Friday, 14 December 2018

Estimated one in 69 children aged 8 years old with autism (not one in 68) in 2012

"On June 5, 2018, the authors informed MMWR [Morbidity & Mortality Weekly Report] about a number of inadvertent errors throughout the report that resulted from reporting of autism spectrum disorder cases among persons who did not live in the geographic surveillance area."

So said a brief note [1] recently listed in the CDC Morbidity & Mortality Weekly Report (MMWR) concerning an important article published in 2016 [2] that described the estimated autism prevalence rate in the United States in 2012 for children aged 8 years old.

The original paper by Deborah Christensen and colleagues [2] was fodder for this blog at the time of publication (see here), with their estimated figures for 2012 (one in 68) showing a potential plateauing of the autism estimated prevalence rate in the US (see here for some discussion on the previous figures for 2010). The 'plateau' proved to be short-lived; as more recent figures published this year (2018) for the surveillance year 2014 once again showed the continuation of the upward trend (see here) in the childhood autism prevalence rate, now up to an estimated 1 in 59 children. Other figures have suggested even 1 in 59 is likely an understatement (see here).

Christensen and colleagues have republished their 2016 paper [3] showing 'where they went wrong'. It's not a wildly different article from their original publication and to a large extent, does not alter the underlying figures in any hugely significant way: 'one in 68' is replaced by 'one in 69'. Looking at the tables accompanying the Christensen republication, I was first drawn to Table 2 showing the: "Estimated prevalence* of autism spectrum disorder [ASD] among 1,000 children aged 8 years, by sex —Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2012." Under the column labelled "Total no. with ASD" it looks like a few participating States had corrections. Arkansas in particular stood out; their total going from 170 with ASD down to 125. Their estimated autism prevalence subsequently dropped from 12 per 1,000 children (aged 8) to 8.8 per 1,000. Other States showed a correction in the opposite direction. New Jersey (which has had an important role to play in the CDC estimates) showed a slight increase (of 3 children) in their "Total no. with ASD" similar also to Missouri.

There's little more to say about the Christensen correction aside from reiterating that: (a) the CDC statistics citing figures like 'one in 69' or more recently 'one in 59' are estimates, and (b) how and what data you include for counting is going to have an important bearing on what (estimated) prevalence rate you arrive at. By saying all that, I've not changed my view that we are witnessing something of at least a partial 'real' increase in cases of autism (see here and see here and see here) as older 'better awareness' and 'diagnostic substitution' arguments become less and less relevant as the numbers (estimated) climb ever higher. And aside from keeping on asking 'why?' the powers-that-be should be putting a lot more money and resources into the services that will inevitably be required, to ensure that children and adults on the autism spectrum aren't (societal) disadvantaged by their diagnosis.

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[1] No authors listed. Correction and Republication: Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2012. MMWR Morb Mortal Wkly Rep. 2018 Nov 16;67(45):1279.

[2] Christensen DL. et al. Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years--Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2012. MMWR Surveill Summ. 2016 Apr 1;65(3):1-23.

[3] Christensen DL. et al. PPrevalence and characteristics of autism spectrum disorder among children aged 8 years — Autism and Developmental Disabilities Monitoring Network, 11 sites, United States, 2012. MMWR Surveill Summ. 2018 Nov 16;65(13):1-23.

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Thursday, 13 December 2018

Middle ear infection and autism (again)

"Autism was more common in children who had had an otitis media infection or who had been treated with antibiotics."

Minus any sweeping generalisations, that was the conclusion reached in the study by Theresa Wimberley and colleagues [1] continuing some important research themes (see here and see here) examining any "interplay among otitis media, antibiotics, and the subsequent risk of developing autism."

Just in case you don't already know, otitis media infection refers to an infection of the middle ear that "causes inflammation (redness and swelling) and a build-up of fluid behind the eardrum." Aside from the use of painkillers, the seriousness of certain otitis media infections can sometimes mean that antibiotics are prescribed to combat any underlying bacterial infection or even in some cases, grommets inserted as treatment.

