"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...

----------

[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.

----------

"The MMR Vaccine Is Not Associated With Risk for Autism"

The quote heading this rather long post - "The MMR [measles, mumps and rubella] Vaccine Is Not Associated With Risk for Autism" - comes from a patient summary covering the the findings reported by Anders Hviid and colleagues [1].

Hviid et al utilised some of those oh-so-useful Scandinavian population registries to provide support for the hypothesis that "MMR vaccination does not increase the risk for autism, does not trigger autism in susceptible children, and is not associated with clustering of autism cases after vaccination." As per some media reporting of the study (see here), such a finding comes at a time when cases of measles in particular, are on the rise (see here) in various parts of the developing and developed world (see here) as a possible/probable consequence of specific viewpoints around vaccination (see here).

The Hviid data, as important as it is, is nothing new in terms of research that has been done on the topic of childhood vaccination and autism risk (see here). Indeed, the author is no stranger to this area of the autism research 'scene' as per other population-based cohort studies looking at "whether vaccination with a thimerosal-containing vaccine is associated with development of autism" [2]. The answer on that peer-reviewed research occasion was probably not: "results do not support a causal relationship between childhood vaccination with thimerosal-containing vaccines and development of autistic-spectrum disorders." The authors have also previously looked specifically at the MMR vaccine and autism risk too [3] albeit with caveats, some of which they addressed in this more recent investigation...

The basics this time around: look through the registry data of some 650,000 children "born in Denmark from 1999 through 31 December 2010, with follow-up from 1 year of age and through 31 August 2013." Collect and collate various information - use of "MMR and other childhood vaccinations, autism diagnoses, sibling history of autism" - and undertake some statistical analysis pertinent to the question of "whether autism developed in children who got the MMR vaccine compared with those who did not during the follow-up period." Researchers also included various potential confounders in their statistical analyses: "maternal age, paternal age, smoking during pregnancy, method of delivery, preterm birth, 5-minute Apgar score, low birthweight, and head circumference."

As per the opening paragraph, the results did not detect any link: "Comparing MMR-vaccinated with MMR-unvaccinated children yielded a fully adjusted autism hazard ratio of 0.93 (95% CI, 0.85 to 1.02)." This based on data where around 95% of the population received the vaccine (around 31,000 were classed as 'MMR-unvaccinated') and 1% (n=6,517) of the total population were diagnosed with autism. A few other observations were also noted by Hviid and colleagues: "The highest risk for autism was conferred by being a boy..., being born in a late birth cohort (2008-2010...), having no early childhood vaccinations..., and having siblings with autism at study entry." Such observations have some important links to other independent findings; for example, children with a sibling already diagnosed with autism are more likely to be diagnosed with autism (see here) and children who did not receive the MMR vaccine were actually slightly more likely to be diagnosed with autism than those who were vaccinated (a trend particularly noted in girls I believe). That last result might tie into other independent findings too (see here).

As with any research study, there were limitations attached to the Hviid investigation. So: "No individual medical chart review was performed" meaning that registry data, as strong as it is, is not the same as "medical records or direct examination of the children by research staff." The use of such population registries across a wide variety of different research topics (see here and see here for examples) carries the same limitation. I'm also minded to mention that population registry data is good for ascertaining population trends, but tends to say little about rare events. Individual issues can sometimes get lost in the statistical noise [4]. The focus of the Hviid study was also specifically on the MMR vaccine. Although not completely au-fait with the vaccination schedule in Denmark (see here) the data say little about the use of other vaccinations, their timing, and any connection (or not) to autism. And finally, I might quibble with the idea that Hviid et al looked at 'susceptible groups' on the basis of the variables they included in their 'autism risk score'. 'Smoking during pregnancy' for example has shown little to no association with autism (see here and see here) (something we can't say when it comes to offspring risk of ADHD for example). Other variables such a maternal metabolic syndrome signs and symptoms during pregnancy (see here) or maternal vitamin supplementation during pregnancy (see here) might have provided some stronger indications of autism risk/susceptibility. And then there's the recent results from Xie and colleagues [5] to also consider...

Still, the Hviid data provide further pretty powerful evidence disproving any population-wide link between MMR vaccine receipt and autism risk. The big question is whether such results, added to quite a lot of other science on this topic, are actually going to make any difference to something like vaccination rates against diseases like measles?

As per an editorial [6] accompanying the Hviid paper we live in an age where scientific data seems to have 'limited persuasive value' for some people and where the concept of 'risk' is often not well understood. The editorial authors also opine that "an alternative explanation of the perceived phenomenon should be provided" which is something else rather important. Not least because some parents, right or wrong, are still adamant that their child had a reaction to one or more of their childhood vaccinations (see here and see here). Autism research has tended to shy away from looking at this specific scenario (see here) thus leaving it unchallenged. Perhaps therefore the time is right for some brave researcher to study those children who were reported to have allegedly undergone a reaction to vaccination and see if anything is significantly 'different' about them on a behavioural and/or biological level? Whether indeed an alternative explanation could be provided for their clinical regression including the influence of variables immediately after the vaccination event [7]?

