"Anti-vaccination arguments are varied" (and not all about autism)

I tread very carefully with my slightly long discussions of the paper by Beth Hoffman and colleagues [1] (open-access available here). The Hoffman paper talks about the role of social media in an important issue: "anti-vaccination rhetoric". Specifically how an analysis of anti-vaccination sentiment on one particular social media platform suggests that "It's not all about autism" when it comes to such views being very publicly espoused. Some people might already know why autism was mentioned by Hoffman, but for others here is some discussion of the previous (peer-reviewed) science on that topic (see here and see here).

I know that there are some significant emotions surrounding this topic. I know it's a subject area that crosses lots of different issues ranging from individual and public health to personal choice and lots more in-between. It's also a topic which in some cases is literally the difference between life and death. And for those reasons it's why papers such as the one from Hoffman et al are so important: to understand why, in the age of social media where the world is literally your audience, such sentiments might occur and how any misgivings about vaccination could be suitably addressed. How much also, the anti-vaccination messages that are being promulgated on social media, actually do impact on people's actual vaccination behaviour is another point of more general study, and specifically why this might happen more for some but not for others [2] (a 'vaccine for anti-vaccination sentiment' perhaps?).

Hoffman continued a growing theme in various research circles where social media footprints represent data (see here and see here). They specifically zoomed in on "197 individuals on Facebook who posted anti-vaccination comments on a local paediatric clinic’s Facebook page" in response to a video about "the human papillomavirus (HPV) vaccine as an anti-cancer vaccine." And before you ask, yes, the HPV vaccine does indeed seem to be an anti-cancer vaccine [3]. The sorts of comments received were sometimes pretty extreme as per "being either (1) threatening (e.g. “you’ll burn in hell for killing babies”) and/or (2) extremist (e.g. “you have been brainwashed”)." That being said, I don't want to tarnish all commentators on the basis of the posting of such extreme comments by some.

Researchers went through the posts - "all publicly available information" - of their nearly 200 selected Facebook accounts, covering material published over a 2 year period. Various codes (N=26) were used to classify the posted content, alongside "8 variables related to sociodemographic information: age, gender, location, political affiliation, marital status (yes/no), parental status (yes/no), whether employment was listed (yes/no), and whether post-secondary education was listed (yes/no)." Results were collated.

"Posts on these individuals’ Facebook profile pages suggest that many are highly mistrustful of the medical and scientific community." That was one of the primary findings. Other observations included: "Of the 116 individuals with at least one public anti-vaccination post from 2015 to 2017, posts about “educational material” (73%), “media, censorship, and ‘cover up’” (71%), and “vaccines cause idiopathic illness” (69%) were the most common topics." 'Educational material' implying "content that claims to provide scientific evidence for the negative impact of vaccines" is perhaps slightly counter-intuitive to the 'mistrust' that Hoffman initially concluded. Indeed, it implies that this isn't necessarily about a general 'mistrust' of science per se that they noticed, but rather more of a selective mistrust of some of the science and/or 'guardians' of that science. This perhaps coincides with their focus on some key weakness of science including that: (a) science is more about probability than it is about absolutes, and (b) science is not produced uniformly; such that peer-reviewed science can still be published as peer-reviewed science irrespective of how well or badly it was designed and conducted. So for example, you can provide someone with a 100 or a 1000 well-designed studies showing 'no connection' between variable X and variable Y in a statistical sense, but it only takes one study *linking* variable X and variable Y appearing in the science literature for someone to be able to say that there is some science behind a possible link between variable X and variable Y (or at least that a link can't be definitively ruled out). That's the way science works for better or worse.

Insofar as the sentiments of 'media, censorship and cover-up' this is another key issue with some overlap with the other details observed. The cries of 'cover-up' and 'censorship' "suggesting that the government, pharmaceutical companies, and/or physicians consciously and wilfully fail to disclose adverse vaccine reactions" play into lots of different themes allied to the previous discussion about science and beyond. Whilst not wishing to stray too far from the Hoffman findings, I'll bring in some quite recent discussions about the whole Cochrane-Gøtzsche saga (see here) as one relevant example. I don't want to rehash that post in its entirety but the Jørgensen paper [4] including Peter Gøtzsche as an author which concluded that "The Cochrane human papillomavirus (HPV) vaccine review missed nearly half of the eligible trials" provides an example of how science again isn't necessarily always as uniform as it appears. On that basis, and with other medical commentators also concerned about clinical trial data not seemingly appearing in a timely fashion for example (see here) alongside some recent quite high-profile judgements (see here), the gaps left provide fertile ground for social media speculation and onward the stoking of potential anti-vaccination comments.

Hoffman et al also talk about various strategies that might be employed to "increase the level of community protection against the propagation of anti-vaccination messaging on social media." Personally I'm not sure whether things like increasing media literacy, the use of entertainment narratives and/or "for medical professionals to be more active on social media" and more [5] are really going to make any significant inroads into changing (often entrenched) hearts and minds. I'm even more doubtful that blanket 'censorship' is an entirely appropriate course of action, despite that being on the cards (see here) precisely because it may play directly into the hands of those cries of censorship.

