practice recently corrected an editorial that included the exact same mistake after I repeatedly requested the editor to take action.

Perhaps you can explain why you and so many of your colleagues–including the 12 co-authors of the PRINCE protocol–appear unable to accurately cite a seminal study in your claimed field of expertise. I assume you would agree that research protocols and public health policy should be based on accurate information. I look forward to seeing the corrected PRINCE protocol.

I am cc-ing BMJ Open editor Adrian Aldcroft on this letter. I am also cc-ing Sarah Bermingham, the lead author of the misquoted study. Because you and others lump ME/CFS into the categories known as MUS and PPS, I am also cc-ing members of the NICE committee currently developing new guidelines for that illness. Finally, I am cc-ing three members of Parliament who have expressed serious concerns about the poor quality of much UK research into ME/CFS, including the PACE trial. I will also post this appeal on Virology Blog.

Thank you for your attention to this matter. Please let me know when the paper has been updated. I trust the correction will be prominently noted, as is standard.

Best–David

David Tuller, DrPH
Senior Fellow in Public Health and Journalism
Center for Global Public Health
University of California, Berkeley
Berkeley, California, USA

By David Tuller, DrPH

I have posted a batch of letters about the Lightning Process study that have been sent to Dr Fiona Godlee, editorial director of BMJ, here, here and here. I have been impressed with how direct these scientists and clinicians have been in expressing their dismay at BMJ’s failure to adhere to its own editorial standards. I get the feeling some of the writers have been inspired by the earlier messages to Dr Godlee.

Anyway, here are three more: from Steven Lubet, a law professor at Northwestern University in Chicago; Robert Garry, a microbiology professor at Tulane University in New Orleans; and Philip Stark, a statistics professor at UC Berkeley. Thanks to all of them for their support. That makes 14 letters so far.

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Dear Dr Godlee: I am a legal ethicist, rather than a physician or scientist, so I will not weigh in on the various methodological and other problems that have been identified regarding “Clinical and cost-effectiveness of the Lightning Process.” I do want to comment, however, on one aspect of the “Correction” recently published in Archives of Disease in Childhood, which accepted “an assurance from the authors that the change in primary outcome was not influenced by (positive) findings in the feasibility phase.” Having spent many decades studying and evaluating conflicts of interest in both academic and professional settings, I find it extremely troubling that a respected scholarly journal would discount acknowledged research irregularities based upon such an obviously self-interested conclusion by the investigators themselves.

To put it bluntly, conflict of interest principles exist because it is impossible to rely upon affected individuals to provide objective assessments of their own decisions. In this instance, the “Lightning Process” authors have a quite evident stake in avoiding retraction of their article, which they only now admit “was not fully ICMJE compliant.” Thus, no matter how sincere they may be in defending their work, they should never have been the ones to determine whether the change in primary outcome had been influenced by their earlier positive findings.

In legal and judicial ethics, the applicable standard for disqualification is whether an individual’s “impartiality might reasonably be questioned.” Let me kindly suggest that the standards of BMJ Archives of Disease in Childhood ought to be no less rigorous.

In this instance, the authors of the “Lightning Process” article cannot possibly appear impartial regarding the validity of their own study, much less the question of whether their outcome swapping had been influenced, consciously or otherwise, by the pre-registration findings. Applying the most basic conflict of interest principles, the decision to issue a correction, rather than a retraction, should not have been based, even in part, on the authors’ after-the-fact assurances.

Sincerely,

Steven Lubet
Williams Memorial Professor
Northwestern University Pritzker School of Law
Chicago IL 60611

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Dear Dr. Godlee,

I am writing to urge you to reconsider the decision to republish the pediatric study of the Lightning Process conducted by investigators from the University of Bristol and published in Archives of Disease in Childhood.

My own perspective is as a virologist, with a long-standing interest in chronic illnesses such as chronic fatigue syndrome. Although I am not a physician, I have met many individuals with these conditions, and have at least one family member that is afflicted. Chronic fatigue syndrome is not a state of mental confusion that can be corrected by the pseudo-scientific incantations of the Lightning Process.

I am sure that you are aware that the International Committee of Medical Journal Editors has stated clearly* that, “The integrity of research may also be compromised by inappropriate methodology that could lead to retraction.”

If there was ever an instance when there was “inappropriate methodology,” this is it.

My recommendation is immediately publish an “Expression of Concern” regarding this multiply flawed study in accordance with COPE guidelines.

I then urge you to consult with other experts outside of the Bristol sphere of influence and follow their guidance.

I am confident that an independent group of experts will come the very same conclusion as the distinguished group copied here – this manuscript must be retracted.

Very sincerely,

Robert F. Garry, PhD

Robert F. Garry, PhD
Professor, Department of Microbiology and Immunology
Assistant Dean, Graduate Program in Biomedical Sciences
Program Manager, Viral Hemorrhagic Fever Consortium
Director, Tulane Center of Excellence, Global Viral Network
Chief Scientific Advisor and Co-Founder, Zalgen Labs, LLC
Tulane University School of Medicine
New Orleans, LA 70118

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[From Philip Stark, Professor of statistics at UC Berkeley]

Dear Dr. Godlee–

I hope you reconsider your decision.

Leaving this paper in place is a disservice to science and to public health–although it does provide a lovely [(negative) example for teaching ethics in science and illustrates how skirting proper statistical practice may lead to erroneous conclusions.

