Tuesday, 17 July 2018

The prevalence of autism in China meta-analysed

"Based on diagnostic criteria the pooled prevalence of ASDs [autism spectrum disorder] was 39.23 per 10,000... specifically, the prevalence of autism was 10.18 per 10,000."

That was the conclusion reached by Fei Wang and colleagues [1] following their "comprehensive meta-analysis of the pooled prevalence of ASDs in China" based on data from 44 studies comprising about 2.3 million people aged below 18 years of age. Relying on data published from database inception up to February 2017, authors trawled the peer-reviewed scientific domain  - "PubMed, EMBASE, PsycINFO, China National Knowledge Infrastructure, Chinese biomedical literature service system (SinoMed) and Wan Fang" - looking for pertinent articles regarding the epidemiology of autism in China. Their results covered "30 provinces/ municipalities/ autonomous regions in China" and were in the most part conducted in the 21st century. A few studies (n=7) were rated as being of 'high methodological quality' with the remaining meeting guidance for 'moderate quality'.

Accepting that diagnosis via DSM or ICD was not the only inclusion criteria - also including "screening tools [such as the Clancy Autism Behavior Scale (CABS), Children Autism Spectrum Test (CAST) and Checklist for Autism in Toddlers (CHAT)]" - the collected figures arrived at 0.39% and 0.01% for ASD and autism are quite a bit lower than we're typically used to seeing. Take for examples, the most recent stats from the US CDC on [estimated] ASD prevalence (see here) talking about 1.7% of 8-year olds diagnosed with autism or the data from Northern Ireland (see here) (2.9% of school-aged children), and you can see quite a stark difference. Only when Wang took into account the prevalence of ASD solely based on those studies utilising screening tools does the figure of 429.07 per 10,000 equating to 4.29% look anything like the data from those other countries.

What could all this mean? Well, we do have to be a little careful not to read too much into these collected statistics. As per another paper [2] published at roughly the same time as the Wang paper, there may be various factors - 'challenges' - influencing the particular status of autism screening and case ascertainment in China that might need consideration. As far as I can see, there is for example, no national screening guidance for autism covering all of China, so "inconsistencies in screening and diagnostic procedures... and discrepancies between diagnostic criteria" are going to be potentially significant variables. Indeed, other studies have pointed to a 'high prevalence rate of suspected autism' in some parts of China (see here) which is directly contrary to the Wang findings. Alongside other potentially important factors such as 'willingness' to screen for autism and socioeconomic factors influencing 'ability' to screen for autism, and the picture that emerges is a complicated one.

But... one also has to entertain the possibility that the prevalence of autism in China *might* be different to other countries around the globe. I've kinda touched upon this quite recently (see here). I don't want to speculate too much about why this might be at this point, but some combination of genes and elements of environment could be relevant (see here) with lots more science to be done...

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[1] Wang F. et al. The prevalence of autism spectrum disorders in China: a comprehensive meta-analysis. Int J Biol Sci. 2018 May 12;14(7):717-725.

[2] Pang Y. et al. Challenges of case identification and diagnosis of Autism Spectrum Disorders in China: A critical review of procedures, assessment, and diagnostic criteria. Research in Autism Spectrum Disorders. 2018; 53: 53-66.

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Monday, 16 July 2018

"A strict and lifelong gluten-free diet can help recover vitamin D level without any supplementation"

The quote titling this post - "A strict and lifelong gluten-free diet can help recover vitamin D level without any supplementation" - comes from the results published by Fabiana Zingone & Carolina Ciacci [1].

These authors inspected the peer-reviewed literature looking at vitamin D levels in relation to the archetypal 'diet can affect health' autoimmune condition that is coeliac (celiac) disease. They looked at both something called calcifediol, otherwise known as 25-hydroxyvitamin D (25(OH)D), and also something called calcitriol, also known as 1,25-dihydroxyvitamin D3. The difference between the two 'forms' of vitamin D is that one represents the 'pre-hormone' version  - (25(OH)D) - that is typically quantified to give a 'where you're at' measurement of biological vitamin D levels, and the other - 1,25-dihydroxyvitamin D3 - is the 'active' metabolite. Through the wonders of something called mass spectrometry, these and other 'forms' of vitamin D are able to be quite accurately measured [2] in various biological fluids.