There is however one thing that I think could be worth looking further into: dialogue. Minus any sweeping generalisations about equating anti-vaccination sentiments with anything else, most people here in Blighty will know about the history of Northern Ireland. Years and years of arguments, fighting, murders and more weren't solved by censorship (I remember the days when the voice of Gerry Adams was banned) but rather by talking and having constructive discussions. It was an unpalatable process for some people, particularly those who were personally touched by the violence in Northern Ireland, but dialogue happened and lives were probably saved as a result. I know some people would find the idea of talking to prominent people with anti-vaccination views likewise to be a difficult prospect. But the truth of the matter is that we're never going to get to the core of why people believe what they believe and say what they say without asking them about what motivates their view(s). It's kinda been done a little bit before in the peer-reviewed science arena and beyond but lots more data is required. And it appears that such 'dialogue' has been suggested by others too...

I'm also minded to mention that part of that dialogue needs to include discussions about 'experience'; something that could also be an important variable when it comes to vaccine hesitancy and its propagation among specific groups (see here and see here). Indeed, a realisation that those who express anti-vaccination views or opinions probably include many different people who arrived at their position for lots of different reasons is an important point. Probably not all of them having some inherent disposition to being anti-vaccination or indeed necessarily "in favour of magical or superstitious thinking" [6] as others have previously opined. Opening dialogue is a difficult prospect but if it saves one life from a vaccine-preventable disease, it's got to be worth a try.

Vaccination is a cornerstone of public health, a life-saving cornerstone of public health, something that should never, ever be forgotten. Indeed it's probably because people forget what measles for example and other childhood disease did to some children and adults that some complacency about vaccination has set in. If you need to see some of the effects of vaccine-preventable diseases in action, read about what measles did to the author Roald Dahl's daughter (see here). Anti-vaccination sentiment is a significant issue that has been with us since vaccination began. It needs to be approached head on to counter mis-information and calm and allay any fears. The way to tackle this issue is however going to be as complicated as the issue itself is. Yes, it needs to realise that social media is often an 'echo chamber' [7] giving people an opportunity to literally speak their mind and adapt accordingly. But another part of that strategy - an important part of that strategy - needs to be an understanding of why people think the way they do. In that respect, dialogue, however unappealing that might be to some people, is eventually going to be key...

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[1] Hoffman BL. et al. It's not all about autism: The emerging landscape of anti-vaccination sentiment on Facebook. Vaccine. 2019 Mar 14. pii: S0264-410X(19)30303-2.

[2] Zhang EJ. et al. Influence of political and medical leaders on parental perception of vaccination: a cross-sectional survey in Australia. BMJ Open. 2019 Mar 26;9(3):e025866.

[3] Palmer T. et al. Prevalence of cervical disease at age 20 after immunisation with bivalent HPV vaccine at age 12-13 in Scotland: retrospective population study. BMJ 2019; 365.

[4] Jørgensen L. et al. The Cochrane HPV vaccine review was incomplete and ignored important evidence of bias. BMJ Evid Based Med. 2018 Oct;23(5):165-168.

[5] Gesualdo F. et al. To talk better about vaccines, we should talk less about vaccines. Vaccine. 2018; 36: 5107-5108.

[6] Bryden GM. et al. Anti-vaccination and pro-CAM attitudes both reflect magical beliefs about health. Vaccine. 2018 Feb 21;36(9):1227-1234.

[7] Schmidt AL. et al. Polarization of the vaccination debate on Facebook. Vaccine. 2018 Jun 14;36(25):3606-3612.

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PACE trial for chronic fatigue syndrome (still) being put through its paces: a reply

I'm bringing the paper published by Michael Sharpe and colleagues [1] to your attention today in the interest of balance and peer-reviewed 'right to reply'.

The Sharpe paper concerns the PACE trial, the study which reported that "when added to specialist medical care, cognitive behaviour therapy and graded exercise therapy were more effective in improving both fatigue and physical function in participants with CFS [chronic fatigue syndrome], than both adaptive pacing therapy and specialised medical care alone."

Anyone with a little bit of knowledge about the PACE trial will know that it's a 'contentious' topic within CFS (and ME, myalgic encephalomyelitis) circles. Indeed, the Sharpe paper comes about as a direct result of a reanalysis paper (see here) which reported findings raising "serious concerns about the robustness of the claims made about the efficacy of CBT [cognitive behavioural therapy] and GET [graded exercise therapy]" in the context of CFS/ME. 'Serious concerns' is putting it mildly considering how others have described the PACE trial and some of its tenets (see here).

