"Gluten-free prescribing is in a state of flux"

Consider this off-core-topic post an extension of previous other off-topic chatter on this blog talking about the prescription of gluten-free foods here in Blighty (see here). On that previous blogging occasion, I discussed a 'head-to-head' debate on whether the prescription of gluten-free foods for conditions such as coeliac disease was still 'relevant' in an age when supermarkets have shelves loaded with gluten-free products as part of a societal fascination with 'going gluten-free'. Whether there may be other models - such as the use of a voucher scheme - that could save time and money yet still ensure that the important use of a gluten-free diet in relation to coeliac disease is maintained and supported.

Well, the recent findings reported by Alex Walker and colleagues [1] add to this debate, and their look at "long-term national trends in gluten-free prescribing, and practice and Clinical Commissioning Group (CCG) level monthly variation in the rate of gluten-free prescribing (per 1000 patients) over time." CCGs by the way, are groups here in England "responsible for the planning and commissioning of health care services for their local area."

Walker et al relied on a retrospective cohort study design that analysed prescribing and spending data from various sources, and covered various geographical areas of England in relation to gluten-free prescribing. Alongside, other potentially pertinent data were included in the statistical mix, for example: "Index of Multiple Deprivation (IMD) score; patients with a long-term health condition (%); patients over 65 (%) and whether each practice is a ‘dispensing practice’ with an in-house pharmacy service (yes or no)."

Results: including data from over 7600 medical practices, authors reported that between July 2012 and June 2013, some 1.8 million prescriptions for gluten-free products were dispensed costing around £25.4 million. Fast forward to the period July 2016 - June 2017 and fewer prescriptions were made: "1.3 million gluten-free prescriptions nationally... with a total expenditure of £18.7 million." This, bearing in mind, that rates of diagnosed coeliac disease are seemingly only going in one direction - up [2].

Researchers also reported that there was "substantial variation in prescribing rates among practices" which was captured by some other reporting on the Walker paper as per bylines such as: "Prescribing of gluten-free products in England differs largely and “without good reason”, researchers have concluded." Indeed Walker and colleagues concluded that much of the geographical discrepancy in the gluten-free prescribing rates was "driven at the CCG level, where there is also a great deal of variation." For some CCGs, the decision was to provide gluten-free prescriptions; for others, there seems to be "a partial or complete withdrawal of prescriptions." A bit of a postcode lottery if you like.

As to those other variables included in the analysis, a few other important details emerged. So: "practices in the most deprived areas had a significantly lower rate of gluten-free prescribing than those in less deprived areas." Further: "We also found that percentage of patients over 65 is strongly associated with gluten-free prescribing, which is unsurprising given that coeliac disease prevalence increases with age." That first finding in relation to deprivation *might* be linked to things like an under-diagnosis of something like coeliac disease in those areas. But it could point to other factors potentially coming into play as well...

At the time of writing / publishing this post, we are still living in the age of austerity here in Blighty. Government in particular, [still] wants to 'balance the books' yet is still expecting national services such as health to provide for the population they serve. Set within that context, and also how health budgets are having to deal with more people with more complex needs, it's probably not surprising that for some geographical areas, 'low hanging fruit' such as gluten-free prescriptions are seen as fair game when it comes to balancing the books. It shouldn't, but there you go.

I do stand by the idea that if things are seemingly 'on the downward slide' in terms of gluten-free prescribing patterns, there may be other models to look at that could help (i.e. that voucher scheme idea). Patients and their relevant organisations need to have a voice in this process to ensure that gluten-free diets are maintained and health does not unduly suffer. Food, for people with coeliac disease - gluten-free food - is medicine, and one should never forget that and the absolute requirement to provide such medical provision.

To close, and entirely unrelated to today's post, I see Belgium have some historical and/or statistical advantage when it comes to the World Cup starting soon...

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[1] Walker AJ. et al. Trends, geographical variation and factors associated with prescribing of gluten-free foods in English primary care: a cross-sectional study. BMJ Open. 2018 Apr 16;8(3):e021312.

[2] Holmes GKT. & Muirhead A. Epidemiology of coeliac disease in a single centre in Southern Derbyshire 1958-2014. BMJ Open Gastroenterol. 2017 Apr 1;4(1):e000137.

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Early lead (Pb) exposure and risk of ADHD: yet more 'nothing good comes from exposure to lead'

Lead (Pb) is a metal that has cropped up more than once on this blog (see here and see here and see here) in relation to early exposure and it's *possible* links to various childhood behaviour(s). As per part of the title of this post - 'nothing good comes from exposure to lead' - there really does seem to be very little good to say about exposure to lead (see here) given an apparent lack of any (advantageous) biological role when it comes to the human body. In short, we should be doing everything we can to ensure that exposure levels for everyone, particularly the very youngest, are kept to an absolute minimum...

