Saturday, 23 June 2018

One in five 8-year olds "received a psychiatric diagnosis"

"Question: What is the cumulative incidence of psychiatric diagnosis and use of psychotropic medications in a Medicaid-insured birth cohort by age 8 years?"

Answer: About 1 in 5 children were in receipt of a psychiatric diagnosis at age 8, and about 10% were in receipt of psychotropic medication.

So said the findings reported by Dinci Pennap and colleagues [1] who relied on "Medicaid claims data for newborns in a mid-Atlantic state in 2007... and followed up for 96 months or less through December 31, 2014." As per the focus on Medicaid - an initiative that 'helps with medical costs for some people with limited income and resources' - this was a study conducted in the United States, and included data for over 35,000 infants/children. The sorts of psychiatric diagnoses examined by Pennap et al included "ADHD [attention-deficit hyperactivity disorder], disruptive disorders, learning disorder (LD), adjustment disorder, anxiety disorders, depression, ASD [autism spectrum disorder], and other psychiatric diagnoses" all diagnosed by a clinician, but also requiring "2 or more diagnosis claims on separate days."

Venturing further into the study results, we learn some potentially important details. So, across the years of study, approaching two-thirds of the diagnoses received were defined as 'behavioural'. As probably expected (see here), a diagnosis of ADHD was the most popular label - "accounted for 43.9% (1999 of 4550)" - followed by a learning disorder (disability) diagnosis received by just over 30% of the group. White children were seemingly more likely to receive any psychiatric diagnosis than African American children or Hispanic children, and there were some important sex/gender differences noted across various diagnostic labels. If I'm also reading the results correctly with regards to the label of ASD (autism spectrum disorder) (see here), it looks like about 2-2.5% of boys had received a diagnosis, bearing in mind that this is a figure showing as a percentage of those who had received a psychiatric diagnosis. As a function of the entire cohort (N=35,244), the cumulative incidence of ASD across the years (2007-2014) and across the genders was 0.89%.

Then to the issue of pharmacotherapy or medication prescription. Bear in mind that Pennap and colleagues were looking at psychotropic medication being delivered to infants and young children; a group where even greater caution than usual should be expected. They reported that just over 10% of the entire cohort had some history of psychotropic medication use. Alongside those stats on ADHD as a diagnosis, so the medicines classed as stimulants (indicated for ADHD) made up the biggest class of medication used. The authors also zoomed in on a few particular parts of their medication findings. First: "girls were twice as likely as boys to initiate treatment with anxiolytics and hypnotics (25.2% [173 of 686] vs 13.2% [199 of 1510]; P < .001)", also noting that "there is insufficient evidence to support the use of anxiolytics and hypnotics as first-line treatment for pediatric mental health conditions." Second, they discuss evidence suggesting that: "antipsychotics are largely used for off-label behavioral management in the birth cohort, highlighting the need for a delicate benefit-risk balance." Yes, indeed there is a need for exploring that 'delicate benefit-risk balance' (see here and see here). The other rather important finding concerned the use of more than one psychotropic medicine over a prolonged period of time: "approximately 20% of medicated children (433 of 2196 [percentage adjusted for right censoring]) received 2 or more classes concomitantly for 60 days or more." Remember again, these were young children that were under study.

The picture painted by Pennap et al is an important one. It adds to other independent evidence to suggest that across different geographies, psychiatric disorders including behaviourally and emotionally-defined conditions, are prevalent, dare I even say frequent (see here and see here). I'd also add in the 'yet newer' recent US CDC 'estimates' of autism in 8-year olds in this context too (see here).

In relation to the medication side of things, well, 10% of their total population have had some exposure to psychotropic medication, which is important. Accepting that (very) careful medicines management is required given the young age of the group, I'm gonna stick to a line that I've mentioned before regarding the clinical need for such medicines [generally] outweighing the risk(s). I say this on the basis that prescribing clinicians know their clinical population and know something about the risk-benefit profile of the medicines they're administering. I'd also add that when it comes to something like stimulants as a class of medicines, the clinical profile of such medicines is typically 'safe' (benefits outweighing risks) and can, in a few cases, literally be a life-saver (see here and see here). But all that does not mean that science shouldn't be looking to other avenues for intervention for various labels (see here and see here for examples), alongside keeping a sharp eye on ways and means of making such medicines even safer for such younger populations...

And just in case you thought the figure 1 in 5 only holds for the United States, you're wrong and resources and services here in Blighty are seemingly still struggling...

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[1] Pennap D. et al. Patterns of Early Mental Health Diagnosis and Medication Treatment in a Medicaid-Insured Birth Cohort. JAMA Pediatrics. 2018. April 30.