Wimberley et al report results based on "the entire Danish population", well, over three-quarters of a million children "followed from birth (January 1, 1997 to December 31, 2008) until December 31, 2012." They calculated various 'risk of autism' statistics as a function of a previous medical diagnosis of otitis media and "antibiotic prescriptions redeemed at Danish pharmacies." Yes folks, yet again those big data Scandinavian population registries have been used to good research effect.

Results: "The absolute risk of autism before age 10 was increased among children with otitis media (1.2% for females and 3.3% for males) and in children who had redeemed an antibiotic prescription (0.6% and 2.7% for females and males) compared to children without a history of otitis media and antibiotics usage (0.4% for females and 1.9% for males)." Researchers also reported finding "little evidence of a synergistic effect between otitis media infections and treatment with antibiotics" despite them being over-represented in relation to autism. They also caution that cause-and-effect cannot be inferred from their observational results.

What more can one say about the Wimberley findings? Well, echoing the idea that correlation is not the same thing as causation, I'd say that there is quite a bit more research to do on this topic. Further investigations are required into the possible mechanisms through which autism may manifest at least partially as a result of a history of ear infection (or indeed vice-versa). Mention of antibiotics also brings in areas of additional research interest such as the gut microbiome and what antimicrobials might 'be doing' to the trillions of passengers that are carried in the deepest, darkest recesses of the human body. I'm also minded to suggest that alongside antibiotic use to potentially treat infections like otitis media, researchers might also want to focus in on other medicines that might be accessed in such case such as over-the-counter pain relief in light of other *associations* that have been made (see here).

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[1] Wimberley T. et al. Otitis media, antibiotics, and risk of autism spectrum disorder. Autism Res. 2018 Oct 3.

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Wednesday, 12 December 2018

Elevated zonulin levels in ADHD = more hyperactivity and "impairment of social functioning"

"Children with ADHD [attention-deficit hyperactivity disorderhad higher serum zonulin levels and were more impaired in social functioning compared to controls."

So said the findings reported by Gonca Özyurt and colleagues [1] exploring a topic quite close to my research heart, zonulin and the assumption that "the level of zonulin increases when intestinal permeability is impaired."

Before heading further into the Özyurt findings, I'll perhaps refer you to some of my previous musings on the topic of zonulin (see here) and the hows-and-whys of this potentially important compound. It's rooted in the idea that intestinal permeability is perhaps rather more than it should be in some people with some labels (see here) and this *could* have some important implications for biochemistry and beyond; particularly the notion of a 'gut-brain' relationship (see here).

Özyurt et al examined zonulin in the context of attention deficit hyperactivity disorder (ADHD) based on the idea that: "Zonulin has been shown to be associated with social impairment in children with autism spectrum disorder" but such functions (and other attention-related behaviours) have not yet been looked at with ADHD in mind. Based on the examination of serum zonulin levels in some 40 kids diagnosed with ADHD and a similar number of not-ADHD controls, analysed via "enzyme-linked immunosorbent assay", researchers reported that: "Children with ADHD had higher serum zonulin levels and were more impaired in social functioning compared to controls." Also: "The level of zonulin was independently predicted with hyperactivity symptoms and SRS [Social Responsiveness Scalescores in regression analysis."

Bearing in mind that the Özyurt study was a fairly small scale study that utilised a methodology that has its critics (see here), I'm cautiously interested in the presented findings. I don't want to say anything further about this at the present time; aside that is, from the need for quite a bit more data on this potentially interesting relationship...

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[1] Özyurt G. et al. Increased zonulin is associated with hyperactivity and social dysfunctions in children with attention deficit hyperactivity disorder. Compr Psychiatry. 2018 Oct 29;87:138-142.