The study results published by Yuelong Ji and colleagues [1] add to a pretty large peer-reviewed research literature observing a possible connection between biological lead levels "in early childhood" and risk of childhood psychopathology. They concluded that: "Elevated early childhood blood lead levels increased the risk of ADHD [attention-deficit hyperactivity disorder]."

The source material for the Ji study was the Boston Birth Cohort (a research initiative that has cropped up before on this blog) and specifically the examination of blood lead levels in conjunction with "physician-diagnosed ADHD" in some 1500 infants: "299 ADHD, 1180 neurotypical." Various other co-variates were also included in the statistical mix and sex/gender was analysed as an independent variable. And before you mention it, yes, as per my other musings on the word 'neurotypical' in the context of autism (see here), I'd prefer another term to denote not-ADHD such as er, 'not-ADHD'.

Results: approaching 1 in 10 of the cohort had elevated blood lead levels defined as a value between 5-10 µg/dL. This is quite worrying, particularly as various agencies have started to reduce the cut-offs/definition of a 'safe' level of lead in recent years (see here). For the 8.9% of the cohort with such blood lead levels, authors noted that this was "associated with a 66% increased risk of ADHD." Boys also seemed to be particularly vulnerable to the effects of elevated blood lead levels in relation to ADHD: "Among boys, the association was significantly stronger."

What else?  Well, bearing in mind the observational methodology employed in the Ji study, authors noted that the relationship between blood lead levels and ADHD also seemed to be mediated by other factors. So, the "risk of ADHD in boys was reduced by one-half if the mother had adequate high-density lipoprotein levels or low stress" where high-density lipoprotein (HDL) typically refers to the 'good type of cholesterol' (bearing in mind that biology is rarely so black-and-white) and 'low stress' refers to stress during pregnancy. In effect, whilst early lead exposure (or blood lead levels) may be important when it comes to risk of ADHD, other factors also seem to play a role; some potentially protective, others not so much (see here for example). This is something that has been noted in other studies looking at other heavy metals and neurodevelopmental outcomes (see here).

In conclusion, still nothing good comes from (early) exposure to lead...

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[1] Ji Y. et al. A Prospective Birth Cohort Study on Early Childhood Lead Levels and Attention Deficit Hyperactivity Disorder: New Insight on Sex Differences. J Pediatr. 2018 May 8. pii: S0022-3476(18)30488-8.

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Is 'escape' the most common function of challenging behaviours in autism?

'Challenging behaviour', 'disruptive behaviour' and 'behavioural crises' are terms that have been used to describe a range of behaviours "that are not culturally or socially acceptable, put the physical safety of the individual and/or others in jeopardy, affect learning, and/or limit access to community setting" in the context of autism and beyond.

A recent paper published by Esther Hong and colleagues [1] continued the research interest in this area (see here and see here) specifically focusing on gaining "perspective on what are the most commonly treated topographies of challenging behaviors" and "to identify the most commonly reported functions of those challenging behaviors." I'm assuming use of the word 'topography' in this context means 'profile' in terms of what types of challenging behaviours were noted.

Relying on behavioural data from over 3200 people diagnosed with an autism spectrum disorder (ASD) who were "receiving a minimum of 20 h of ABA [applied behavior analysis] treatment per month", researchers examined data on a range of behaviours falling into the category of 'challenging'. These included: "(a) aggression, (b) disruption, (c) elopement, (d) inappropriate sexual behavior, (e) lying, (f) noncompliance, (g) obsessive behaviors, (h) pica, (i) self-injurious behavior, (j) stealing, (k) stereotypy, (l) tantrums, and (m) teasing/bullying." Accepting that ABA in the context of autism is not everyone's cup of tea (despite some important data emerging [2]), one of the 'benefits' to this study at least, was that behaviour was recorded in some detail as a function of the implementation of ABA using something called The Skills™ database. This also allowed researchers to examine the potential 'function' of such behaviours too: "Skills™ also contains a field denoting the function of the behavior as identified by the supervising behavior analyst at the time of observation. Functions are classified as “attention,” “automatic,” “escape,” or “tangible.”."