Zingone & Ciacci reported that "most of the studies on vitamin D in adult CeD [coeliac disease] report a 25 (OH) vitamin D deficiency at diagnosis that disappears when the patient goes on a gluten-free diet, independently of any supplementation." This finding really intrigued me. It got me thinking of a few things; notably about mechanisms and biological relationships and indeed, how applicable such a finding could be to the general 'not coeliac' population or those 'around the diagnostic edges' of CeD.

OK, it should be noted that part-and-parcel of CeD is an issue with malabsorption, where 'the body does not fully absorb nutrients' (see here). The inflammatory processes at work in CeD do some pretty awful things to the structure and functioning of the mucosal lining of the bowel which aren't really conducive to optimal absorption of nutrients from food. The implementation of a gluten-free diet does help matters; and so logic dictates that absorption of something like vitamin D from food sources will be improved when a gluten-free diet is implemented. I've also blogged about how this process *may* also be part of the effect noted in relation to [some] autism and the use of similar dietary intervention strategies (see here). Alongside, I'll mention that, done right, a gluten-free diet is actually not the most unhealthiest diet in the world either.

Having already sort-of mentioned something like non-coeliac gluten/wheat sensitivity in the contest of the 'diagnostic edges' of CeD, I do wonder if there could be a further plan of research there too. Y'know to look at questions like whether such not-quite-coeliac-disease conditions also (a) manifest as having low levels of vitamin D when not diet treated and (b) whether the use of a gluten-free or other diet (see here) might similarly positively effect vitamin D levels in those circumstances?

There's also another potentially important explanation to consider which was tweeted by Dr Emily Deans (she of the fabulous Evolutionary Psychiatry blogs): could vitamin D deficiency be a marker of something more general? To quote from Dr Deans' tweet (shown pictured above): "Because it’s [vitamin D] an inverse acute phase reactant and goes down with illness and up with health." There is some sound logic behind such an observation insofar as vitamin D insufficiency/deficiency being associated with all manner of physical and behavioural/psychiatric diagnoses/conditions/states (see here and see here for examples). Correction of vitamin D deficiency is all well and good when it comes to correcting biological measures, but outside of treating something like rickets, the evidence for extra-skeletal effects from such supplementation is currently not that great.

Finally, I'll draw your attention back to some work suggesting that vitamin D might itself have some interesting effects on gut barrier function (at least in mice) (see here). One wonders what this could also mean for CeD and the spectrum of gluten-related issues?

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[1] Zingone F. & Ciacci C. The value and significance of 25(OH) and 1,25(OH) vitamin D serum levels in adult coeliac patients: A review of the literature. Dig Liver Dis. 2018 Apr 13. pii: S1590-8658(18)30702-3.

[2] van den Ouweland JM. et al. Vitamin D and metabolites measurement by tandem mass spectrometry. Rev Endocr Metab Disord. 2013 Jun;14(2):159-84.

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Saturday, 14 July 2018

Shocker alert: gut problems in autism impact on sleep (again)

"Increased odds of sleep problems were most frequently associated with gastrointestinal distress (GID) and non-verbal IQ (NVIQ), followed by male sex and age."

That was one of the findings reported by Ann Johansson and colleagues [1] who set out to examine "the relationship between sleep problems and characteristics of children with ASD [autism spectrum disorder] in a large, nationwide sample." Mention of the words 'Simons Simplex Collection' in the Johansson article provides a clue as to the source population examined in this study and some of the hows-and-whys of the research. From what I also understand, this paper is part of a doctoral thesis by Johansson looking at some of the possible genetics of sleep with autism in mind (see here). Indeed, if one scrolls to page 70 of the thesis, one finds the study in question...

The Simons Simplex Collection Sleep Interview (SSCSI) was the instrument of choice for assessing sleep issues. This is a short parent-report questionnaire that includes both a composite score for total sleep issues and subscale scores for things like 'sleep duration issues'. Alongside, GID was classified "if they were reported (yes/no) to have bloating/excess gas, celiac disease, constipation, diarrhea, ulcers, gastroesophageal reflux disease, inflammatory bowel disease (Crohn’s disease, ulcerative colitis), irritable bowel syndrome, abdominal pain, unusual stools, vomiting, and/or other GID." Throw in scores on the ADOS "used to measure ASD severity" and crunch the data...

I've inserted the word 'again' into the title of this post because this is not the first time that functional gastrointestinal issues 'over-represented' in autism have been connected to sleep issues (see here). This time around, researchers mention that over 40% of their cohort (2000+ children) "were categorized as having mild or moderate/severe sleep problems" according to their SSCSI composite score. 'Difficulty falling asleep' seemed to be one of the more frequently reported issues. GID - gastrointestinal distress - was the strongest factor linked to sleep issues (odds ratio = 2.79), again based on the SSCSI composite score for sleep issues. There were other combinations of symptoms potentially linking to sleep noted by the authors but I'm minded to put them to one side for now.