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Tuesday, 11 December 2018

Gut symptoms are important for 'psychiatric outcomes' in autism

"Individuals with autism spectrum disorder (ASD) are at heightened risk of psychiatric comorbidities across the lifespan, including elevated rates of internalizing, externalizing, and self-injurious behaviors." And: "Gastrointestinal (GI) conditions are of particular interest, as they are prevalent among those with ASD, may share genetic or neurobiological etiologies with the core features of ASD, and are linked with psychiatric difficulties in the general population."

Putting the issue of 'psychiatric comorbidities' and 'gastrointestinal (GI) conditions' together are the results of the findings reported by Emily Neuhaus and colleagues [1] who concluded that: "the presence and quantity of GI symptoms should be considered when evaluating psychiatric and behavioral concerns among children with ASD." Importantly too, they talk about how 'alleviating' accompanying bowel issues in the context of autism *might* also have some important influences on some of those psychiatric issues.

The starting point for Neuhaus and colleagues was a recognition that autism does not exist in some sort of diagnostic vacuum. This means that various 'comorbid' conditions/labels seem to be over-represented when it comes to autism, covering the behavioural/psychiatric (see here) and also the somatic (see here). The authors specifically zoomed in on GI symptoms because they've mentioned over and over and over again as being part-and-parcel of quite a few instances of autism (see here). Marrying the psychiatric and gastrointestinal together, they had two aims: "First, we sought to document the prevalence and variety of GI concerns within a large, well-characterized sample of children and adolescents with ASD. Second, we sought to understand relationships between ASD symptoms and GI concerns over and above the effects of psychosocial factors."

So, authors "draw on data from nearly 2,800 children and adolescents with ASD within the Simons Simplex Collection" pertinent to their aims and objectives. The Simons Simplex Collection (SSC) is no stranger to autism research for various reasons (see here and see here). Importantly too, the SSC is not stranger to specifically looking at GI issues in relation to autism (see here). They reported that: "Consistent with previous literature, families in the SSC frequently reported that their child with ASD had significant GI symptoms" to the tune of over one third of their sample experiencing at least one GI symptom.

Looking at their types of psychiatric symptoms - "internalizing, externalizing, and self-injurious behaviors" - they observed "evidence of unique variance associated with GI symptoms across all three measures of psychiatric symptoms we examined." This didn't mean that GI symptoms were 'the' [singular] cause of those psychiatric/behavioural issues; merely that the presence of such physical symptoms should be considered as one possible factor alongside things like "ASD symptoms, verbal IQ, adaptive behavior, family income." Given that something like self-injurious behaviour (SIB) can be pretty hard-hitting in terms of effects on the person and the people around them (see here), the idea that GI issues might be 'in the mix' alongside "more ASD symptoms, lower adaptive behavior, lower income" should not be ignored. To quote again: "levels of GI symptoms accounted for unique variance in psychiatric outcomes over and above these other factors, linking increased GI problems with increased psychiatric symptoms in children with ASD."

There is a further scheme of work to be followed in this important area.

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[1] Neuhaus E. et al. Gastrointestinal and Psychiatric Symptoms Among Children and Adolescents With Autism Spectrum Disorder. Front. Psychiatry. 2018. Oct 22.

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Monday, 10 December 2018

"the incidence of ADHD, ASD, and DD significantly increased after TBI events in early childhood"

TBI mentioned in the title of this post refers to traumatic brain injury, and represents the 'target variable' examined by Hsuan-Kan Chang and colleagues [1] in the context of rates of "attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and developmental delay (DD)."

Consistent with various other research published by this authorship group, the fantastic but sadly now defunct National Health Insurance Research Database (NHIRD) in Taiwan was the resource used by Chang et al in pursuit of their research goal. And the participant numbers under study reflected the use of the NHIRD: "A total of 7,801 and 31,204 children were enrolled in the TBI and control cohorts, respectively."