And as for the message about ensuring children (and adults, particularly vulnerable adults) are vaccinated and protected against diseases, I once again turn to the writings of Roald Dahl, and how measles devastated his family (see here) and what vaccination would have meant to his daughter. A powerful personal message that perhaps needs to be used a little more often alongside the dissemination (and translation) of scientific data to promote the benefits of vaccination to individuals and populations alike...

----------

[1] Hviid A. et al. Measles, Mumps, Rubella Vaccination and Autism: A Nationwide Cohort Study. Ann Intern Med. 2019 Mar 5.

[2] Hviid A. et al. Association between thimerosal-containing vaccine and autism. JAMA. 2003 Oct 1;290(13):1763-6.

[3] Madsen KM. et al. A population-based study of measles, mumps, and rubella vaccination and autism. N Engl J Med. 2002 Nov 7;347(19):1477-82.

[4] Poling JS. et al. Developmental regression and mitochondrial dysfunction in a child with autism. J Child Neurol. 2006 Feb;21(2):170-2.

[5] Xie S. et al. Family History of Mental and Neurological Disorders and Risk of Autism. JAMA Network Open. 2019; 2: e190154.

[6] Omer SB. & Yildirim I. Further Evidence of MMR Vaccine Safety: Scientific and Communications Considerations. Ann Intern Med. 2019 Mar 5.

[7] Schultz ST. et al. Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: the results of a parent survey. Autism. 2008 May;12(3):293-307.

----------

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...

----------

[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.

----------

"Twitter Bots and Russian Trolls Amplify the Vaccine Debate": Blame content pollutors first and foremost

"Nyet Comrade"

I'm slightly outside of my comfort zone when talking about the findings reported by David Broniatowski and colleagues [1] which has been reported in the lay media with headlines such as: "Russian trolls 'spreading discord' over vaccine safety online".

Outside of my comfort zone not just because this topic is one on the periphery of the core material of this blog (see here and see here for examples) but also because I've long held the belief that this blog should be apolitical and areligious. There are plenty of other outlets online to satisfy such needs these days. To reiterate, the typical currency on this blog is peer-reviewed science and science really should be free from politics, religion and 'allegiance'.

But here I am talking about a paper titled: "Weaponized Health Communication: Twitter Bots and Russian Trolls Amplify the Vaccine Debate" and a study which did mix science with politics. Indeed, a paper which seemingly complements a whole debate on how social media in particular, really is the mouthpiece of the masses in a global sense, but at the same time, is a media ripe for 'promoting discord'.

Set within the reality that people say pretty much anything and everything on social media and that you don't really know who you're 'socialising with' when using such resources (ever heard of 'stranger danger'), Broniatowski et al set about looking to "understand how Twitter bots and trolls (“bots”) promote online health content." The specific online health content they were interested in was "vaccine-relevant messages" as part of a scheme of work previously undertaken by some of the authors. On this occasion, they looked at well over a million tweets over a 3 year period (2014-2017) and "estimated the likelihood that users were bots, comparing proportions of polarized and antivaccine tweets across user types." They also "conducted a content analysis of a Twitter hashtag associated with Russian troll activity."

Results: "Compared with average users, Russian trolls..., sophisticated bots..., and “content polluters”... tweeted about vaccination at higher rates." Researchers observed that 'content pollutors' - "bot accounts that distribute malware, unsolicited commercial content and disruptive materials" tended to post more 'anti-vaccine content'. One would assume this was because their aim is to 'distribute malware and related materials' and by posting such provocative material, it is more likely to get people to click 'their way'.

Also: "Whereas content polluters posted more antivaccine content..., Russian trolls amplified both sides." Bearing in mind that the overall numbers of those tweets from accounts linked to that Twitter hashtag with Russian activity was small, very small, as a percentage of the whole dataset - "the researchers found 253 tweets containing the #VaccinateUS hashtag among their sample" - their content was more mixed - "43% were pro-vaccine, 38% were anti-vaccine, and the remaining 19% were neutral" - if not actually more likely to be pro-vaccine or neutral. The authors interpret this by saying "its messages were more political and divisive."

I have to say that I'm left slightly unimpressed with the interpretation being made from the Broniatowski data. I'm not quibbling with the idea that: "Accounts masquerading as legitimate users create false equivalency, eroding public consensus on vaccination" or that "More research is needed to determine how best to combat bot-driven content." Yes, social media typically does not typically have many filters ('evidence-based' or otherwise) and that is a downside to the content that users are exposed to.

But the whole 'Russian trolls' promoting 'discord' and being 'divisive' thing seems to be built on fairly flimsy evidence at best. I say this on the basis of the small number of tweets from those Russian troll accounts and the majority direction of their stance with regards to vaccines (neutral if not pro-vaccine in the majority). The bigger story here is the continued effects of 'content pollutors' and how, through their attempts to spread their 'mal-wares', so vaccination policy is being potentially undermined as a result. I say all that wearing the objective blinkers of science and recognising that I am not affiliated to any particular political group, red or otherwise.

I know there's something of an obsession these days about how 'social media is being used to subvert democracy', and how the population at large are somehow unable to form their own opinions as a function of 'what social media says'. Personally, I've always felt such sentiments belittle people, and indeed, say more about those who subscribe to such 'control' ideas than those who are actually exposed to them.