Caveats? Well, one big caveat sticks out: the reliance on parent-reported responses to a questionnaire about sleep without any reference to objective measures of sleep. I've gone on and on (and on) about the use of actigraphy when it comes to sleep research relating to various diagnostic labels (see here and see here for examples) and well, keep coming to the same conclusion about a strong requirement for such objective measures on sleep-wake cycles. I appreciate that there may be some 'consumer resistance' to wearing a wristband for example, to measure activity and rest cycles (see here), but surely someone, somewhere can engineer something when kids don't want to wear such gadgets? Insofar as the classification of GID also relying on parental report, I'm a little kinder to this because the evidence is pretty good for suggesting that parents might be tuned into what is typical and what is not typical from a functional bowel habits perspective in their offspring (see here)...

No mind, the results do accord with other independent data on how gut issues present in autism can seemingly have some far-reaching effects. As to 'how', well, I would always start with the obvious explanation: pain and discomfort caused by bowel issues affecting sleep, and then work back from there. Indeed, as if I need to say it again, bowel issues (both functional and more pathological) are truly 'over-represented' when it comes to a diagnosis of autism (see here) and science and clinical practice really need to do a lot more to tackle such issues as and when they are reported/detected...

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[1] Johansson AEE. et al. Characteristics of sleep in children with autism spectrum disorders from the Simons Simplex Collection. Research in Autism Spectrum Disorders. 2018; 53: 18-30.

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Friday, 13 July 2018

"little evidence for the involvement of Mg2+ in the mood disorders"?

Mg2+ described in the title of this post refers to magnesium, a mineral that participates in quite a few important biological reactions in the human body. Outside of its proposed involvement in a variety of somatic conditions and diagnoses, a deficiency in magnesium has also been *linked* to various psychiatric and behavioural issues too (see here). The findings reported by Danny Phelan and colleagues [1] however, stress caution in making too many sweeping generalisations on the basis of the currently available peer-reviewed data, albeit with hints that magnesium might have some role to play for some...

The name of the research game for Phelan et al was 'systematic review and meta-analysis', which basically means identifying, collating and 'boiling down' the [currently available] relevant research into some sort of coherent whole. Some 58 research articles including over 45,000 participants were used for 'quantitative synthesis' across a variety of different effects: the prevalence/incidence of depression as a function of magnesium intake, magnesium levels as a function of mood disorder status, magnesium concentration according to mood disorder severity and mood disorder status as a function of magnesium treatment. The results were interesting...

"Adherence to a diet high in Mg2+ was associated with a lower prevalence of depression in cross-sectional studies... but not in longitudinal cohorts that assessed the incidence of new-onset depression." Taking into account the difference in study design, this finding translates as a suggestion that "dietary Mg2+ intake may play a part in the pathology of depression" with the caveat that cause-and-effect was not proven. Accepting also that 'depression' as an umbrella term covers quite a bit of diagnostic ground, authors observed that: "There were no studies which reported on the effects of dietary Mg2+ on symptoms of bipolar disorder" so no conclusions can be currently formed either way.

Next: "Against expectations, we found higher Mg2+ levels in bodily fluids in patients with a mood disorder relative to healthy control subjects." This is a peculiar finding and one that needs further explanation beyond possibly just reflecting "the hypothesis that an increase in Mg2+ may underlie the clinical efficacy of (fast-acting) antidepressants" or dehydration *caused by* the use of pharmacotherapy indicated for mood disorders. I might add that such a findings could just be indicative of magnesium showing a epiphenomenal relationship with mood disorder too.

Finally: "In line with expectations, we found that treatment with Mg2+ supplements was associated with a decline in depressive symptoms." The authors yet again mention that study design/type may have something to do with the results observed; in particular, that a such an effect seemed to be confined to those studies with no placebo condition.

I was initially a little unsure about the 'cautiousness' expressed by Phelan et al on a possible role for magnesium in [some] mood disorders. Statements like: "Our results provide little evidence for the involvement of Mg2+ in the mood disorders" didn't seemingly really reflect the findings being reported on, but with a bit of further critical thinking I've changed my tune a bit. I would still perhaps argue that it would have been more accurate to say something along the lines of 'there is evidence out there for an effect on dietary magnesium potentially being associated with a lower instance of depression but that evidence is not as methodologically strong as one would hope'. But oh-um. Certainly I think we can conclude that there is an additional scheme of research to follow to aid in future position statements on this topic.