As well as instances of TBI being listed in the NHIRD "from 1998-2008", researchers also had access to "the incidence of subsequent ADHD, ASD, or DD (according to ICD-9 criteria)." They observed that: "The TBI cohort exhibited a higher incidence of subsequent ADHD, ASD, or DD than the controls" and that said developmental diagnoses tended to be made "at a younger age compared with the controls" (non-TBI controls). They concluded that TBI seemed to increase the risk of each developmental diagnosis and that "severe TBI, repeated TBI events, and TBI at a younger age" were all (variably) potentially important factors for the labels.

This is interesting and thought-provoking research. It does require some 'treading carefully' sentiments; not least with the idea that within the huge heterogeneity and variability of labels such as ADHD and autism (ASD), TBI *might* be a route or part of a possible route towards a diagnosis. Whilst not discounting the idea that sub-clinical signs and symptoms of developmental disorders could actually put someone at greater risk for TBI (see here for example), the possibility that TBI 'might lead to' a developmental diagnosis should not be shied away from. Indeed, other independent findings might also be important (see here). I say that mentioning that TBI is a general term that says nothing about the reason for the injury, the type of injury or what specific part of the brain may be affected. If one however takes autism as an example, it's not beyond the realms of possibility that certain TBIs could 'mimic' effects seen in other examples of 'acquired autism' where brain injury is part-and-parcel of the clinical picture (see here and see here). Indeed, similar sentiments have been expressed in relation to ADHD too (see here).

Whatever the relationship and mechanisms involved, the Chang findings imply that further investigations are needed in this area. Also, far greater efforts need to go into first preventing and then managing TBI...

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[1] Chang HK. et al. Traumatic Brain Injury in Early Childhood and Risk of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder: A Nationwide Longitudinal Study. J Clin Psychiatry. 2018 Oct 16;79(6). pii: 17m11857.

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Saturday, 8 December 2018

"Anti-Candida albicans IgG antibodies in children with autism spectrum disorders"

The quote titling this post - "Anti-Candida albicans IgG antibodies in children with autism spectrum disorders" - reflects the title of the paper by Paul Ashwood & Heather Hughes [1] who set out to "determine if children with ASD [autism spectrum disorder] exhibit elevations in antibodies that target C. albicans, indicating current or previous overgrowth of this fungal species." Such work is based on the still developing idea that "individuals with ASD have significant aberrations in the composition of their gut microbiota, known as dysbiosis" and part of that dysbiosis might also stretch to fungal as well as bacterial species.

Candida albicans also known as C. albicans is described as a 'opportunistic pathogenic yeast' quite readily observed in quite a large proportion of 'healthy adults'. For most people, this yeast does not cause any issues. On occasion however, C. albicans can lead to problems, particularly among those who are described as 'immunocompromised'. This is not the first time that C. albicans has been examined in the context of autism. Granted, the studies so far have been relatively small scale [2] and in requirement of follow-up [3] but this topic is no stranger to the peer-reviewed science literature. The Ashwood & Hughes paper should also be viewed in the context of other science discussions from this authorship group [4]; indeed several [5].

So: "We measured anti-C. albicans immunoglobulin (IgG) in plasma from eighty children enrolled in the UC Davis MIND Institute CHARGE study." IgG antibodies, represent 'immune status' with regards to a history of encountering specific pathogens. So, being positive to "anti-C. albicans immunoglobulin (IgG)" means that someone has been exposed to C. albicans at some point in their lifetime and retained something of an 'immune memory' to it. This subsequently means that your immune system is 'primed' in case that specific pathogen is encountered once again.

Results: "Plasma anti-C. albicans antibody positivity was found in 36.5% (19/52) of children with ASD. Anti-C. albicans antibodies in typically developing controls was (14.3%; 4/28)." I'm sure that you can see the disparity between the groups, bearing in mind that this was not an 'all-or-nothing' finding in relation to the separation of the groups. I should also mention that researchers also reported that gastrointestinal (GI) symptoms, also examined in this cohort, did not seemingly play a role in C. albicans antibody positivity.