Regards,
Philip

TWiV 565: Karolinska Virology

From the Karolinska Institute in Stockholm, Vincent speaks with Niklas Björkström, Ali Mirazimi, and Matti Sällberg about their work on the impact of chronic hepatitis C virus infection on NK cells, Crimean-Congo hemorrhagic fever virus vaccines, and immunotherapy to block entry of hepatitis B and D viruses.

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After infection with poliovirus, only about 1% of individuals develop paralysis. I have always wondered whether genetic polymorphisms underlie the rarity of this disease outcome. The results of study carried out in Denmark provide the first insights.

The study group consisted of 17 individuals who developed poliomyelitis in the pre-vaccine years, 1940-1950, and one who was paralyzed in the early 1970s. Bioinformatic analyses of whole-exome sequencing results identified 39 heterozygous missense mutations in 36 genes. None were shared between any of the patients. These polymorphisms were specific to poliomyelitis because they were not observed in a cohort of 18 patients with herpes simplex encephalitis.

Most of the mutations are in genes with either similar biological functions, or that are part of common signaling pathways. For example, variants in some genes are involved in autophagy or apoptosis. Both are antiviral processes and a reduction in them could lead to higher levels of poliovirus reproduction. Increased viremia could make it more likely that virus invades the brain and spinal cord.

Additional variants were identified in the genes encoding the innate immune system RNA sensors Mda5 and TLR3, and in the gene encoding the type I IFN receptor. Defects in the IFN pathway could also lead to higher viral replication and invasion of the CNS as suggested above.

To determine whether any of these mutations have an effect on poliovirus reproduction, infections were carried out with cultures of peripheral blood mononuclear cells and monocyte derived macrophages from the patients. Virus yields were generally higher in cells from poliomyelitis patients. However this difference could not be ascribed to mutations in any specific genes. Furthermore, there appeared to be no defect in IFN responses after viral infection.

It is formally possible that small numbers of polioviruses enter the brain and spinal cord during most infections, but do not proceed to paralysis. In individuals with specific mutations identified in this study, reproduction in neurons might be facilitated. The authors did not address this possibility by examining the effect of these genetic changes on replication in neural cells.

This study is the first to reveal potential genetic susceptibility loci in patients with paralytic poliomyelitis. The identified mutations should be introduced in cell types known to be relevant to infection, such as intestinal epithelial cells and neurons, to determine their effect on viral yields. The effect of such mutations in a mouse model for poliomyelitis should also be determined. Furthermore, susceptibility loci should be identified in patients who developed vaccine-associated polio (VAPP). The latter are even more rare (1 in 1.5 million recipients of oral poliovirus vaccine). Such an analysis could reinforce the observations made in the study discussed above, or identify variants in different genes that predispose vaccine recipients to VAPP.

By David Tuller, DrPH

The trickle of letters from top experts to Dr Fiona Godlee about BMJ’s decision to republish Professor Esther Crawley’s Lightning Process study continues. The letters excoriate BMJ’s actions in this matter and urge Dr Godlee to retract the dung-heap otherwise known as “Clinical and cost-effectiveness of the Lightning Process in addition to specialist medical care for paediatric chronic fatigue syndrome: randomised controlled trial.”

I have previously posted six letters, here and here. Below are five more. They were e-mailed directly to Dr Godlee and cc’d to many of the 55 scientists, clinicians and other experts who signed Virology Blog’s recent open letter about the matter. The writers are: Dr Steve Olsen of Kaiser Permanente’s Northern California region; Professor Alison Bested of Nova Southeastern University in Florida; Professor Rebecca Goldin of George Mason University in Virginia; Professor Ronald Tompkins of Harvard Medical School; and Professor Brian Hughes of National University of Ireland, Galway.

[continue reading…]

By David Tuller, DrPH

Last week I posted three comments sent to Dr Fiona Godlee, editorial director of BMJ, in support of retraction of the biased and discredited Lightning Process. All three–Professor Ola Saugstad of University of Oslo, Professor Vincent Racaniello of Columbia University, and Professor Elisa Oltra of University Catolica de Valencia San Vicente Martir–were among the 55 experts who signed Virology Blog’s recent open letter to Dr Godlee. That letter expressed concern and dismay that Archives in Disease in Childhood, the BMJ journal that published the study two years ago, had acknowledged the methodological violations documented on Virology Blog but nonetheless republished the original, seriously compromised findings. When I sent the letter to Dr Godlee, I cc’d many of the signers.

[continue reading…]

From the 16th Smögen Summer Symposium on Virology, Vincent speaks with Erling Norrby about how he has used archival material to provide insight into early Nobel Prizes for research on viruses.

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Ebolavirusby Gertrud U. Rey

The Democratic Republic of the Congo (DRC) is currently experiencing its worst outbreak of Ebola virus disease in history. More than 3,000 people have been infected with the virus, and nearly 1,900 have died since the outbreak began in 2018.

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By David Tuller, DrPH

As Virology Blog has reported, the lead author of the revised version of Cochrane’s Risk of Bias tool, published last week in BMJ, is a long-time Bristol University colleague of Professor Esther Crawley. In that capacity, he is a co-author of two high-profile studies that violated key principles of scientific investigation—the Lightning Process study, published by Archives of Disease in Childhood two years ago, and the 2011 school absence study published in BMJ Open.

[continue reading…]