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Friday, 22 June 2018

"results support HLA involvement in ASD"

HLA mentioned in the title of this post - "results support HLA involvement in ASD [autism spectrum disorder]" - refers to the human leukocyte antigen (HLA) system. This is an important part of our biology that "helps the immune system distinguish the body's own proteins from proteins made by foreign invaders such as viruses and bacteria." Y'know, making sure that our immune system is able to correctly distinguish between 'self' and 'not-self' in terms of its decision on who to 'attack'...

The findings reported by Meriem Bennabi and colleagues [1] provide further analysis of the HLA system in the context of autism with their study designed to "more precisely explore the polymorphisms of the HLA class II loci, at allele, genotype and haplotype levels." Before further journeying through the Bennabi paper, I'll direct you to some other discussions I've had on this blog in relation to the HLA system and autism (see here). Specifically, how certain HLA links with autoimmune conditions such as coeliac disease, *might* overlap with some autism (see here). I'd also like to take this opportunity to remember one of the first people to look at the HLA in relation to autism [2]: the late Reed Warren.

The starting point for the Bennabi study was the idea that immune 'dysfunction' is no stranger to autism research. Indeed, the authors list three important 'immune-related' areas as evidence: "(i) a deleterious effect of prenatal or perinatal infectious pathogen exposure; (ii) a pro-inflammatory state often concomitant with abnormal cell-mediated immunity or inflammatory-mediated gut dysbiosis; (iii) a frequent autoimmune component observed in mothers of ASD off-spring as well as in ASD patients, with circulating anti-brain autoantibodies sometimes correlating with disease severity and/or behavior impairments." And yes, they did actually mention 'gut dysbiosis' too...

The authors move further into speculating about a possible role for the HLA system in some of those 'immune-related issues', and specifically whether subtle genetic differences to the HLA system might be involved.

"HLA genotyping data was available only for 474 ASD and 350 HC subjects on which the statistical analysis were performed." HC refers to the pretty awful term 'healthy control' which I, personally, dislike in the context of autism and other behavioural labels. Bearing in mind that I've already mentioned the classic 'diet affects physiology' autoimmune condition that is coeliac disease (CD), I note some important findings observed by Bennabi et al: "the HLA-DRB1 *11-DQB1*07 haplotype was more prevalent in ASD patients, versus HC (Pc = 0.001), partially replicating previous data and possibly linking to gastro-intestinal (GI)-related pro-inflammatory processes, given that this haplotype associates with pediatric celiac disorders." They also note that there may be a potentially 'protective' HLA haplotype too: "the HLA-DRB1 *17-DQB1*02 haplotype was higher in HC, versus ASD patients (Pc = 0.002), indicating that this is a protective haplotype." The stuff about linking autism related scores (function and severity of autism) with haplotype also documented by the authors are interesting but perhaps fodder for another blogging occasion.

So what might this all mean? Well, y'know when people talk about dietary gluten potentially showing a *relationship* with some facets of autism? They could actually be on the something. Whether that be the 'over-representation' of a formal diagnosis of coeliac disease in relation to autism (see here) or the idea that something 'not quite coeliac disease but something close' might be present (see here and see here), there is a peer-reviewed evidence base to consider. I know this kind of 'diet' research can furrow brows in some quarters, but peer-reviewed science is peer-reviewed science and well, there's already enough physical health inequality in relation to autism.

Alongside mention of the 'gut-brain axis', authors also discuss another potentially important area that may link to their results: "the involvement of the HLA system in wider physiological processes, including synaptic pruning." Yes, it is true that the HLA system probably does more than just serve as a 'pattern-recognition' system for differentiating between 'self' and invading pathogens and this could also be important to a diagnosis like autism. And there's more, as per another quote from the authors talking about... "the presence of the human endogenous retrovirus K (HERV-K) and increased expression of C4A molecules, with both related to excessive synaptic pruning during specific developmental windows." C4A is part of the complement system related to immunity. Going back to my mention of Reed Warren, he and his research group looked at another aspect of the complement system with autism in mind: C4B [3]. Talk about HERVs - human endogenous retroviruses - by Bennabi et al, is also a subject quite close to my heart (see here). HERVs have been investigated in the context of labels such as autism before (see here and see here) and whilst 'activation' of elements of such fossil viruses probably has many different effects, there has been some chatter about them being possible 'superantigens'. This in the context that whilst parts of these fossil viruses have been 'incorporated' into our genetic being and so considered 'self', there's always the possibility that they might be recognised as 'foreign' under certain circumstances and thus setting off an autoimmune cascade. That's the theory anyway...