It's also interesting that, outside of the continuing search - often a desperate search - for examples of how Russia is somehow trying to 'take over the world' (😏), mention of the word 'vaccine' in the paper from Broniatowski and colleagues, taps into another topic which can ruffle feathers. I shouldn't really need to emphasise how important vaccines are as part of the modern-day medical arsenal (read Roald Dahl's account if you need more evidence of this). But there does seem to be a general feeling that if one even mentions something that distracts from the life-saving message about vaccines, one becomes persona non grata in certain quarters. Y'know, like the idea that for some groups - "immunodeficient individuals are more likely to develop complications resulting from live-virus vaccines" - vaccination might not be potentially advantageous, or how side-effects, rare as they are, can occur: "Within 48 hours after immunizations... the patient developed a fever to 38.9°C, inconsolable crying, irritability, and lethargy and refused to walk." By linking Russian trolls to social media posts about vaccination, it's not difficult to further 'demonise' various groups of people; and with it, 'pull in' (mainly) parents, some of whom are not 'anti-vaccine' but rather, have some genuine concerns about the potential effects of vaccination on their children (see here)...

And just in case anyone needs any advice on vaccination, there are lots of helpful resources around (see here and see here).

Update: 25 August 2018. The Broniatowski paper is open-access (see here).

----------

[1] Broniatowski DA. et al. Weaponized Health Communication: Twitter Bots and Russian Trolls Amplify the Vaccine Debate. AJPH. 2018. Aug 23.

----------

"Prenatal Tdap vaccination was not associated with an increased ASD risk"

The findings published by Tracy Becerra-Culqui and colleagues [1] reporting on a lack of any significant *association* between exposure to tetanus, diphtheria, acellular pertussis (Tdap) vaccination during pregnancy and subsequent risk of autism spectrum disorder (ASD) provide the blogging fodder today.

Such results, based on a cohort size of 80,000+ children with continuous enrolment at Kaiser Permanente Southern California (KPSC) hospitals in the United States (US), should set minds at ease when it comes to the safety of this important vaccine when used during pregnancy. Even more so when one realises that pregnancy infection and vaccination analysis in the context of autism is a bit of strong point when it comes to Kaiser Permanente data (see here for example).

Tdap vaccination used during pregnancy, according to the US CDC, is an important tool specifically in the fight against pertussis, also known as whooping cough; so named as a result of the characteristic 'whoop' that occurs during the illness. The immunity provided by vaccination to a pregnant mum is able to also cover the important period after birth before an infant is old enough to be themselves vaccinated against the disease. The data on the effectiveness of pregnancy Tdap vaccination is encouraging, insofar as reducing the risk of infant whooping cough illness prior to them receiving their own vaccination.

As the authors point out (and a search of PubMed confirms), at the current time there doesn't previously appear to have been any peer-reviewed research suggestion that pregnancy use of Tdap vaccination raises the risk of offspring autism. The vaccine has also been 'cleared' in relation to "risk of small for gestational age, preterm delivery, or low birth weight in infants"; factors which have been *linked* to offspring autism risk previously (see here for example) alongside various other developmental outcomes on more than one occasion. But before this study "longer-term outcomes such as the risk of ASD, an outcome of significant public interest" had not been specifically looked at or mentioned in the context of Tdap.

The results of the Becerra-Culqui study have been summarised in an editorial in an affiliated outlet [2] to the journal where published and have also featured in other news sites too (see here). The long-and-short of it was that the rate of offspring autism was not significantly different when mum received the Tdap vaccine during pregnancy compared with mums who didn't. The autism incidence rate "was 3.78 per 1000 person years in the Tdap exposed and 4.05 per 1000 person years in the unexposed group." Variables like year of birth and parity also didn't seem to alter the results either.

But there were some issues to consider in the study design that were also highlighted by the authors. So for example: "There was an average difference of 6 months in follow-up time between both groups (unvaccinated, mean: 4.44 years [SD: 1.18]; vaccinated, mean: 3.85 years [SD: 1.29])" which meant that the study could have 'missed' some later diagnosed cases of autism, particularly in the vaccinated group. Indeed authors conclude: "we likely did not capture some children with ASD born in later study years considering that some children with milder ASD would not be diagnosed until they reach school age." Accepting that the description of 'milder ASD' is not a technical term, it's a shame that a more uniform follow-up period was not built into the study design. Particularly when there is data indicating that: "The median age of earliest known ASD diagnosis was 52 months" [3] in the United States; a figure that has not varied significantly over the past few years [4] and a median age of diagnosis that is not so dissimilar from one also reported here in Blighty (see here). And given that Becerra-Culqui has also previously published on the 'timing of autism spectrum disorder diagnosis' [5] so perhaps authors should have been aware of the literature on 'what age autism is typically diagnosed at' and adjusted accordingly.

What's more to say? Well, not much more really. Pregnancy Tdap vaccination appears to be safe based on such population data analysis and bearing in mind the follow-up caveat just discussed. Given the important protection the vaccine affords both to mums-to-be and their offspring against a pretty awful disease such as whooping cough, physicians can confidently recommend it. By saying this, I don't want to play down those follow-up differences nor the possibility of rare side-effects occurring for certain people (see here). But increasing offspring autism risk when such a vaccine is used during pregnancy does not seem to one of them...

----------

[1] Becerra-Culqui TA. et al. Prenatal Tetanus, Diphtheria, Acellular Pertussis Vaccination and Autism Spectrum Disorder. Pediatrics. 2018. Aug 13.