Sharpe et al, who were authors listed on the original PACE trial paper [2], have had to defend their work/findings before in the peer-reviewed realm (see here). Same as before, the name Carolyn Wilshire is addressed and her teams reanalysis of the PACE trial data [3]. Said data was, I might add, (partially) released only following intervention from the Information Commissioners Office (ICO) here in Blighty (see here). More recent events have similarly reiterated that 'access to raw study data' is something that CFS/ME researchers perhaps need to bear in mind at study conception (see here).

I'm not going to clinically dissect the Sharpe paper in this post because (a) 'interpretation' forms quite a bit of the reply to the Wilshire reanalysis, and (b) your opinion on the scientific quality of the Sharpe reply is most likely going to be shaped by where you stand in terms of the whole CBT/GET for CFS/ME discussion. Indeed, a peer-reviewer of the Sharpe paper also said as much (see here). What I will comment on is how the Wilshire reanalysis paper and the more recent Sharpe reply to the reanalysis paper might further inform research more generally with CFS/ME in mind.

Oh, and it's probably just a coincidence that the Sharpe paper comes out only days after a news headline reads "Online activists are silencing us, scientists say" talking about a familiar topic.

So:

• Point 1: Design a good trial analysis plan and stick to it. From my 'outsider looking in' perspective, the changes made to "the scoring of the pre-specified outcomes" regarding fatigue and physical functioning in the PACE trial, however innocent they might have been, have created tension. Lots of tension. Such changes, whether agreed by "Trial Data Monitoring and Steering Committees" or not, can be construed in various different ways. It's better not to make such changes in the first place.
• Point 2: If you are going to study something like physical functioning in relation to CFS/ME, don't just rely on things like questionnaires and Likert scales; use actigraphy too. Self-report is always a good thing but I've never understood why, with the wide range of cost-effective technology out there (available I believe, even in the early 2000s), wearable trackers such as pedometers or similar were not also utilised during such studies (see here). If you're spending £5 million on a trial, a few quid for some pedometers is not exactly going to break the bank and will inevitably bring some further quality data to the table.
• Point 3: Recovery. As per other discussions (see here), most people would characterise recovery as a complete remission of symptoms and/or return to typical functioning. If you're not going to use this description, don't use the word recovery. Use something else instead. Indeed, use 'partial remission' or 'improvement' if you need to but don't call anything less than the complete remission of symptoms 'recovery'.
• Point 4: Long-term outcomes. It's probably best to avoid any sweeping statements after the arms of a trial - a "randomised trial" not necessarily a "randomised controlled trial" according to Wilshire et al - have been completed. More so when you're measuring such long-term outcomes via a postal question minus any objective measure(s) (see point 2). It's probably also a good idea to ask patients about their quality of life too and whether that has changed (see here).
• Point 5: Even if your paper states in no uncertain terms that: "The effectiveness of behavioural treatments does not imply that the condition is psychological in nature" the use of something like CBT for CFS/ME implies that you probably think there is a substantial psychological 'component' to the condition. This is compounded when you're for example, a Professor of Psychological Medicine. If you were pitting CBT in particular against a specific pharmacological or biological intervention 'for CFS/ME' (see here for example), I'd be more inclined to see your view in a more 'rounded sense'. Indeed, if you were to study one or two biological parameters as well as behavioural ones looking for any change following intervention, you might convince more people that psychology is not the primary line you take. And whilst on the topic of psychology and CFS/ME, it's probably also best not to use 'psychobabble' terms like 'deconditioning' in your research. Such terms are pretty much scientifically untestable and, given the recent discussions about the legacy of some adherents to something like psychosomatic research (see here), is likely to be consigned to the scientific dustbin as some later point.

I think I've covered the main points as I see them. Please feel free to agree/disagree as you wish.

End of Line.

Addition: 26 March 2019. Not quite 'End of Line' it seems, as a reply to a reply to a reply emerges [4]. Peer reviewed science is far from slow...

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[1] Sharpe M. et al. The PACE trial of treatments for chronic fatigue syndrome: a response to WILSHIRE et al. BMC Psychology. 2019; 7: 15.

[2] White PD. et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011; 377(9768):823-36.

[3] Wilshire CE. et al. Rethinking the treatment of chronic fatigue syndrome—a reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT. BMC Psychology. 2018; 6: 6.

[4] Wilshire CE. & Kindlon T. Response: Sharpe, Goldsmith and Chalder fail to restore confidence in the PACE trial findings. BMC Psychology. 2019; 7: 19.

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On transparency in science: lessons from the Pandemrix vaccine and 'partial' evidence-based practice

Minus any hype or sweeping generalisation, I want to draw your attention to a feature article recently published by Peter Doshi [1] titled: "Pandemrix vaccine: why was the public not told of early warning signs?" complete with some media interest (see here).