The HLA system is not an easy system to get your head around. It's particular link to autoimmune conditions - where self is not recognised as self by the immune system - fits well with other research-based observations with [some] autism in mind. It does still require quite a bit of further investigation; and, bearing in mind the significant heterogeneity present in autism on various different levels, is probably going to be more relevant to some people diagnosed on the autism spectrum, than for others. But where one sees potential overlaps between the HLA system in autism and other autoimmune conditions like coeliac disease, one would assume a lot more research should be really be forthcoming...

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[1] Bennabi M. et al. HLA-class II haplotypes and Autism Spectrum Disorders. Scientific Reports. 2018; 8: 7639.

[2] Warren RP. et al. Immunogenetic studies in autism and related disorders. Mol Chem Neuropathol. 1996 May-Aug;28(1-3):77-81.

[3] Warren RP. et al. Increased frequency of the null allele at the complement C4b locus in autism. Clin Exp Immunol. 1991 Mar;83(3):438-40.

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Thursday, 21 June 2018

Do childhood sleep issues "have a causal role" in 'chronic disabling fatigue' in adolescence?

There's those words again: 'chronic disabling fatigue' or CDF, being used as a proxy for chronic fatigue syndrome (CFS, also known as 'ME') as per the findings reported by Simon Collin and colleagues [1].

Elements of this authorship group seem to be using CDF quite a bit (see here and see here) in their various research studies, and I have to say it's starting to get a little confusing (see here). I'll come back to my thoughts on the term CDF in a moment...

On this research occasion, Collin et al set out to explore whether "sleep might be a causal risk factor for CFS/ME" (or should that just be CDF) on the basis that sleep issues have been reported in that context previously [2]. Once again, "data from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort" was the research source material, and researchers were specifically looking at: "sleep patterns of children aged 6 months to 11 years, who were subsequently classified as having (or not having) 'chronic disabling fatigue'... between the ages 13 and 18 years." Sleep duration was quite a big element to this study.

So yeah, shorter night-time sleep duration from 6 months to 11 years of age did seem to show some connection to CDF. To quote: "The odds of CDF at age 13 years were 39% lower... for each additional hour of night-time sleep at age nine years, and the odds of CDF at age 16 years were 51% lower... for each additional hour of night-time sleep at age 11 years." This and a few other observations led authors to conclude that sleep abnormalities might have a role to play in relation to CFS/ME (sorry, CDF).

I have to say however, that I'm not particularly impressed with these findings. I say that on the basis that one set of variables (sleep) are being *correlated* with another later variable (CDF) and well, correlation does not necessarily equal causation. As per other work from this authorship group [2], they've also previously suggested that level of physical activity *might* also correlate with CFS/ME (sorry CDF) albeit with a reduced timescale between the variables. This dual research based on the same cohort I assume, kinda disqualifies any one variable from being related to CDF. Assuming that is, that sleep and physical activity are not somehow connected...

And then there's the issue of how sleep duration was measured in the latest Collin paper: "The sleep durations in our study were obtained from parents’ (mostly mothers’) answers to questions about the child’s usual bedtime and waking time, rather than from data collected in a sleep/wake diary or by actigraphy." So, they basically asked what time children went to bed and what time they woke up. There's nothing wrong with asking such questions but likewise there is little to confirm that children actually closed their eyes and nodded off the minute they went to bed and/or woke up the minute of parental report on waking. Anyone who has children knows that this is 'optimistic' at best (and indeed, takes no account of things like duration of night waking or quality of sleep for examples). The lack of use of actigraphy - that fabulous wearable tech that allows us to objectively chart sleep and activity cycles - is a real problem for elements of CFS/ME research (see here), and is something that is getting harder and harder to overlook. This includes the lack of use in this particular research study too.

Then, back to CDF. CDF basically comes about because we are told that "children in [the] study were not examined by a physician" when it comes to CFS/ME. Further: "CDF at ages 13 and 16 years was defined as fatigue (feeling tired or lacking in energy) of >6 months’ duration that was associated with absence from full-time school or that had prevented the child from taking part in activities ‘quite a lot’ or ‘a great deal’, excluding fatigue possibly associated with sport, snoring, and other illnesses." So fatigue is a primary symptom. But how can you exclude fatigue associated 'other illnesses'? Did the authors for example, screen for something like fatigue due to mitochondrial issues or disorders (see here)? No, they didn't appear to. Similarly there is no mention as far as I can see of another primary symptom of CFS/ME: post-exertional malaise (PEM). Important too was another quote from the authors: "Our definition of CDF did not exclude children with comorbid depressive symptoms." I'll say little more on this topic.