[2] Jenco M. Study: Prenatal Tdap not linked to autism. AAP News. 2018. Aug 13.

[3] Baio J. et al. Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2014. MMWR Surveill Summ. 2018 Apr 27;67(6):1-23.

[4] Wingate M. et al. Prevalence of autism spectrum disorder among children aged 8 years - autism and developmental disabilities monitoring network, 11 sites, United States, 2010. MMWR Surveill Summ. 2014 Mar 28;63(2):1-21.

[5] Becerra-Culqui TA. et al. Parental First Concerns and Timing of Autism Spectrum Disorder Diagnosis. J Autism Dev Disord. 2018 May 12.

----------

Vaccination rates and patterns among kids with autism and their siblings (again)

The publication of the paper by Ousseny Zerbo and colleagues [1] garnered some media headlines insofar as their conclusion that: "Children with ASD [autism spectrum disorder] and their younger siblings were undervaccinated compared with the general population."

Drawing on data from "6 integrated health care delivery systems across the United States within the Vaccine Safety Datalink" researchers looked at immunisation status for over 3700 children diagnosed with ASD and over half a million kids not diagnosed with autism alongside their respective younger siblings. They were specifically looking at the proportion of children who "received all of their vaccine doses according to ACIP [Advisory Committee on Immunization Practices] recommendations."

Results: "For vaccines recommended between ages 4 and 6 years, children with ASD were significantly less likely to be fully vaccinated compared with children without ASD." Vaccination rates were also significantly lower for younger siblings of those with autism too. Further discussion of the details of the Zerbo results can be seen here.

Although headline grabbing, this research topic - vaccination rates among children with autism and their siblings - is by no means a new one (see here and see here for examples). The Gena Glickman findings [2] published last year (2017) for example, did not attract the same degree of media attention but highlighted how (a) parents of children diagnosed with autism were extremely vaccine compliant when it came to their earlier born children, and (b) "Families with children who had autism spectrum disorder were less likely to vaccinate subsequent children." To quote from some of the media on the latest Zerbo paper: ""We did not look at vaccination rates before the children were diagnosed with autism," Zerbo noted"; a pretty important omission by all accounts.

What's then also missing from the current data in this area? Well, the question of why - why are children with autism and their siblings less likely to be vaccinated - is a rather glaring omission, and one that stretches into other age ranges [3] too. Yes, it's easy to say that 'fear of the autism-vaccine link' is a primary reason for the undervaccination statistics, particularly with the data on age being a factor in the Zerbo findings and despite the 'too many too soon' argument having some strong evidence against it (see here). But... as per the Glickman and other data, many parents are/were extremely vaccine compliant when it came to earlier born children. If they were going to have long-standing fears about vaccination and indeed, act upon those fears, I would have thought that they would have influenced vaccination behaviour across all their children and not just as and when autism was diagnosed in a family member. Neither do I give much [research-based] credence to the idea that parents of children with autism are somehow over-represented among the so-called 'anti-vaxxer' groups (see here); not that is, as being a long-standing issue.

Glickman et al do provide another possible explanation in their study results that: "changes in vaccination behavior may relate to adverse reactions to vaccine" in their cohort. A sort of once bitten, twice shy sentiment if you like *might* potentially be in action, which kinda makes more sense. I know this takes us down a rather uncomfortable path in that, whilst acknowledging that vaccines represent an important cornerstone of modern healthcare (yes, they do), they are not somehow magically without side-effects for some. Hackles are bound to be raised by such utterances; despite some potentially important clues already appearing in the peer-reviewed research literature [4] relevant to this topic. But without even attempting to try and answer such 'why' questions, we are left with a fairly large number of children who "are at increased risk of vaccine-preventable diseases" with no real solutions in sight for protecting their health and/or the health of the wider population.

Answers are therefore required and required quickly. The simplest and perhaps most logical solution I can see would be to go and ask parents/primary caregivers, under scientifically controlled study, why their children are undervaccinated; perhaps building on important work such as that by Hilton and colleagues [5]. There is the issue of recall to overcome (see here) and I'm sure the range of answers is going to be long and complicated in relation to undervaccination. Armed however, with such answers or at least clues from the parents/caregivers themselves and not just 'speculation', science and policy can perhaps then start to move things forward to further protect the health of all concerned. Hopefully also, such knowledge can be used to chip away at yet another important health inequality that seems to follow a diagnosis of autism throughout the lifespan (see here)...

----------

[1] Zerbo O. et al. Vaccination Patterns in Children After Autism Spectrum Disorder Diagnosis and in Their Younger Siblings. JAMA Pediatrics. 2018. Mar 26.

[2] Glickman G. et al. Vaccination Rates among Younger Siblings of Children with Autism. N Engl J Med. 2017 Sep 14;377(11):1099-1101.

[3] Filliter JH. et al. The next vaccine-autism question: Are school-aged youth with autism spectrum disorder undervaccinated and, if so, why? Paediatr Child Health. 2017 Aug;22(5):285-287.

[4] Poling JS. et al. Developmental regression and mitochondrial dysfunction in a child with autism. J Child Neurol. 2006 Feb;21(2):170-2.