The feature is based around the vaccines developed to counter the 2009 flu pandemic that starred the H1N1 influenza virus which was sweeping across the globe at the time. The 2009 flu pandemic was potentially serious insofar as its infection pattern and fatalities linked to infection although in reality did not turn out to be quite the 'global killer' that was prophesied. The rush to bring to market a vaccine to protect lives and counter the rise of H1N1 also brought with it controversy from several perspectives [2]; some later talking points seemingly stemming from the inclusion of a specific adjuvant - AS03 - in some vaccine preparations, and data suggestive of a possible correlation between onset of narcolepsy and use of certain flu vaccines containing the AS03 adjuvant (see here). Narcolepsy - a sleep disorder - was one potential adverse side-effect talked about, but other labels/conditions were also the source of some inquiry too (see here). On the basis of the emerging published data, court cases ensued, some of which have apparently unearthed some "internal reports" suggesting that some manufacturers "were aware of other serious adverse events logged" in relation to certain H1N1 vaccines...

The Doshi feature goes through some of these 'revelations' that did not seem to have been made public at the time. He talks about an 'undisclosed problem' whereby one vaccine in particular, Pandemrix, seemed to have a greater frequency of various adverse events reported according to those internal company reports. Most worrying are the reports of 'fatal outcome' across different vaccine preparations, particularly Pandemrix. He also writes: "And the raw numbers of adverse events were not small" highlighting how in one of the latest internal reports dated March 2010 seen by himself (or at least, the British Medical Journal) over 5000 reports of "serious adverse events for Pandemrix" had been received by the company behind the vaccine.

It's timely that the Doshi feature appears now at the time of writing this post, just days after the Peter Gøtzsche - Cochrane drama (see here) and at the same time as other relevant pieces have been published (see here and see here [3]). The similarities around questions of transparency in science (particularly industry-derived science that has a public health aspect attached to it) are very noticeable. As is also the question of 'how much detail should the public be provided with?' when it comes to science in general and then specifically, science and science communication linked to the potential cost-benefit ratio of particular medicines or medical preparations. It's interesting too that Doshi also references some past debate in Germany [4] about the 2009 flu pandemic where it was apparently reported that "the German interior ministry rejected accusations that the ministry had ordered a less risky vaccine for top officials" in light of some newspaper headlines published at the time. 'All animals are equal, but some animals are more equal than others' perhaps springs to mind...

I don't think the issue of less than full transparency in science and the question 'how much detail should the public be provided with' are going to go away any time soon. Such issues strike to the heart of the matter of how peer-reviewed published science is seemingly only one part of a much bigger picture when it comes to the search for a complete truth. One wonders for example, how many other 'internal reports' lie in [research] file cabinets around the world that could conceivably influence evidence-based decisions on the effectiveness and safety of various medicines and other interventions indicated for various conditions? Without such documents ever seeing the cold light of day, how can science ever truly be said to be complete, transparent or indeed settled?

Such a 'transparency' situation also makes initiatives like OpenTrials - calling for all research to be more 'discover-able' and 'traceable' - all the more vital and important. Issues such as the requirement for pre-registration of all studies via databases such as ClinicalTrials.gov and importantly, the timely release and publication of results (see here) are pressing features. Study pre-registration (especially prospective registration) in particular, should perhaps be pushed a lot more than it currently is, and shouldn't just be reserved for big studies of drugs and medicines either.

Science is great and is getting better all the time. But it still has lots of issues and problems to overcome. A lack of research transparency seems to be a particularly important issue that, whilst starting to receive some much required attention, will if present, always mean that evidence-based practice really should be re-branded as 'partial evidence-based practice'. And that has lots of implications...

To close, given the subject matter included in the Doshi paper, I want to end with a reminder about not making sweeping generalisations. At the same time I'd also champion the words included in another recent article by Jørgensen and colleagues [5] (yes, also including Peter Gøtzsche as an author) responding to the idea that public confidence in public health initiatives such as vaccination may be "undermined" by even having such discussions in public. To quote: "Debates over sources of evidence must take place in public, especially when public health interventions are at stake." This is again, with the idea that science needs transparency - even better in the peer-reviewed domain - and closed door discussions rarely aid such transparency.

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[1] Doshi P. Pandemrix vaccine: why was the public not told of early warning signs? BMJ 2018;362:k3948

[2] Doshi P. Influenza: marketing vaccine by marketing disease. BMJ 2013;346:f3037.

[3] Jørgensen L. et al. Challenges of independent assessment of potential harms of HPV vaccines. BMJ 2018;362:k3694

[4] Stafford N. Only 12% of Germans say they will have H1N1 vaccine after row blows up over safety of adjuvants. BMJ 2009;339:b4335.

[5] Jørgensen L. et al. Response to Cochrane editors: Jørgensen, Gøtzsche and Jefferson. BMJ EBM Spotlight. 2018. Sept 23.

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On Cochrane and 'facts' and 'politics' in evidence-based medicine

The controversy surrounding the reported expulsion of Peter Gøtzsche from the Cochrane Collaboration (or should that just be Cochrane?) is something that I've been following for a few days now (see here). Cochrane, under the heading "Trusted evidence. Informed decisions. Better health", represents one of the premier go-to sources for evidence-based healthcare advice on a range of topics. Some of those topics have been previous fodder for this blog too (see here and see here for examples).