So, again, unfortunately I have to say that I'm left unimpressed by these latest findings from Collin and colleagues. And once again, I have to point out that CDF whilst described as "a proxy for chronic fatigue syndrome/ME" is not necessarily CFS or ME (and indeed, neither it seems, could it be both).

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[1] Collin SM. et al. Childhood sleep and adolescent chronic fatigue syndrome (CFS/ME): evidence of associations in a UK birth cohort. Sleep Med. 2018 Jun;46:26-36.

[2] Collin SM. et al. Physical activity at age 11 years and chronic disabling fatigue at ages 13 and 16 years in a UK birth cohort. Arch Dis Child. 2018 Jun;103(6):586-591.

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Wednesday, 20 June 2018

The International Classification of Diseases version 11 (ICD-11) has arrived...

Although peer-reviewed science research is the typical fodder for this blog, I am inclined to post about other important papers and/or events as they emerge. Today is such an occasion, as I draw your attention to an important announcement from the World Health Organization (WHO) recently titled: "WHO releases new International Classification of Diseases (ICD 11)."

Yes, this announcement covers the release of the the much anticipated ICD-11 system "for identifying health trends and statistics worldwide" also including "around 55 000 unique codes for injuries, diseases and causes of death." The ICD-11 schedule as it currently stands can be accessed here.

I might add that the release of ICD-11 is not the same as the 'roll out' of ICD-11, which are we informed "will come into effect on 1 January 2022." This 'advance preview' is basically a way of introducing the new schedule to the world and helping to facilitate a smooth transition from the version currently in use to this new system.

The ICD-11 has not been without some controversy as for example, a new condition known as 'gaming disorder' has been picked up by some media outlets (see here). Others have opined about the inclusion of "Traditional Medicine conditions - Module I" (see here) (where "disorders and patterns which originated in ancient Chinese Medicine and are commonly used in China, Japan, Korea, and elsewhere around the world" have been added in).

Relevant also to this blog - being a blog predominantly about autism research - is the entry on autism, and how the term 'Asperger syndrome' doesn't seem to figure (same as in the DSM-5). Instead, there is the umbrella term 'Autism Spectrum Disorder', complete with various sub-categorisation of diagnosis on the basis of intellectual development 'level' and functional language 'level'. The waning of the term Asperger syndrome is seemingly coincidental to the recent revelations about Hans Asperger (see here) but perhaps reflects long-standing 'doubts' about it's inclusion in previous versions of the diagnostic manual used (see here). There are other changes noted in ICD-11 which are also pertinent to autism (see here) including those relevant to the idea that a diagnosis of autism rarely exists in some sort of diagnostic vacuum (see here).

It's still very early days for the ICD-11 and so we'll have to wait and see what else emerges as physicians and the like across the globe come to terms with the revised schedule. I don't doubt that the evolving diagnostic nature of autism will also create discussions (and arguments) aplenty...

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Tuesday, 19 June 2018

"Greater ADHD symptom severity was associated with higher odds for feeling less happy"

Of course correlation does not necessarily equal causation, but the *correlative* results published by Andrew Stickley and colleagues [1] observing that: "Greater ADHD [attention-deficit hyperactivity disordersymptom severity was associated with higher odds for feeling less happy" were worthy of some blogging attention.

Drawing on data derived from the 2007 Adult Psychiatric Morbidity Survey based here in Blighty, researchers tackled quite an important question: how do ADHD signs and symptoms potentially impact on happiness?

So: "Information was collected on ADHD symptoms using the Adult ADHD Self-Report Scale (ASRS) Screener, while happiness was assessed with a single (3-point) measure." Including data for over 7000 people - adults aged 18 years and over - researchers observed that important negative relationship between ADHD symptoms and happiness. Alongside, they also noted that various other variables might also play a role in such a [correlative] relationship: "Mood instability (percentage mediated 37.1%), anxiety disorder (35.6%) and depression (29.9%) were all important mediators of the association between ADHD and happiness."

I'm a great believer that we need more of this kind of research asking relatively simple questions about whether someone is happy or not across various different labels and combinations of labels. I reiterate the whole 'correlation does not necessarily equal causation' mantra and the fact that happiness is not a 'setting' switched to the on position every moment of someones life. One also has to be slightly careful about extrapolating the Stickley results to diagnosed ADHD, and the various issues that come with such a diagnosis (including enhanced risk of comorbidity or 'symptoms' of other diagnostic labels).

But it strikes me as 'logical' that the manifestation of certain types of behaviour - hyperactivity, inattentiveness, impulsivity - might not be all that great for a person when it comes to perceived happiness at certain points in life. I say this in the context that a diagnosis of ADHD has already been *linked* to quite a few adverse life events (see here) including some enhanced risk for something like suicidality (see here). One has to wonder therefore, what role happiness might play in the context of such extremes of behaviour, and whether intervention 'for ADHD' (whatever form this might take) might have some important effects on subjective and objective markers of happiness alongside the manifestation of signs and symptoms...