[5] Hilton S. et al. MMR: marginalised, misrepresented and rejected? Autism: a focus group study. Archives of Disease in Childhood. 2007;92(4):322-327.

----------

Treading carefully: vaccination rates among younger siblings of kids with autism

'Treading carefully' is a requirement for any discussion about a research study that mentions 'vaccination' and 'autism' in the same breath. I say this on the basis that vaccine coverage is an important cornerstone of public health and now appears to be making significant in-roads with regards to public health, at least here in Blighty.

But much like [scientific] discussions covering other areas of the important public health topic of immunisation, one shouldn't be afraid to look, examine and yes, talk about this subject (see here) particularly where there may be a need for further study minus any hype, sweeping generalisations or logical fallacies...

The paper by Gena Glickman and colleagues [1] discussed an important topic in relation to vaccination behaviour - "whether or not and when parents choose to vaccinate a child" - in the context that parents who already have a child with autism may perhaps be slightly more hesitant to vaccinate their other children in light of "the perceived link between vaccines and autism spectrum disorder." This is a topic that has cropped up on this blog previously (see here). Far be it from me to question any parent about their own child, but I will refer you to some of the peer-reviewed science already done on this topic (see here and see here).

Based on a sample of over 200 families, Glickman et al looked at "vaccination behaviors" as a function of having a child with autism or not. From what I surmise from their report, the focus was specifically on "vaccination against measles–mumps–rubella (MMR)." They reported: "no significant difference between rates of vaccination among children with and those without autism" which is rather comforting. Minus too much politics or anything related, this data suggests that anti-vaccination sentiments are not naturally rife among parents/caregivers of children with autism, at least before a diagnosis of autism is given. Indeed with vaccination rates of 100% among children with autism vs. 98% in the slightly larger control group, one might argue that parents of children with autism are/were extremely vaccine compliant when it came to their first born child.

But then also: "Families with children who had autism spectrum disorder were less likely to vaccinate subsequent children." Authors observed that: "the rate of vaccination among full biologic infant siblings of children with autism spectrum disorder was 83.1%, as compared with 97.0% among low-risk infants."

One can speculate (and speculate) about the reason(s) why younger siblings of children with autism were seemingly less likely to be vaccinated but I'm sure the answers are going to be complex. The authors suggest that: "parents who had an older child with autism spectrum disorder retrospectively reported a higher rate of adverse reactions to vaccination among the older child than did those who did not have an older child with autism" and that this may have impacted on subsequent vaccination behaviour. The rates of adverse reactions reported - 22% in the autism group vs. ~4% in the control group - are not to be sniffed at and indeed, seemingly filtered down to observations of adverse reactions in younger siblings too (6.9% vs. 0.8%). Authors also noted that: "Reported reactions included fever, diarrhea, unusual crying or screaming, and general malaise."

This is a nice piece of research. It doesn't go overboard in it's interpretations of the findings and calmly suggests that "a better understanding of the relationship between perceived adverse reactions to vaccine and autism spectrum disorder is necessary in order to more effectively address concerns about vaccination." It is important to note that the authors don't mention 'onset of autism' or anything like that in their discussion of 'reported reactions' following vaccination, despite the seemingly 'once bitten, twice shy' sentiments portrayed in the findings.

Personally, I would have like to have seen more details about the hows-and-whys of this study insofar as what "available data on vaccination behaviors" were used and whether important information on the timescale(s) of adverse reactions were also available keeping in mind certain issues [2]. Some idea of the rate of autism recurrence among younger siblings might also have been useful too (something that at least one of the authors on the Glickman paper seems to be interested in [3]). Given also the quite apparent differences noted in the rates of reported adverse reactions among those with autism vs. controls, there is also a requirement for further careful investigation in this area. Specifically, whether aspects of the biology (or genetics [4]) of at least 'some' autism (or it's possible comorbidity [5]) might be something to consider when it comes to studies of adverse reactions [6] or indeed whether for example, other medications used at the same time of vaccination might have had an effect [7] onward to finding ways and means to minimise such issues.

To close, although some ten years old, the paper by Shona Hilton and colleagues [8] still stands the test of time in this often fractious area...

----------

[1] Glickman G. et al. Vaccination Rates among Younger Siblings of Children with Autism. N Engl J Med. 2017 Sep 14;377(11):1099-1101.

[2] Ozonoff S. et al. Reliability of parent recall of symptom onset and timing in autism spectrum disorder. Autism. 2017. Sept 13.

[3] Ozonoff S. et al. Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium study. Pediatrics. 2011 Sep;128(3):e488-95.

[4] Verbeek NE. et al. Effect of vaccinations on seizure risk and disease course in Dravet syndrome. Neurology. 2015 Aug 18;85(7):596-603.

[5] Poling JS. et al. Developmental regression and mitochondrial dysfunction in a child with autism. J Child Neurol. 2006 Feb;21(2):170-2.

[6] McClenathan BM. et al. Metabolites as biomarkers of adverse reactions following vaccination: A pilot study using nuclear magnetic resonance metabolomics. Vaccine. 2017 Mar 1;35(9):1238-1245.

[7] Schultz ST. et al. Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: the results of a parent survey. Autism. 2008 May;12(3):293-307.

[8] Hilton S. et al. MMR: marginalised, misrepresented and rejected? Autism: a focus group study. Archives of Disease in Childhood. 2007;92(4):322-327.