And then there is the question of 'why?'. Why should magnesium affect mental health? And what about any effects from various 'different types' of magnesium available?

To close, I've linked to this before but here it is again: possibly the best opening to a film ever...

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[1] Phelan D. et al. Magnesium and mood disorders: systematic review and meta-analysis. BJPsych Open. 2018 Jul;4(4):167-179.

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Thursday, 12 July 2018

Risk of poisoning in ADHD: meta-analysed

There was something inevitable about the results published by Maite Ruiz-Goikoetxea and colleagues [1] looking at the currently amassed scientific data "quantifying the risk of poisoning in children/adolescents with ADHD [attention-deficit hyperactivity disorder]."

Inevitable, because the results of their meta-analysis observing that "ADHD is associated with a significantly higher risk of poisoning" kinda tallies with other enhanced risk(s) in relation to general injury coinciding with this diagnosis, mentioned by the same authorship group (see here).

Poisoning - "defined by the World Health Organization as “an injury that results from being exposed to an exogenous substance that causes cellular injury or death”" - covers quite a bit of ground. The authors headed into this particular topic on the basis of their previous research foray (which I blogged about) on meta-analysing injury risk in the context of ADHD [2]. They started out with the premise that "a plausible hypothesis is that ADHD symptoms (inattention, hyperactivity and impulsivity) could lead to a similar increase in the risk of poisoning."

Nine studies including some 85,000 children and adolescents diagnosed with ADHD and 1.4 million not-ADHD controls, were included in their meta-analysis. Diagnosis of ADHD were garnered from various sources but most commonly 'administrative coding' on the basis of diagnosis and/or medication being dispensed for ADHD. Exposure to a poisoning event was also analysed; predominantly based on the use of registry data and predominantly utilising the ICD classification of poisoning.

"Overall, poisoning cases were uncommon" is an important point made by the authors; indicating that the absolute numbers of poisoning cases in ADHD and not-ADHD were actually low. So: "The median number per study of poisoned individuals that suffered from ADHD was 14..., whereas the median number per study of poisoned individuals who did not suffer from ADHD was 29." Bearing in mind there were more not-ADHD participants than diagnosed ADHD participants cumulatively reviewed by Ruiz-Goikoetxea et al, the calculated prevalence rates (per 1000) of poisoning "ranged between 3.5 and 60 (median 16) in children and adolescents with ADHD and between 0.8 and 37.3 (median 4.8) in children and adolescents without ADHD."

Still, the calculated risk - relative risk - was elevated in relation to poisoning events in those diagnosed with ADHD to the tune of something like them being three times more likely to suffer a poisoning event. Authors also noted that: "the relative risk of poisoning in individuals with ADHD compared to individuals without it was statistically higher than the overall relative risk of physical injuries" thus hat-tipping their previous research efforts.

There are some other details included in the Ruiz-Goikoetxea that are noteworthy insofar as age-effects - "poisoning incidence has two peaks across the child life span" - and how "the poly-pharmacy status in many ADHD patients could increase the likelihood of an accidental poisoning." But the bottom line is that, yet again, a diagnosis of ADHD seems to put someone as some significantly heightened risk of injury, and we should be doing everything we can to minimise any additional risks to those diagnosed.

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[1] Ruiz-Goikoetxea M. et al. Risk of poisoning in children and adolescents with ADHD: a systematic review and meta-analysis. Sci Rep. 2018 May 15;8(1):7584.

[2] Ruiz-Goikoetxea M. et al. Risk of unintentional injuries in children and adolescents with ADHD and the impact of ADHD medications: a systematic review and meta-analysis. Neuroscience & Biobehavioral Reviews. 2018; 84: 63-71.

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Wednesday, 11 July 2018

The [estimated] global prevalence of schizophrenia in 2016... 0.28%

The findings reported by Fiona Charlson and colleagues [1] looking at the "GBD [global burden of disease] 2016 estimates of schizophrenia prevalence and burden of disease with disaggregation by age, sex, year, and for all countries" provide the brief blogging fodder today.

As per the title of this post, when all the data were captured (from a "total of 129 individual data sources") and numbers crunched, the "global age-standardized point prevalence of schizophrenia in 2016 was estimated to be 0.28%."