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[1] Stickley A. et al. Attention-deficit/hyperactivity disorder symptoms and happiness among adults in the general population. Psychiatry Res. 2018 May 5;265:317-323.

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Monday, 18 June 2018

Selective mutism and autism

The findings reported by Hanna Steffenburg and colleagues [1] make for potentially important reading reporting: "In this study of a clinical group of children who were diagnosed with SM [selective mutismand assessed at a center for neurodevelopmental disorders, 63% also met criteria for ASD [autism spectrum disorder]."

Selective mutism (SM) refers to an anxiety disorder typically manifesting during early childhood that affects the use of spoken language in certain social situations such as at school. 'Literally being unable to speak' is a phrase that follows SM in certain contexts, where speech and language skills are not typically affected when and where family or close friends are around. It's not surprising that there is 'overlap' between SM and autism given the characterisation of SM in terms of being "nervous, uneasy or socially awkward" and "stiff, tense or poorly co-ordinated" (minus any sweeping generalisations). And just before you question it, 'poorly-coordinated' is perhaps an under-rated aspect for many people diagnosed as being on the autism spectrum (see here).

Steffenburg and colleagues - including the notable ESSENCE-related name of Christopher Gillberg - sought to examine the possible 'overlap' of SM and autism on the basis that various diagnoses/labels can occur alongside SM; quite a few of them also recognised in relation to autism (see here). Approaching 100 children/young adults diagnosed with selective mutism were assessed at the premier 'autism spectrum conditions' clinic in Gothenberg, Sweden. The clinical assessment undertaken of course covered the diagnosis of autism but also various cognitive functions too.

Almost two-thirds of those with SM who were assessed also met criteria for an autism spectrum disorder (ASD). Added to that: "A further 20% (n=19) had autistic features that were “subclinical”, but, nevertheless, sufficiently marked to have an impact on everyday life." Only 17% were described as having no ASD symptoms. Those are pretty interesting percentages.

Authors also mention how: "The level of cognitive function was average in more than half of the study group but more than one-third of the study group had a borderline IQ or an ID [intellectual disability]." They use such a finding in the context of the ESSENCE term - Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations - where overlapping diagnoses/labels is the rule not the exception.

The implications? Well, screen and keep a continual eye open for autism in cases of SM seems to be an important first implication. That also includes keeping in mind those 'subclinical' signs and symptoms, which could be relevant to discussions about the broader autism phenotype (BAP) (see here) and also that curious DSM-5 diagnostic category known as social communication disorder (SCD) (see here). The focus on 'anxiety' in relation to SM might also be important given the pretty well-established connection between autism and anxiety (see here for example) following in the footsteps of some often forgotten autism research history (take a bow Mildred Creak and colleagues for including the term "acute, excessive and seemingly illogical anxiety"). I'm also minded to mention that given the pretty high rate of autism described in SM by Steffenburg and other researchers, further investigations perhaps need to be directed towards shared biology/genetics as well as shared behavioural presentation? Y'know, along the lines of whether 'comorbidity' might be something more 'core' (see here)?

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[1] Steffenburg H. et al. Children with autism spectrum disorders and selective mutism. Neuropsychiatr Dis Treat. 2018 May 7;14:1163-1169.

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Saturday, 16 June 2018

ALSPAC says... "Social communication impairments had the strongest association with a depression diagnosis at age 18 years"

ALSPAC mentioned in the title of this post refers to The Avon Longitudinal Study of Parents and Children, one of the premier research initiatives here in Blighty, that has provided all-manner of interesting and important research associations. With autism in mind, ALSPAC has opined on various different research questions (see here and see here for examples) including the issue of a possible 'real' increase in the numbers of children presenting with autistic traits (see here).

On this particular research occasion, ALSPAC was the source data for the findings reported by Dheeraj Rai and colleagues [1] who set out to "compare trajectories of depressive symptoms from ages 10 to 18 years for children with or without ASD [autism spectrum disorder] and autistic traits, to assess associations between ASD and autistic traits and an International Statistical Classification of Diseases, 10th Revision (ICD-10) depression diagnosis at age 18 years, and to explore the importance of genetic confounding and bullying." I might add that some of this authorship group are making some real research waves when it comes to investigations using population registries with autism in mind (see here).