Results: "The most commonly treated challenging behaviors were stereotypy, noncompliance, aggression, tantrums, SIB, elopement, disruption, and obsessive behaviors, respectively." Although 'stereotypy' ('the persistent repetition of an act) was the most frequently observed 'challenging behaviour', I'd personally be a little reluctant to put it into this category. I say this because there have been some reports suggesting that such a behaviour serves an important purpose in terms of being calming and aiding coping in certain situations for certain people. The majority of those challenging behaviours were coded most frequently in terms of 'escape' when it came to perceived function by the therapists who were doing the coding. Interestingly, and going back to my point about stereotypy, this behaviour was most frequently coded as 'automatic' alongside another behaviour that probably shouldn't be seen as a challenging behaviour: obsessive behaviours. Automatic, I assume, means just that: involuntary and well, automatic.

Alongside such information, authors also detail some nice Venn diagrams to illustrate how various categories of behaviours (and their specific manifestations) might meet and *correlate* based on their acquired data. Certainly, in the context of aggression and self-injurious behaviour (another important topic), there are some potentially important details to discern.

Although ABA still remains a point of contention among some, in the context of the Hong report, I can see how the quite detailed data collection on behaviour that it accrues holds some important information in the presence of some often, quite distressing behaviours. I'm happy to think that 'escape' could be a quite common function of various challenging behaviour(s), and moves to making 'some controlled escape' from particular situations might perhaps be useful to reduce the presence of such challenging behaviours. I know others will talk about 'demand avoidance' as being important too, but I'm cautious that this might not be an effective strategy in the longer term in helping people to build up 'resilience' to certain situations and environments.

But... I also think that 'escape' is not the whole story when it comes to challenging behaviours. I do still think that issues such as 'frustration' for example, can play a role. Also moving away from a purely 'behavioural' point of view, there is other evidence pointing to biology and physiology as being potentially involved in the presence of certain challenging behaviours. Fatigue? Yep, that's been mentioned (see here). Communication? Yep, that too (see here); particularly when verbal communication might be limited. And I'm also minded to mention that challenging behaviours can also be associated with things like the expression of pain (see here) that probably ties into the communication issue(s) too. In short, it's going to be complicated [3].

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[1] Hong E. et al. Topography and Function of Challenging Behaviors in Individuals with Autism Spectrum Disorder. Advances in Neurodevelopmental Disorders. 2018; 2: 206-215.

[2] Makrygianni MK. et al. The effectiveness of applied behavior analytic interventions for children with Autism Spectrum Disorder: A meta-analytic study. Research in Autism Spectrum Disorders. 2018; 51: 18-31.

[3] Rattaz C. et al. Challenging behaviours at early adulthood in autism spectrum disorders: topography, risk factors and evolution. J Intellect Disabil Res. 2018 May 24.

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Allergy and autism linked (again)

There was something rather timely about the publication of the result by Guifeng Xu and colleagues [1] observing that: "In a nationally representative sample of US children, a significant and positive association of common allergic conditions, in particular food allergy, with ASD [autism spectrum disorder] was found."

Timely, because earlier the same day I read a rather disparaging piece titled 'oversold diets' *trying* to condense down the findings reported by Gogou & Kolios [2]. This duo looked at the "current literature data about the effect of therapeutic diets on autism spectrum disorder", where certain diets are often put in place because of a perceived allergy or intolerance to certain foodstuffs and effects on behaviour and physiology. Gogou & Kolios concluded that: (a) "No serious adverse events have been reported" ('first, do no harm' and all that) and (b) the currently available peer-reviewed data on things like the use of a ketogenic diet and/or a gluten- and casein-free (GFCF) diet 'for' autism is promising but: "More research is needed to provide sounder scientific evidence." I agree that lots more resources and money need to be put into the scientific examination of such diets in the context of autism (see here and see here) including identifying potential best-responders [3]. I'd also like to see gastrointestinal (GI) issues included in the research agenda, in light of other promising peer-reviewed data too on a potential tie-up with said diets and autism (see here)...

Anyhow, back to the Xu findings, which have seemingly attracted some media attention (see here for example). The source of the data was the "National Health Interview Survey [NHIS] collected between 1997 and 2016", a US initiative designed to 'monitor the health of the United States population through the collection and analysis of data on a broad range of health topics'. Including parent or guardian responses on a questionnaire used as part of the NHIS, and specifically the questions: "during the past 12 months, has your child had (1) any kind of food or digestive allergy; (2) any kind of respiratory allergy; (3) eczema or any kind of skin allergy?", data was crunched for nearly 200,000 children.

Authors reported that as a total group (N=199,520), the weighted prevalence of food allergy being reported was about 4%. For a respiratory allergy, the prevalence came in at about 12% and 9% for a skin allergy.