I don't profess to have any unique insight into the various goings-on leading to the reported expulsion of Gøtzsche and resignations of fellow members beyond that which has been discussed in various sections of the science media (see here and see here and see here). From what I gather, things look like they've been 'brewing' for a while with regards to Cochrane and the views and opinions expressed by some of those who are seemingly departing. Such a public spat however, is unlikely to be good for science or evidence-based medicine, and indeed may have some wider implications for some fundamentals of science and science communication...

One of the possible [late] precipitating events mentioned around the Gøtzsche saga was the publication of a quite scathing article by Lars Jørgensen and colleagues [1] (including Gøtzsche as an author) questioning the published results of a recent Cochrane review [2] titled: "Prophylactic vaccination against human papillomaviruses [HPV] to prevent cervical cancer and its precursors". The original review by Marc Arbyn et al garnered media headlines when published (see here) as per conclusions such as: "There is high‐certainty evidence that HPV vaccines protect against cervical precancer in adolescent girls and young women aged 15 to 26." A comforting finding by all accounts. Accompanying such efficacy data were other statements made by the authors on the basis of the evidence reviewed that: "The vaccines do not increase the risk of serious adverse events, miscarriage or pregnancy termination."

Jørgensen and colleagues however put forward their [peer-reviewed] view that the Arbyn paper fell short of the expected standards from Cochrane: "We do not find the Cochrane HPV vaccine review to be ‘Trusted evidence’, as it was influenced by reporting bias [3] and biased trial designs." They highlighted several 'issues' with the original review stretching from trial selection for the review, to the assessment of "serious and systemic adverse events" to potential "conflicts of interest." Similar sentiments had been voiced about other Cochrane reviews too that were subsequently pulled from the scientific literature. Feathers were inevitably ruffled (see here) by the Jørgensen paper, even as far as prompting a response from the journal that published the paper [4] about the peer-review process leading to publication of the critique. Things are getting serious when a journal has to defend its publication of a paper.

Without wishing to reduce this saga to any one event, I don't think it would be unreasonable to assume that the Jørgensen paper might have influenced matters quite considerably; perhaps even bringing them to a head. As per involvement on the Boesen paper [5] Gøtzsche is no stranger to calling out Cochrane reviews that seemingly don't make the grade, alongside also voicing opinions on various other matters down the years. To quote: "... in another book, [he] likened the pharmaceutical industry to "organized crime""; such forthright statements stretching back some years are unlikely to have made too many friends in certain circles.

As per the title of this post mentioning the words 'facts' and 'politics', one particular write-up of this saga I think hits the nail on the head. The opinion piece from Trish Greenhalgh [6] presents the two sides to this 'dispute': on the one hand is that the “crisis” is "philosophical (relating to the nature of facts)" and on the other, "political (relating to organisational governance)." The philosophical side of things is pretty evident as per the publication of the Jørgensen paper as a counter to the Arbyn paper. Greenhalgh mentions about how "Gøtzsche might be classified as an evidence-based medicine purist" given his views and sizeable contribution to various "statements on how to undertake and publish research." In this respect, his published views on the original Arbyn paper (and similarly in other reviews) seem to detail scientific standards not being met, or at least not being met to his and his co-authors standards. And certainly on points such as access to trial results and data, he's seemingly not alone in his concern (see here).

On the political side of things, well, at the time of writing we just don't know enough to reasonably comment. Greenhalgh mentions that: "The political explanation for Cochrane’s crisis relates to the tension between governing an organisation and respecting individual members’ academic freedom to express dissent." The fact that such dissent has over the years covered various important public health topics - "cast doubts about the safety of a vaccine against human papillomavirus (HPV), a cause of cervical cancer, and says psychiatry has “gone astray” by coercing patients into taking medication, such as antidepressants, they don’t want to use and that cause “brain damage” over the long run" - is likely to have really stretched those organisational relationships with Gøtzsche. Not least because immunisation and antidepressant use reflect important pillars of modern public healthcare and, historically, uptake of such medicines is very, very susceptible to differences in scientific views, opinions and beyond.

As to the idea mentioned by Greenhalgh that: "We should cut it [Cochrane] some slack while it gets its house in order", I'm not exactly sure how it's going to approach this 'house in order' requirement and what this means for the future credibility of Cochrane. Based solely on the 'facts' side of this saga, it strikes me that organisations like Cochrane actually need people like Peter Gøtzsche and their "evidence-based medicine purist" beliefs. They need them in order to critically (really critically) boil down the ever-growing research literature into scientifically sound statements for public and policy consumption without fear or favour. Minus such voices, it's more likely that evidence-based messages originating from such initiatives are perhaps going to be weakened, which in turn means that population healthcare is potentially going to suffer. Moreover, I assume also that just because Gøtzsche is reportedly not part of Cochrane any more does not mean that he won't be heard from again in the peer-reviewed domain...

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[1] Jørgensen L. et al. The Cochrane HPV vaccine review was incomplete and ignored important evidence of bias. BMJ Evidence-Based Medicine. 2018. July 27.