The starting point this time around was the notion that a diagnosis of autism is in no way protective when it comes to a diagnosis of depression and/or the expression of depressive signs and symptoms. Again, it's a topic that has cropped up before on this blog (see here) and is perhaps one of the longer term associations that have been made down the years. The idea that depression or depressive symptoms *might* be something much more than just 'comorbid' in the context of at least 'some' autism is something else that has been banded around the peer-reviewed research literature before (see here) but the evidence base is not particularly big or strong in this area at the moment.

There were a few different research questions asked by Rai et al, including looking at children "with or without ASD or high scores on autistic trait measures" and any relationship(s) with depression and depressive traits. They report findings for over 6000 children ("maximum sample with complete data") where questionnaire items on bullying were also included ("Relational and overt bullying was assessed as separate yes or no items at ages 8, 10, and 13 years using the modified Bullying and Friendship Interview Schedule") alongside various other potentially confounding variables.

Results: "children with ASD and those with higher scores on all autistic trait measures had more depressive symptoms at age 10 years than the general population, and these remained elevated in an upward trajectory until age 18 years." I don't think there's anything too novel in such findings, aside from the observation that depression / depressive symptoms may start quite early on in childhood. I can remember when I started out in autism research a couple of decades ago hearing about depression being typically linked to the onset of adulthood in the context of autism. This current data suggests otherwise.

Next: "Social communication impairments had the strongest association with a depression diagnosis at age 18 years. Findings were robust to adjustment for a range of confounders, including maternal depression and anxiety and the child’s polygenic risk for autism." This is important. What it suggests is that there may something 'more than just comorbid' about depression or depressive symptoms appearing alongside autism or at least in connection to certain autistic traits. I know some people have already taken exception to this possibility alongside the use of the word 'impairment' by the authors. But much like other research on an important bedfellow to depression - anxiety - one may have to entertain the possibility that there may be some enhanced 'predisposition' to something like depression alongside the presentation of autistic traits (see here and see here) perhaps mediated by factors such as rumination and perseveration for example [2]. This doesn't mean that depression is solely a product of autistic traits; merely that certain traits may potentially form an important vulnerability factor. I'm similarly minded to bring in other work from the ALSPAC initiative [3] (including Rai and colleagues as authors) where related findings were mentioned: "Social communication impairments are an important autistic trait in relation to suicidality." This on the basis that depression and suicidality show an important association.

Also: "We found evidence of a substantial role of bullying in contributing to and explaining a higher risk of depression in individuals with ASD and autistic symptoms." Bullying in the context of autism is another long-standing topic (see here). Bullying covers a lot of ground in terms of behaviour and also source (see here). The authors opine that: "Previous work has shown strong links between the experience of bullying and later depression... although confounding could have a role, the association is considered to be at least partially causal." It's also important to note that social-communication 'issues' were reported to be potentially predictive of being bullied according to the authors. The model that then appears hints that the appearance of depression *might* be linked to "reduced self-esteem or social isolation after the bullying" accepting that causality is not established and also not accounting for other variables: "other relevant characteristics, including comorbidities with neurodevelopmental conditions (eg, attention-deficit/hyperactivity disorder) and classroom placement could be important in this association within or outside the context of bullying." That last point is important in the context that autism rarely exists in some sort of diagnostic vacuum (see here).

There are a few caveats attached to the Rai findings that need to be kept in mind outside of any 'correlation does not necessarily equal causation' sentiments. So: "atypical presentations of depression are common in ASD, and our study has the potential for outcome measurement error because we used scales... that have not been adapted for autism." Indeed. I've previously talked about how bipolar disorder for example, might not follow a typical pattern when present in the context of autism (see here). I daresay that this could also hold for other types/forms of depression too. I'm also minded to reiterate that depression, as well as being a heterogeneous condition, also seemingly has many pathways to it. Some of those pathways will include psychological and social variables such as bullying and perhaps even more extremes of 'trauma'; where a diagnosis of PTSD is for example, no stranger to autism (see here). 'Happiness' and perceived quality of life (see here) are also likely to exert an important effect too.

Other pathways to depression seem to be more biologically defined as per depression in the context of physical ailments (see here) that may have a *link* to some autism (see here) or following the use of seemingly common medicines according to recent news reports (see here). I'll also mention that things like physical activity and exercise *seem* to show an important relationship with depression (see here). This could also be pertinent to the data suggesting that physical activity levels are typically not optimal where and when autism is diagnosed (see here). Other factors (fatigue, sleep, etc) also need to be mentioned in the context of depression. In short, there are lots and lots of potential variables to consider [4].

Outside of the important messages from the Rai findings on how depression is over-represented in relation to autism and how social factors like bullying seem to be linked  to it and thus are subsequently 'modifiable', there is another important point to consider: depression is typically treatable. Minus any medical or clinical advice being given or intended, the first step in managing/treating depression is identifying it. Perhaps the Rai findings might serve as a further call to action for preferential screening in the context of autism...