Then to the autism vs. not-autism comparisons where: "A diagnosis of ASD was reported in 1868 children (weighted prevalence, 0.95%; 95% CI, 0.89%-1.01%)." Parents/guardians of those diagnosed with autism were significantly more likely to report all of those various allergies compared to the not-autism group. The figures were: food allergy (autism: 11.25% vs. not-autism: 4.25%), respiratory allergy (autism: 18.7% vs. not-autism: 12%) and skin allergy (autism: 16.8% vs. not-autism: 9.8%). Further: "After adjustment for age, sex, race/ethnicity, family highest education level, family income level, and geographical region, the OR [odds ratio] of ASD was more than doubled (OR, 2.72; 95% CI, 2.26-3.28; P < .001) among children with food allergy compared with those without food allergy." This last observation basically said that there was more chance of autism being reported among those with a food allergy than those without a food allergy.

Caveats? Well, a few to mention. First of all, you'll have noted the words 'parent or guardian responses on a questionnaire' being used, which need to be taken into consideration. No, I'm not casting any aspersions on reporting accuracy of anything like that (parents can be very sensitive to lots of things), but this was not a study of hospital records and tests or anything like that. Second is the use of the word 'allergy'. The medical definition of allergy (see here) is something like 'a biological response to a normally harmless substance'. Allergy is obviously immune-related and typically involves something called IgE (immunoglobulin E) among other things. Whilst some people might think they have an allergy to this, that or t'other, there is still some confusion about whether 'allergy' is the most suitable word in that context without for example, suitable allergy testing being undertaken. I might be being a bit pedantic, but words count...

That all being said, the Xu findings are not the first time that allergy and autism has been raised as being *associated* (see here and see here for examples). Indeed, allergic illness such as something like asthma, has quite a long association with autism (see here) and hints at a possible 'immune-related' connection to at least 'some' autism. That also one of the most common 'comorbid' conditions over-represented in relation to autism - attention-deficit hyperactivity disorder (ADHD) - seems to have an even stronger connection with allergy (see here) is also important to mention, and further strengthens some immune system involvement where there is diagnostic intersection. It also *might* have intervention implications too (see here) (with no medical advice given or intended)...

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[1] Xu G. et al. Association of Food Allergy and Other Allergic Conditions With Autism Spectrum Disorder in Children. JAMA Network Open. 2018; 1: e180279.

[2] Gogou M. & Kolios G. Are therapeutic diets an emerging additional choice in autism spectrum disorder management? World Journal of Pediatrics. 2018. May 30.

[3] Whiteley P. Nutritional management of (some) autism: a case for gluten- and casein-free diets? Proc Nutr Soc. 2015 Aug;74(3):202-7.

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"DNA methylation data from neonatal blood spots can be used to accurately predict age and maternal smoking status"

There were two primary reasons why I wanted to blog about the findings reported by Eilis Hannon and colleagues [1]: first, the focus of the study was "to identify DNA methylation biomarkers of ASD [autism spectrum disorder] detectable at birth", and second, the authors actually "identified robust epigenetic signatures of gestational age and prenatal tobacco exposure, confirming the utility of DNA methylation data generated from neonatal blood spots."

The first reason, looking at DNA methylation biomarkers in relation to autism, follows other similar initiatives down the years (see here for example) on the back of some significant interest in how "epigenetic variation induced by non-genetic exposures" might complement/fill in some gaps left by more traditional genetic studies. Epigenetics by the way, seemingly means different things to different people, but is currently summarised as "the study of heritable changes in gene function that do not involve changes in the DNA sequence." DNA methylation reflects one epigenetic process (there are others). The second reason - robust epigenetic signatures linked to gestational age and prenatal tobacco exposure - actually turned out to be the more important finding, or at least the more significant finding, reported by Hannon et al hence the title of this post...

'Guthrie cards' are mentioned as the starting material for the Hannon paper, and yet another hat-tip to a true medical pioneer, Robert Guthrie (and his team), who has saved multitudes of lives with his cards used to collect and store neonatal blood spots. As well as being used to screen for various potential inborn errors of metabolism (some of which seem to have something of a relationship with some autism), those archived blood spot cards have also proved to be important research fodder too (see here).

Hannon garnered neonatal methylomic data for approaching 1300 individual - "comprising equal numbers of ASD cases and matched controls, 50% male/female" - derived from "the iPSYCH case–control sample" based in Denmark. We are told that: "DNA methylation was quantified across the genome using the Infinium HumanMethylation450k array" bearing in mind this technique/system "only assays ~ 3% of CpG sites in the genome." Alongside: "Matched genome-wide single nucleotide polymorphism (SNP) genotyping data from the same individuals enabled us to undertake an integrated genetic–epigenetic analysis of ASD, exploring the extent to which neonatal methylomic variation at birth is associated with elevated polygenic burden for ASD."