----------

On vaccinated and un-vaccinated homeschooled children: the disappearing-reappearing-disappearing-reappearing studies

I originally began writing this post in the last week of November 2016 following first sight of the study abstract by Anthony Mawson and colleagues [1] and their journey into a topic that has had its fair share of discussion/argument* (*delete as appropriate) with autism in mind down the years: are vaccines or immunisation patterns potentially linked to [some] autism?

As it happened, this post was shelved for some time because (a) only an abstract appeared despite a publication date accompanying the initial open-access submission in a Frontiers journal and (b) the subsequent sudden disappearance of the abstract from the publishers website following some discussions on social media about the paper and the review process (see here and see here for more information).

The study then appeared in a different journal (April 2017) before once again disappearing.

Now it's back - for now - in the same journal, so once again it's fodder for this blog...

As I always do when it comes to any chatter specifically on this topic, I should reiterate a few things: (a) the prime directive of this blog - no clinical or medical advice is given or intended - and (b) that vaccines save lives. I know some people attribute other factors to that 'life-saving' angle when it comes to vaccines over the longer term (better health, better environment, etc), but one really only needs to look at the protective effect of the various meningitis vaccines for example, to see their results in something like real-time. I repeat again: vaccines save lives.

What however does seem to be missing from at least some of the general discussion about vaccines as a whole and their very positive health effects is the fact that they are medicines. As such they are not somehow impervious to potentially producing side-effects for some people, albeit a small proportion of people who use them. The problem at the moment is, that we don't really know everything there is to know about which people might be at greater risk of side-effects than others (although some clues are emerging) and importantly, how all those side-effects may manifest. Science - metabolomic science - is however starting to tackle some aspects of these issues [2] minus too much hype at the present time.

As per the title of this post, Mawson et al set about examining whether there were differences between those children who were vaccinated and those un-vaccinated across "a broad range of health outcomes." In line with the previous history hypothesising about autism and specific vaccination, the authors focused on any 'association' between vaccination status and neurodevelopmental disorders (NDD) taking into account other potentially confounding variables.

The source data for those vaccinated / un-vaccinated children participants (N=666) was an anonymous online questionnaire completed by mothers of children who were members of various homeschooling organisations in four regions of the United States. Homeschooling refers to a situation where a child is educated at home outside of the mainstream education system choices. Homeschoolers were selected for study because, according to the authors, a "higher proportion are unvaccinated compared to public school children."

Results: around 40% of the participants were indeed described as un-vaccinated in the Mawson cohort. This is quite a bit higher than other estimates [3] specifically looking at homeschooled children. Then to some of the details: "Vaccinated children were significantly less likely than the unvaccinated to have been diagnosed with chickenpox and pertussis." If you needed more evidence that vaccines work, that last sentence kinda provides you with it, particularly in light of what diseases like pertussis can potentially do to the most vulnerable.

And then some potential controversies: vaccinated children were significantly more likely to have been diagnosed with pneumonia, otitis media, allergies and NDDs (defined as autism spectrum disorder, attention deficit hyperactivity disorder, and/or a learning disability). After some statistical adjustment for potentially confounding variables, authors reported that "vaccination, nonwhite race, and male gender were significantly associated with NDD after controlling for other factors." I might also draw your attention to the reported finding that: "preterm birth and vaccination combined was strongly associated with NDD in the final adjusted model with interaction, more than doubling the odds of NDD compared to vaccination alone." This might suggest that there are synergistic variables at work influencing any identified risk continuing a research theme [4]. Indeed, the same authors have devoted a whole other article to this finding [5] (this paper also went through the same disappearing-reappearing act too).

Wearing the objective blinkers of science, this is by no means perfect research. Not only are there potential issues related to the use of an on-line questionnaire (and anonymous at that), the focus on subjective reports over inspection of more objective medical records (even though parents were asked to obtain and use their child's vaccination record(s) when completing the questionnaire), and problems associated with recall (including possible telescoping effects), there are a whole host of other issues that one could cite in relation to such research and potential biases that could/might have influenced the results (including factors such as this one). I might also add that the Mawson study did not appear to 'name names' when it came to which individual vaccines may or may not have been involved in their findings despite asking questions about if and when specific immunisations were administered to participants. Indeed authors noted: "We did not set out to test a specific hypothesis about the association between vaccination and health." Then there is also the 'reaction' angle to papers such as this one to mention; bearing in mind that science these days does not exist in some sort of social/cultural vacuum as per other very recent and very relevant examples. Cumulatively, you can see that there are issues and factors to consider, as there are in relation to other investigations in this still contentious area (see here).

Does then the Mawson paper therefore provide definitive proof of any link between vaccination status and NDDs including autism? No it doesn't, bearing in mind that science generally deals in probabilities over and above 'proof'.