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[1] Rai D. et al. Association of Autistic Traits With Depression From Childhood to Age 18 Years. JAMA Psychiatry. 2018 Jun 13.

[2] Patel S. et al. Association between anger rumination and autism symptom severity, depression symptoms, aggression, and general dysregulation in adolescents with autism spectrum disorder. Autism. 2017 Feb;21(2):181-189.

[3] Culpin I. et al. Autistic Traits and Suicidal Thoughts, Plans, and Self-Harm in Late Adolescence: Population-Based Cohort Study. J Am Acad Child Adolesc Psychiatry. 2018 May;57(5):313-320.e6.

[4] Köhler CA. et al. Mapping risk factors for depression across the lifespan: An umbrella review of evidence from meta-analyses and Mendelian randomization studies. J Psychiatr Res. 2018 May 25;103:189-207.

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Friday, 15 June 2018

'What really grinds my gears': a "slight uptick' in the estimated prevalence of autism

For those who watch the sometimes 'cutting' TV show called Family Guy, the first part of the title of today's post - "what really grinds my gears" - will make sense. For those who don't, it represents a TV segment offered to one of the main characters of the series, Peter Griffin, during which he aired increasingly bizarre opinions of things that 'irk' him. At the close, he revealed that just about everything 'grinds his gears'.

Whilst I'm not typically a person that is easily irked (much of my early years irking has dissipated as a result of age and my hobby), I was a little put out by the opening sentence included in the news piece published by Bridget Kuehn [1] talking about the most recent autism estimated prevalence figures published by the US CDC [2] (see here for my take). To quote: "A slight uptick in US cases of autism spectrum disorders (ASDs) was detected in 2014 compared with the years between 2010 and 2012, according to a new CDC report."

It was the use of the word 'slight' that furrowed my brow. And how a 15% increase in the estimated autism prevalence rate in the US over 2 years - translating as a move from an estimated 1 in 66 8-years olds being diagnosed to 1 in 59 8-years olds being diagnosed - is somehow inferred to be less important than it actually was. Words matter.

I know prevalence (and incidence) rates (estimated or actual) when it comes to autism can invoke some often heated discussions. Such debates perhaps tie into wider views held about autism, and whether you're of the opinion that autism has always been with us, or autism is a relatively new 'condition'; whether autism is primarily explained by genetics or whether non-genetic environmental factors play a significant role; whether you view autism as a serious public health issue or are more inclined towards the idea of an 'autistic identity'. I'm sure there are other polar opinions to add, but the end result is that [peer-reviewed] data can sometimes become a secondary consideration when it comes to such views and opinions.

Personally, I go with the data. I go with the data that suggest that autism prevalence is still increasing, and not just in the United States (see here and see here for examples). I go with the associated idea that explanations such as 'increasing awareness' and 'diagnostic substitution' probably play some role in the increase, but don't provide a wholly intellectually satisfying explanation for the increasing numbers (see here and see here). I go with the idea that alongside increasing numbers of cases of autism being diagnosed, so more needs to be done in terms of the provision of educational and social support being offered for an often complicated clinical pictures (see here). I also go with the idea that research questions need to be asked (and answered) about what factors could be driving the remarkable increase in autism over the past couple of decades without fear or favour.

I also go with the idea that there needs to be a bit more urgency in the response to such figures. I'm not talking about the use of 'inflammatory' language or soundbites which are bound to make some people nervous or angry. Merely that behind the CDC statistics there are real children and there are families and other loved ones. And they deserve a lot more and a lot better than society is currently providing (see here)...

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[1] Kuehn B. Uptick in Autism. JAMA. 2018 Jun 12;319(22):2264.

[2] 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. Morbidity and Mortality Weekly Report (MMWR). 2018; 67(6): 1-23.

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Thursday, 14 June 2018

"Theme 3: Inadequate Provision for Post-diagnostic Support" for autism

The qualitative findings reported by Laura Crane and colleagues [1] on the topic of autism diagnosis here in Blighty provide some useful information that *could* help make the diagnostic process easier and more 'user-friendly'. The findings also highlight some important gaps in the current mechanisms being utilised...