[2] Arbyn M. et al. Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors. Cochrane Database Syst Rev. 2018 May 9;5:CD009069.

[3] Jørgensen L. et al. Index of the human papillomavirus (HPV) vaccine industry clinical study programmes and non-industry funded studies: a necessary basis to address reporting bias in a systematic review. Syst Rev. 2018 Jan 18;7(1):8.

[4] Heneghan C. & Onakpoya I. Editors’ response to concerns over the publication of the Cochrane HPV vaccine review was incomplete and ignored important evidence of bias. BMJ Evidence-Based Medicine. 2018. Sept 12.

[5] Boesen K. et al. The Cochrane Collaboration withdraws a review on methylphenidate for adults with attention deficit hyperactivity disorder. Evid Based Med. 2017 Aug;22(4):143-147.

[6] Greenhalgh T. The Cochrane Collaboration—what crisis? BMJ. 2018. Sept 17.

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Fidget spinners: "their alleged benefits remain scientifically unfounded"

Fidget spinners, those spinning toys that have taken the world by storm in recent months, are great little things. My brood have several and, at least for the first few days of getting them, were constantly spinning them on their fingers or any other suitable surface. A welcome - if temporary - distraction from the tablets, phones, games consoles et al that pervade their lives.

Some of the claims however, that have been made about fidget spinners are not so great. Namely that these toys might have some almost magical qualities in 'eliminating anxiety' in relation to various diagnostic labels such as attention-deficit hyperactivity disorder (ADHD) or autism. The paper by Rachel Schecter and colleagues [1] confirms however that as things currently stand: "their alleged benefits remain scientifically unfounded."

Accepting that the research literature on the use of fidget spinners is, at the moment, pretty much nil, Schecter et al provide a little peer-reviewed clarity on the various claims being made around fidget spinners and conditions like ADHD and autism. They suggest that because  "fidget spinners and other self-regulatory occupational therapy toys have yet to be subjected to rigorous scientific research" any medicinal claims around them should really be reserved until appropriate scientific evidence emerges. Further that such toys may represent "potential choking hazards" so medical professionals (and I assume parents and caregivers also) need to be mindful. Such findings follow other opinions from members of this authorship group on other modern day trends and fads [2].

I don't want to undermine the popularity and usefulness of something like fidget spinners as a toy. I can remember the hacky sack sharing a similarly popular position when I was a kid; albeit not accompanied by any psychobabble explanations of improved this-or-that accompanying such use. I neither want to totally poo-poo the idea that for some at least, fidget spinners *might* offer some relief for something like stress under certain circumstances. But what I will continue to take exception to is the way that loose words about a toy having some medicinal qualities for one or more groups can seemingly fill the marketing airways without rigorous scientific evidence to back them up...

To close, vicars... careful when you go to the pub.

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[1] Schecter RA. et al. Fidget spinners: Purported benefits, adverse effects and accepted alternatives. Curr Opin Pediatr. 2017 Jul 7.

[2] Serino M. et al. Pokémon Go and augmented virtual reality games: a cautionary commentary for parents and pediatricians. Curr Opin Pediatr. 2016 Oct;28(5):673-7.

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The continuing trials and tribulations of PACE

I honestly hadn't intended talking about the PACE trial - "pacing, graded activity, and cognitive behaviour therapy: a randomised evaluation" in relation to chronic fatigue syndrome (CFS) - quite so much on this blog. Others have done it so much better than I ever could.

My interest however keeps being piqued in relation to the results originally produced suggesting that: "CBT [cognitive behaviour therapy] and GET [graded exercise therapy] can safely be added to SMC to moderately improve outcomes for chronic fatigue syndrome" and the subsequent myriad of voices quite unanimously suggesting that one perhaps needs to be a little careful with such sweeping generalisations (see here).

OK, for anyone new to this topic, below are a few of the previous occasions that it has been discussed on this blog in chronological order:

• Chronic Fatigue Syndrome and various factors (2014) (see here)
• Chronic fatigue syndrome and the detrimental application of the 'biopsychosocial model' (2016) (see here)
• PACE-gate! (2016) (see here)
• PACE trial recovery data and chronic fatigue syndrome (2017) (see here)
• PACE trial recovery data and chronic fatigue syndrome - a reply (2017) (see here)

I want to add a few more 'science references' to this issue because some important things are being discussed in the peer-reviewed domain, in the context that CBT and GET at the moment, are considered 'best practice' here in the UK and beyond when it comes to CFS. That may change in future times (see here) as it has in other parts of the world (see here) but that's where we are at the time of writing. I might add that the addition of new references to this post is a rather more descriptive thing minus too much additional commentary from me, and that the views represented are those of the authors. I wrote this post on 9 April 2017 so it is accurate up to that point.