Results: with regards to a neonatal methylomic 'signature' for autism or ASD, nothing significant was detected. Obviously one has to bear in mind the limitations of the assay/method used and the fact that blood from bloodspots represents only one type of tissue (DNA methylation patterns are not necessarily the same across different tissues). I was also interested to see the authors talk about "the chronology of sample collection prior to ASD diagnosis" and the 'plausability' that they were "looking too early on in the disease process." No, autism isn't 'a disease', but this work might provide some support for the idea that the processes and onset of autism is not always set either during conception nor during gestation (see here). Dangerous thinking for some people of a sweeping generalisation ilk...

Having said all that, researchers did talk about a "significant association between increased polygenic burden for autism and methylomic variation at specific loci" but I'd like to see replication of this effect before any big claims are made.

Then to those other findings of "robust epigenetic signatures of gestational age and prenatal tobacco exposure" and what that could mean to several different areas of research, autism and beyond. I'm a little surprised that the authors didn't make more of their 'robust findings' in their discussion of these results. I appreciate that their primary aim to "identify DNA methylation biomarkers of ASD detectable at birth" was not met with startling success but the suggestion of a tell-tale epigenetic sign of exposure to maternal smoking during pregnancy for example is, I would have thought, an important advance. Certainly one that could be at least relevant to various other studies, including those related to an important comorbidity that seems to be 'over-represented' in relation to some autism (see here) and perhaps more.

To close, it's not the first time that the Star Wars universe has been subject to peer-reviewed 'science' but the paper by Hatters Friedman and colleagues is an interesting one...

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[1] Hannon E. et al. Elevated polygenic burden for autism is associated with differential DNA methylation at birth. Genome Med. 2018 Mar 28;10(1):19.

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"ADHD was a risk factor for suicide attempt"

The findings reported by Kai-Lin Huang and colleagues [1] continue an important research theme (see here) on how a diagnosis of attention-deficit hyperactivity disorder (ADHD) may increase the risk of suicidal behaviours (see here). Further, that timely management of the symptoms of ADHD via indicated pharmacological means in particular, may provide some important risk-reduction from such behaviours; again substantiating previous investigations in this area (see here).

Based, yet again, on the fabulous but now sadly non-functional resource that is/was the National Health Insurance Research Database (NHIRD) in Taiwan, researchers undertook a "longitudinal cohort study [that] enrolled 20 574 adolescents and young adults with ADHD and 61 722 age- and gender-matched controls between 2001 and 2009." This is yet another example of Taiwanese 'big data' in action on the important topic of suicide (see here and see here). Alongside detailing any psychiatric comorbidities accompanying the diagnosis of ADHD, Huang and colleagues looked for diagnostic codes indicating suicide attempt(s) and whether or not medication(s) clinically indicated for ADHD were prescribed.

Results: "ADHD was an independent and direct risk factor for any suicide attempt, and an even stronger risk factor for repeated suicide attempts." As per my previous blogging forays into this topic, such news is by no means novel. The use of "long-term methylphenidate treatment" being associated with "a significantly decreased risk of repeated suicide attempts in men with ADHD" is also not new news, but does once more, provide yet more evidence for the use of such strategies and their seeming effects well beyond just symptom reduction/management.

What's more to say? Well, one might need to delve a little more into what it is about ADHD that *might* predispose to such extremes of behaviour. Whether this be a heightened risk of other comorbidity occurring as a function of ADHD (see here) impacting on suicidal behaviour(s) or something rather more directly linked to ADHD (see here), there is a schedule of further research to continue. I'm also minded to direct your attention to the findings reported by Mars and colleagues [2] and how general population 'risk factors' might also provide some clues. Minus any medical or clinical advice given or intended, I'll reiterate how the use of something like lithium seems to be quite useful in the context of potentially reducing suicide risk (see here) and how further work perhaps needs to be done on this compound with specific focus on suicide risk and ADHD. I say this, bearing in mind that lithium has a risk profile of its own.

Oh, and need I remind you that ADHD as being an 'over-represented' feature of autism for quite a few people (see here) might also imply some 'association' in the very serious statistics talking about suicide risk in the context of autism (see here)...

Again, if anyone needs to talk to someone, there are organisations out there willing to listen.

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[1] Huang KL. et al. Risk of suicide attempts in adolescents and young adults with attention-deficit hyperactivity disorder: a nationwide longitudinal study. Br J Psychiatry. 2018 Mar 4:1-5.

[2] Mars B. et al. What distinguishes adolescents with suicidal thoughts from those who have attempted suicide? A population-based birth cohort study. J Child Psychol Psychiatry. 2018 Mar 1.

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