Does the Mawson paper provide any relevant information on vaccination status and the variety of health outcomes included for questioning? Well, on this point I'm gonna cautiously say maybe; at least with the requirement for further scientific investigation. Bearing in mind the caveats discussed previously, it is interesting that the authors' analysis of those fully vaccinated, partially vaccinated and not-vaccinated for example, suggested something when it comes to risk of things like allergic rhinitis, ADHD, eczema, a learning disability, and NDD in a sort of dose-related pattern. This of course, could be due to chance, but without further study we don't or won't know. Yes, I know that the 'too many, too soon' question has already been discussed in the peer-reviewed domain and hasn't stood up well to scrutiny (see here) but perhaps further studies are indicated to confirm/refute such dose-related findings and if necessary, identify any potentially relevant mechanism that might be at work? I say all that with the realisation that something like allergy and atopic disease already has a potentially interesting relationship to the presentation of ADHD (see here) and/or [some] autism (see here).

Within the context of quite a lot of research indicating that, at a population level, vaccinations are pretty safe medicines and probably not linked to autism (possibly even protective when delivered under certain circumstances [6]) one has to be careful not to inflate the Mawson findings above what they currently represent on the hierarchy of scientific evidence. This was, by no means, perfect research. The fact however that this topic continues to be discussed in various parts of society (including the peer-reviewed domain) suggests that science might still have an important role to play in this area particularly in the context of the pluralised autisms (and other labels) and taking into account some chatter a while back about various 'kingdoms of autism'. But such investigations need to be done with care and without grand, sweeping statements being made that could undermine the vital service that immunisation provides to the population as a whole. The associated use of seemingly under-vaccinated populations such as homeschoolers for example, might also represent something of an 'under-used' natural research cohort to further enable more rigorous science to be conducted into such 'hot potato' research areas...

To close, and without too much chatter, Roald Dahl and his experience of measles. Not to scare, not to name-call, not to stigmatise, just to remember a time when measles was rife and for some, measles was deadly.

----------

[1] Mawson AR. et al. Pilot comparative study on the health of vaccinated and unvaccinated 6- to 12-year-old U.S. children. J Transl Sci 2017. 3.

[2] McClenathan BM. et al. Metabolites as biomarkers of adverse reactions following vaccination: A pilot study using nuclear magnetic resonance metabolomics. Vaccine. 2017; 35: 1238–1245.

[3] Thorpe EL. et al. Homeschooling parents’ practices and beliefs about childhood immunizations. Vaccine. 2012; 30:  1149–1153.

[4] Wang C. et al. Prenatal, perinatal, and postnatal factors associated with autism: A meta-analysis. Medicine (Baltimore). 2017 May;96(18):e6696.

[5] Mawson AR. et al. Preterm birth, vaccination and neurodevelopmental disorders: a cross-sectional study of 6- to 12-year-old vaccinated and unvaccinated children. J Transl Sci. 2017; 3.

[6] Berger BE. et al. Congenital rubella syndrome and autism spectrum disorder prevented by rubella vaccination - United States, 2001-2010. BMC Public Health. 2011; 11: 340.

----------

Anthony R Mawson, Brian D Ray, Azad R Bhuiyan, & Binu Jacob (2017). Pilot comparative study on the health of vaccinated and unvaccinated 6- to 12-year-old U.S. children Journal of Translational Science : 10.15761/JTS.1000186

Neuropsychiatric disorder onset "temporally related to prior vaccinations"?

"Given the modest magnitude of these findings in contrast to the clear public health benefits of the timely administration of vaccines in preventing mortality and morbidity in childhood infectious diseases, we encourage families to maintain vaccination schedules according to CDC guidelines."

The quote opening this post comes from the paper published by Douglas Leslie and colleagues [1] (open-access) and offers not a conclusion from their study looking at the possibility that "the onset of some neuropsychiatric disorders may be temporally related to prior vaccinations in a subset of individuals" but a caution that cause-and-effect were not 'proven' in their study. Anyone with any knowledge about previous occasions where administration of vaccines have been correlated with specific psychiatric or behavioural outcomes (see here and see here for examples) will recognise how important such a caution is, bearing in mind that vaccines are medicines (albeit preventative) and are subject to similar monitoring for safety and the small possibility of adverse effects as other medicines.

Based on the examination of "the MarketScan® Commercial Claims and Encounters database", a US drug and medical insurance claims database, researchers looked at various diagnoses of interest including OCD (obsessive compulsive disorder), AN (anorexia nervosa), anxiety disorder, tic disorder, major depression, bipolar disorder and ADHD (attention-deficit hyperactivity disorder) in children/young adults aged 6-15 years old. This alongside several other classes of diagnosis including broken bones and 'open wounds'. Participants were matched one-to-one with controls without said neuropsychiatric diagnoses and exposure(s) to various vaccinations - "influenza, tetanus and diphtheria (TD), hepatitis A, hepatitis B, meningitis, and varicella" - were 'tracked'. Interestingly, this is not the lead authors' first foray into using the MarketScan database [2], where autism was the previous topic of analysis (specifically healthcare service use and costs).

Results: bearing in mind that samples sizes varied according to those diagnoses under investigation, the authors report: "Receipt of any vaccine in the previous 6 months was highest for children with AN (21.4%), followed by OCD (15.9%) and tic disorder (15.8%), and was lowest for children with open wounds (10.3%)." This information needs to be treated carefully because - again - it tells us nothing about any cause-and-effect relationship, just correlation and trend; trends that could be there for all-manner of different reasons outside of the variables looked at. Further: "HRs [hazard ratio] associated with receipt of any vaccine were highest for children with AN... followed by OCD."