OK, starting with the editorial from Keith Geraghty [1] mentioned in that PACE-gate! post, we have an authors reply to some of the points raised [2]. The main crux of the reply is to correct "misunderstandings and misrepresentations of the PACE trial." Next up was a paper by Leonard Jason [3] (someone with quite an impressive research track record when it comes to CFS) and some comments on the pacing intervention (adaptive pacing therapy, APT) used and "patient selection ambiguity." This is a particularly interesting paper because APT - "based on the envelope theory of chronic fatigue syndrome" where the symptoms of CFS are "not reversible by changes in behaviour" - did not hit the 'research spot' according to the original PACE trial results.

I want to next include the paper by Luis Nacul and colleagues [4] into proceedings, and a role for "selection bias and disease misclassification" when it comes to studies on CFS (and myalgic encephalomyelitis, ME). To quote from them: "When studies using the broad Oxford criteria... were excluded, a virtual disappearance of effect for graded exercise therapy (GET), cognitive behaviour therapy (CBT) and other psychological therapies recommended by the NICE guidelines (National Institute for Health and Care Excellence.. was revealed." Guess which criteria (among the many available) were used in the original trial?

Onward. The paper by Steven Lubet [5] titled: 'Investigator bias and the PACE trial' sets out quite an 'accusation' in that: "the PACE investigators “impartiality might reasonably be questioned”." This is a theme that crops up again shortly. The paper by Tom Kindlon [6] asked whether graded exercise in particular, could be thought of as 'safe and risk-free'? I set this question within the context that the original PACE trial did find that: "Non-serious adverse events were common" and GET did seem to produce the largest number of 'serious adverse effects' in number if not in participants.

Nearly there. Next up is the paper from Carolyn Wishire [7] who, when talking about "lively discussion", reports on various potential forms of bias in behavioural intervention studies using the PACE study as a kind of template. This author was the lead on the recent peer-reviewed commentary (open-access) re-analysing the 'recovery' data subsequently published in relation to the PACE trial. Then, we have the paper by Jonathan Edwards [8] who notes that the PACE trial represents a lesson in how research design needs to develop further when it comes to science in general. To quote: "The failure of the academic community to recognise the weakness of trials of this type suggests that a major overhaul of quality control is needed." And finally Charles Shepherd [9] provides further commentary on the PACE trial and a call for independent review.

And rest.

There is quite a lot to take in from those various publications and I don't doubt that this is not the last we are going to hear about the PACE trial. Allied to articles such as this one describing how: "Physicians used to dismiss the disease as psychosomatic" (past tense) it certainly would not out of place to suggest that there are still questions that need to be answered about the design and results obtained from the PACE trial and their applicability to the (very) wide CFS/ME population. To quote again from the paper by Edwards [8]: "If they are still ill [those diagnosed with CFS/ME], presumably these approaches have failed and the priority is to find something more effective." Wise words indeed.

To close, it's here... the first glimpse of The Last Jedi.

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[1] Geraghty KJ. ‘PACE-Gate’: When clinical trial evidence meets open data access. J Health Psychology. 2016. Nov 1.

[2] White PD. et al. Response to the editorial by Dr Geraghty. J Health Psychology. 2017. Jan 24.

[3] Jason LA. The PACE trial missteps on pacing and patient selection. J Health Psychology. 2017. Feb 1.

[4] Nacul L. et al. How have selection bias and disease misclassification undermined the validity of myalgic encephalomyelitis/chronic fatigue syndrome studies? J Health Psychology. 2017. March 1.

[5] Lubet S. Investigator bias and the PACE trial. J Health Psychology. 2017. March 7.

[6] Kindlon T. Do graded activity therapies cause harm in chronic fatigue syndrome? J Health Psychology. 2017. March 20.

[7] Wilshire C. The problem of bias in behavioural intervention studies: Lessons from the PACE trial 2017. J Health Psychology. March 23.

[8] Edwards J. PACE team response shows a disregard for the principles of science. 2017. J Health Psychology. March 28.

[9] Shepherd CB. PACE trial claims for recovery in myalgic encephalomyelitis/chronic fatigue syndrome – true or false? It’s time for an independent review of the methodology and results. J Health Psychology. April 9.

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Edwards, J. (2017). PACE team response shows a disregard for the principles of science Journal of Health Psychology DOI: 10.1177/1359105317700886





White, P., Chalder, T., Sharpe, M., Angus, B., Baber, H., Bavinton, J., Burgess, M., Clark, L., Cox, D., DeCesare, J., Goldsmith, K., Johnson, A., McCrone, P., Murphy, G., Murphy, M., O’Dowd, H., Potts, L., Walwyn, R., & Wilks, D. (2017). Response to the editorial by Dr Geraghty Journal of Health Psychology DOI: 10.1177/1359105316688953

Publication bias and autism research

The title of the paper by Konstantin Mechler and colleagues - "Defining the hidden evidence in autism research. Forty per cent of rigorously designed clinical trials remain unpublished - a cross-sectional analysis" [1] - provides some discussion today. Drawing on the ideas that publication bias and/or the so-called 'file-drawer problem' - terms that refer to the non-publication of study results potentially skewing the collected scientific opinion in a particular area - might also extend into autism research too, Mechler et al detail results according to their analysis of a particular trial registration database called: ClinicalTrials.gov.