Where next for this area of investigation? Well, alongside perhaps taking these results into consideration with other findings from this research group (see here), the authors mention that "exploring fungal composition within the gut as well as metabolic byproducts of yeast species such as d-arabinitol and ethanol, and identifying associations these might have with behaviors in ASD" could be one direction. In light of other independent research (see here), I'd say that was a sensible next step to take.

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[1] Ashwood P. & Hughes HK. Brief Report: Anti-Candida albicans IgG antibodies in children with autism spectrum disorders. Front. Psychiatry. 2018. Nov 26.

[2] Ekiel A. et al. Intestinal microflora of autistic children. Med Dosw Mikrobiol. 2010;62(3):237-43.

[3] Iovene MR. et al. Intestinal Dysbiosis and Yeast Isolation in Stool of Subjects with Autism Spectrum Disorders. Mycopathologia. 2017 Apr;182(3-4):349-363.

[4] Hughes HK. et al. The Gut Microbiota and Dysbiosis in Autism Spectrum Disorders. Curr Neurol Neurosci Rep. 2018 Sep 24;18(11):81.

[5] Hughes HK. et al. Immune Dysfunction and Autoimmunity as Pathological Mechanisms in Autism Spectrum Disorders. Front. Cell. Neurosci. 2018.

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Friday, 7 December 2018

"hold promise as cross-cultural key indicators for autism"

The quote heading this post - "hold promise as cross-cultural key indicators for autism" - comes from the paper by Sophie Carruthers and colleagues [1] which "aimed to identify the items on the Autism Spectrum Quotient (AQ)-Child that are most predictive of an autism diagnosis among children aged 4–9 years across samples from India, Japan and the UK." Attempting to fill quite an important 'hole' in the use of the go-to 'are you autistic' screener, authors set out to look at the presentation of autistic traits across three different countries, all with some quite different cultural perspectives and contexts.

The Carruthers paper is open-access so doesn't need too many grand discussions from me. The basics: "parent-reported AQ-Child data from India (73 children with an autism diagnosis and 81 neurotypical children), Japan (116 children with autism and 190 neurotypical children) and the UK (488 children with autism and 532 neurotypical children)" was the source material. Once again I'll mention how the term neurotypical is a misnomer (see here); it's use in this paper is all the more surprising given that one of the authors wrote an editorial paper [2] mentioning how "there is no single way for a brain to be normal, as there are many ways for the brain to be wired up and reach adulthood." Oh well.

Results: from the collected data, researchers were able to undertake various statistical analyses. Pertinent to the quote titling this post were some important findings "identified to be universal key indicators" across the different countries and cultures. These were: "In a social group, s/he can easily keep track of several different people’s conversations; s/he enjoys social chit-chat; s/he knows how to tell if someone listening to him/her is getting bored; s/he is good at social chit-chat and s/he finds it difficult to work out people’s intentions." Alongside, various other indicators were rated as "performed excellently or acceptably" across the three different country groups.

The conclusion: "Cross-cultural overlap in the items most predictive of an autism diagnosis supports the general notion of universality in autistic traits whilst also highlighting that there can be cultural differences associated with certain autistic traits." I'd like to see more research done in this area. Quite a few years ago I posed the question 'Is autism the same all over the world?' (see here) and well, I don't have a good answer despite the Carruthers and other results. Obviously such a question needs also to be wrapped in the idea that the plural 'autisms' also exert an effect (see here) and take into account other factors such as comorbidity (if that is the right word). It should also perhaps appreciate that whilst the AQ is undoubtedly 'picking up' something, it might not just exclusively be autism or autistic traits (see here and see here)...

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[1] Carruthers S. et al. A cross-cultural study of autistic traits across India, Japan and the UK. Molecular Autism 2018; 9:52.

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