The authors also looked at specific vaccinations in relation to those neuropsychiatric disorders included in their study. They report: "Influenza vaccinations during the prior 3, 6, and 12 months were... associated with incident diagnoses of AN, OCD, and an anxiety disorder." Conversely: "children with major depression were less likely to have received the influenza vaccine in the previous 3 months" and "children with bipolar disorder were also less likely to have received the influenza vaccine in the previous 3 or 6 months."

OK, it is worth reiterating - yet again - that this was a study looking at possible associations and not necessarily cause-and-effect. Indeed, judging by that last paragraph and the table of HRs produced by the authors (see here) one might easily claim that flu vaccination might potentially shield someone from developing major depression as much as 'cause' AN, OCD and/or anxiety disorder. Such is the nature of such studies and the findings being reported. And indeed someone has actually looked at depressive symptoms (symptoms that is, not depression as a clinical diagnosis) before and after an influenza vaccination and found very little...

I note that with specific regard to the influenza vaccine and the findings that "children with AN, OCD, or a tic disorder were more likely to have received the influenza vaccine in the preceding periods" the authors head into the research talking about narcolepsy and the "AS03-adjuvanted H1N1 vaccine" as a possible template for their findings. This despite not covering the diagnosis of narcolepsy in their study (they could have). I've touched upon this area of research before on this blog (see here) (something that continues to appear in media discussions) and whilst not disputing the findings, do for example, wonder why in the work of Szakács and colleagues [3] ADHD was picked up as a comorbidity present in their "post-H1N1 vaccination (PHV) narcolepsy group" but in the Leslie data the HRs showed little evidence of any relationship. Yes, H1N1 vaccination is not necessarily the same as influenza vaccination reported in the Leslie data (we don't actually know what specific influenza vaccines were administered), but surely if discussions turn to an 'autoimmune' element as a possible mechanistic feature potentially linking vaccination and [some] neuropsychiatric disorder(s), one would expect to see the same/similar pattern of conditions being represented and reported? For balance, I should also point out that other independent study has talked about eating disorders potentially having "immune-mediated mechanisms" connected, particularly those associated with autoimmunity [4] although I don't doubt such a connection is likely complicated and probably not universally applicable.

It's not difficult to find issues with the Leslie paper and no doubt these will be emphasised in any further discussions about the data reported even when the authors stress throughout that "findings do not demonstrate a causal role of vaccination in the pathoetiology of any of these conditions." The strengths of the data - e.g. the use of that administrative database for confirming diagnoses and vaccine exposure - are worth mentioning again in light of other debates on data sources from other 'disappearing' manuscripts in this area. I might also add that by focusing in on various diagnoses but not autism (which again, they could have done) and not a certain vaccine, the authors seem well aware of the history in this area - "the association of the measles, mumps, and rubella vaccine with autism spectrum disorder has been convincingly disproven" - and probably either thought nothing more of it or chose to steer well clear of it (or perhaps a combination of both).

Is there a 'where next' when it comes to the Leslie data? To quote again from the paper: "findings require replication in a larger population-based sample, possibly including assessments of various potentially important host factors, e.g., the individual’s genomic and epigenomic background, the individual’s microbiome, their history of antecedent psychosocial stress, infections, as well as other potentially simultaneously administered vaccinations, the differences in vaccine types, and the route of administration (e.g., intramuscular or intranasal administration of influenza vaccine)." The scientific literature also provides some other avenues for further study in this area [5]. But science does not happen in a social vacuum; any further research needs to be done with care and focus. Mindful of both the important reliance on vaccination in protecting both the individual and population at large and mindful that sweeping generalisations (often emanating from scientific study) need to be minimised.

And on the topic of the research of Douglas Leslie, I'll be coming to another recent paper he published on the important issue of depression in parents of children diagnosed with autism [6] quite soon...

----------

[1] Leslie DL. et al. Temporal Association of Certain Neuropsychiatric Disorders Following Vaccination of Children and Adolescents: A Pilot Case-Control Study. Front Psychiatry. 2017 Jan 19;8:3.

[2] Wang L. et al. Healthcare Service Use and Costs for Autism Spectrum Disorder: A Comparison Between Medicaid and Private Insurance. Journal of autism and developmental disorders. 2013;43(5):1057-1064.

[3] Szakács A. et al. Psychiatric comorbidity and cognitive profile in children with narcolepsy with or without association to the H1N1 influenza vaccination. Sleep. 2015 Apr 1;38(4):615-21.

[4] Raevuori A. et al. The increased risk for autoimmune diseases in patients with eating disorders. PLoS One. 2014 Aug 22;9(8):e104845.

[5] Sadarangani SP. et al. "Let there be light": the role of vitamin D in the immune response to vaccines. Expert Rev Vaccines. 2015;14(11):1427-40.

[6] Cohrs AC. & Leslie DL. Depression in Parents of Children Diagnosed with Autism Spectrum Disorder: A Claims-Based Analysis. J Autism Dev Disord. 2017 Feb 18.

----------

Leslie DL, Kobre RA, Richmand BJ, Aktan Guloksuz S, & Leckman JF (2017). Temporal Association of Certain Neuropsychiatric Disorders Following Vaccination of Children and Adolescents: A Pilot Case-Control Study. Frontiers in psychiatry, 8 PMID: 28154539