ClinicalTrials.gov is one of the premier 'tell everyone about your trial' databases designed to provide a bit of transparency to science. The idea is that you register (pre-register hopefully) your research study, register what you are going to do and how, and importantly, provide some details about what your are going to be assessing (outcomes). Some of the research that I've been involved with has a mention in this database (see here) with more to come in future times. Once your entry is in ClinicalTrials.gov it kinda stops you from making any major 'alterations' to your study potentially based on the results you get, whilst at the same time also getting quite a few prods to post things like your raw study results for everyone to see and analyse as they wish. And believe me, they are quite a persistent bunch over at ClinicalTrials.gov!

So Mechler and colleagues "searched for all completed randomized controlled clinical trials investigating interventions in ASD [autism spectrum disorder] and their results made public." They looked at how many trials had been submitted and how many reported results. Where no results were available on ClinicalTrials.gov or on other 'scientific databases' or after "enquiries of the responsible parties or sponsors listed", the authors listed the trial as 'not published'.

The good news: 60% of trials (n=30) were published in the peer-reviewed domain. The not-so-good news was that reported in the opening sentence of this post as some 40% of trials (n=20) fell into that not published category. Authors also mention that some 1600 participants were included in those not published trials, inferring that data on quite a few people diagnosed with an ASD and agreeing (themselves or by proxy) to participate in research remain 'missing' in a research sense.

"The results emphasize the serious issue of publication bias. The large proportion of unpublished results precludes valuable information and has the potential to distort evidence for treatment approaches in ASD." This an important point in any area of science but perhaps more so when you have a label like autism and a whole host of 'unknowns' about the aetiology, nature and course of presentation. I would like to think that there were some rational reasons why so many trials were missing results (studies having to be halted/stopped, collaborations breaking down, resources being exhausted, etc) but there is always going to suspicion around the non-publication of such results particularly the idea that 'researchers or funders did not get the results they hoped for'. Other discussions on this topic outside of autism (see here) point to the failure to publish being tantamount to an ethical breach. Strong words indeed.

Although Mechler et al focused on data from the ClinicalTrials.gov initiative I'd perhaps suggest that the issues they discuss probably go a lot deeper as a function of there being quite a few other databases where such trial information is held and listed. Perhaps also just as concerning is the fact that many other pieces of research are not listed anywhere when it comes to trial registration and therefore have even less 'motivation' to publish results or are perhaps more likely to be subject to 'alteration' in terms of methodology or outcome(s). All of which contributes to the possible tarnishing of science and the reporting of said science and paves the way for criticism.

Music, it's not Mother's Day or anything like that but do give her a call from time-to-time and treat your mother right...

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[1] Mechler K. et al. Defining the hidden evidence in autism research. Forty per cent of rigorously designed clinical trials remain unpublished - a cross-sectional analysis. International Journal of Methods in Psychiatric Research. 2016. Nov 9.

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Mechler K, Hoffmann GF, Dittmann RW, & Ries M (2016). Defining the hidden evidence in autism research. Forty per cent of rigorously designed clinical trials remain unpublished - a cross-sectional analysis. International journal of methods in psychiatric research PMID: 27862603

Karl Ludvig Reichelt: a research pioneer

This is a short post to mark the passing of a great man of science: Karl Ludvig Reichelt who died on October 29th 2016.

Affectionately known as 'Tiny' to many, in stark contrast to his physical presence, he was quite simply a tour de force when it came to many areas of science and research, not least with an emphasis on schizophrenia and autism (see here for some of his publications). His receipt of the Norwegian 'King's Medal of Merit' was testament to his presence both as a medical doctor and researcher.

I had the pleasure of knowing Tiny for quite a few years and alongside another notable Norwegian researcher, the late Ann-Mari Knivsberg, worked with him on a few research projects and papers notably our ScanBrit project looking at the use of a gluten- and casein-free (GFCF) diet as an intervention for some autism. My colleagues and I were literally standing on the shoulders of giants with our GFCF work, as Tiny and Ann-Mari blazed a research trail stemming from the important work of Curt Dohan on a possible connection between wheat/gluten and some schizophrenia towards the dietary links potentially surrounding some autism. Indeed, there are stories that Dohan, in some of his last days, inspired Tiny to continue his important work.

Alongside his clinical and research life, Tiny had an interesting upbringing as stories of his early childhood in the Far East during World War II fascinated many at the conferences and social gatherings he attended. Indeed, his life continued an interesting family legacy. Channelling the fight and spirit of the Berserkers he was passionate about his science but at the same time always the gentle giant, no better exemplified by his technically brilliant ballroom dancing that I witnessed on several occasions.

Science has lost a true research pioneer. My condolences go to his family and friends. Rest in peace Tiny.