The paper is open-access but basically set out to examine "the views and experiences of ten autistic adults, ten parents of children on the autism spectrum, and ten professionals involved in autism diagnosis, all based in the United Kingdom (UK)." You'll note that the participant numbers for each individual category weren't huge so one has to be slightly cautious about how representative the results are to the wider autism spectrum. Indeed, although not a fan of the term 'functioning' in relation to autism, I note that only two of the children were diagnosed with a learning (intellectual) disability and over half were diagnosed with Asperger syndrome. Alongside the report that of the 10 adults interviewed, nine were diagnosed with Asperger syndrome and several were educated to degree level or above (4/10), and you might reasonably conclude that this was a study weighted towards the more 'able end of the autism spectrum'. I say that again minus the use of the 'functioning' label but understanding that there are 'parts' of the autism spectrum still very much under-represented in this and other research areas (see here)...

No mind, the authors discuss the themes that emerged during telephone interviews with regards to "three important stages of the diagnostic pathway: (1) accessing a diagnostic service; (2) the diagnostic process; and (3) post-diagnostic support." The results are revealing...

I've zoomed in on one of the themes that emerged from the study: "Theme 3: Inadequate Provision for Post-diagnostic Support." I did this because this is the part of the diagnostic machinery that probably has the longest-term effects and has been covered before on this blog (see here). It's not that I don't for example, accept the importance of "vague and inconsistent routes available for accessing an autism diagnosis" or "professionals’ tendency to focus on negatives, not positives". Merely that post-diagnosis, many children and adults are seemingly left to fend for themselves and/or take up further battles in order to get the help and support they require. This, set in a time of increasing need and continuing finite resources (see here).

Within theme 3 around post-diagnostic services and support, we hear some familiar stories. So: "Getting the diagnosis is only the start of the journey and as far as the paediatrician was concerned, that was the end of the journey" and "[you need someone] to support you and direct you…this is where the system fails" are just two of the examples included in the Crane paper. In other words, tick boxes for getting assessments and diagnoses are ticked, but then 'don't let the door hit you on the way out' sentiments seemingly follow. That's not to blame assessment teams or diagnosing clinicians who do a sterling job often under pressure (see here), merely to point out how the system is current set out.

Another phrase included by the authors adds to the 'inadequate provision' sentiments expressed: "When services were made available to support autistic people and their families, these tend not to be offered until crisis point was reached." It seems that one has to be literally be at the end of ones tether before anything like the resources needed are given out, and even then, in a reactive sense. And thereafter: "when support was provided (and was felt to be useful), financial constraints sometimes meant that services were withdrawn". Such issues were seemingly spread across both child and adult experiences, as the call for "a solid, government-backed organisation that could help rather than these sort of variegated charities that are all struggling financially" went out. What a good idea: a national post-diagnosis autism agency...

I'm also going to highlight the 'lack of emotional support' picked up in the Crane paper. The adults diagnosed with autism certainly "found their involvement in the assessment process both emotional and challenging" because sometimes the very probing questions used as part of the assessment process brought up things that some people were probably trying very hard to forget. I personally think that this is an under-appreciated side of post-diagnosis in the context of autism, where the diagnosis of post-traumatic stress disorder (PTSD) is perhaps 'under-used' (see here) in light of the effects of past traumas (I use the word 'trauma' minus the psychobabble connotations).

Crane et al also provide a dose of reality in terms of what parents go through too before, during and after the diagnostic process for their children. So: "I was literally on my knees anyway…it’s so tiring having boys with Aspergers" and "I felt quite on my own. No-one in my family really understood, I didn’t have any friends that had had similar experiences." Such reports are just as important as the other reports included in their study; illustrating how having a child diagnosed with autism can be a roller coaster of emotions, and the strong requirement for "whole family support needs" including things like respite care (see here). I say all this set against a backdrop, particularly on social media, where parents are sometimes/often castigated for speaking their truth and their reality about raising children on the autism spectrum, seemingly because their narrative doesn't fit the agenda of others. Yes, the views of people with autism / autistic people count, but so do the views of those who raise them too (see here). And social media 'discussions' for example, about 'informed consent' before posting pictures and reciting specific child-rearing events, whilst important, cannot just be solely applied to parents of autistic children either...

There are seemingly lots of things that can be done to improve the diagnostic and post-diagnostic experiences related to autism on the basis of the Crane findings. One would hope that policy - (peer-reviewed) evidence-based policy - would be listening and wanting to change things for the good of all concerned: those on the autism spectrum, their parents and other loved ones and the professionals who do a remarkable job with all-too finite resources. I fear however, that the reality is yet again going to be tied into one solitary question; a question that crops up time and time again: how much is it all going to cost?

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[1] Crane L. et al. Autism Diagnosis in the United Kingdom: Perspectives of Autistic Adults, Parents and Professionals. J Autism Developmental Disorders. 2018. June 12.

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Wednesday, 13 June 2018

"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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Tuesday, 12 June 2018

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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Monday, 11 June 2018

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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Friday, 8 June 2018

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 ratioof 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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