Authors talk about schizophrenia as a "low prevalence disorder" highlighting also how there were no sex differences noted and how: "Age-standardized point prevalence rates did not vary widely across countries or regions." Schizophrenia it appears, does not care if you are a man or a woman or where you live. What it does seem to do, quite generally, is affect your quality of life and other life chances, as per another quote from the Charlson findings: "Schizophrenia contributes 13.4... million years of life lived with disability to burden of disease globally." Oh, and it appears to be increasing in frequency too: "Globally, prevalent cases rose from 13.1... million in 1990 to 20.9... million cases in 2016."

I personally, found the Charlson estimate - 0.28% - to be lower than I would have expected. Having talked for example, about schizophrenia prevalence rates in specific countries on this blog (see here) and mention of figures such as 0.83% [2], the global figure seems someway behind. Interestingly also, in the United States, there has been some 'discussion' about the revision of the prevalence estimates of schizophrenia there too (see here), where a quite long-standing 1.1% estimate - "1-year prevalence of schizophrenia in adults in the US" - was recently revised down to 0.3% (a figure not a million miles away from the Charlson estimate).

I guess, there's more to do when it comes to the establishing a precise prevalence of schizophrenia...

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[1] Charlson FJ. et al. Global Epidemiology and Burden of Schizophrenia: Findings From the Global Burden of Disease Study 2016. Schizophr Bull. 2018 May 12.

[2] Chan KY. et al. Prevalence of schizophrenia in China between 1990 and 2010. Journal of Global Health. 2015;5(1):010410.

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Tuesday, 10 July 2018

"anxiety occurring as a consequence of ASD symptoms"

Although not necessarily a popular idea, I have for a while been coming around to the possibility that various 'comorbidities' associated with a diagnosis of autism or autism spectrum disorder (ASD) represent more than just 'comorbidity'. I'm not specifically talking about medical comorbidity such as epilepsy or seizure disorder being intricately related to autism (although there is evidence for such a relationship) but rather that co-occurring clinical and sub-clinical psychiatric issues such as depression and anxiety potentially 'come about' partially as a result of the presence of autistic traits and characteristics (see here and see here).

As I said, this is not a universally popular idea. In the age of the emergence of an 'autistic identity' and an increasingly vocal group of people wanting to discuss what role societal factors play with regards to quality of life in the context of autism (see here), the idea that autistic traits themselves might in some way predispose for various other, often very disabling conditions, is not easy to reconcile. Even more so if the implication for managing things like anxiety and/or depression might mean 'targeting' core autistic features for intervention...

The findings such as those reported by Elizabeth Shephard and colleagues [1] "testing the specificity of early-life (infant and toddler) predictors of mid-childhood ADHD [attention-deficit hyperactivity disorder] and anxiety symptoms compared to ASD symptoms" provide however, another tier of evidence that (a) autism rarely exists in some sort of diagnostic vacuum (see here), and (b) something like the symptoms of anxiety appearing alongside autism could "reflect the presence of common developmental pathways or convergence in early behavioural manifestations."

Shephard et al discuss results obtained from the British Autism Study of Infant Siblings (BASIS) initiative, a collaboration based here in Blighty aiming to "provide a platform for the study of infants at-risk for autism in the UK and to facilitate collaborative links between scientists working in the area." High-risk (i.e. having a sibling diagnosed with ASD) and low-risk infants were followed and tested for various symptoms and traits covering autism and also ADHD and anxiety at various points during their childhood development: "7, 14, 24 and 38 months, and 7 years of age." Importantly, because measuring things like anxiety in young children is still quite a challenge, researchers used other soft signs and symptoms - fearfulness and shyness - as "early-life predictors of anxiety symptoms." Some nifty statistical methods were applied to the collected data.

Results: "Increased activity levels and poor inhibitory control were correlated with ADHD symptoms and not ASD or anxiety; these associations were unchanged in path models controlling for risk-group and ASD symptoms." The authors interpreted these findings as evidence that "these disorders may have distinct developmental origins and are therefore unlikely to reflect a common condition" with a specific focus on autism and ADHD. Ergo, when one sees the data pointing to a rather large over-representation of ADHD in the context of autism (see here), this does not necessarily translate into autism being ADHD or vice-verse or them sharing a common developmental pathway.

Additionally: "early‐life markers of anxiety (without ASD) were associated with later anxiety..., but were also associated with later ASD symptoms." When looking at those early-life markers of [possible] anxiety, and how they *linked* to the symptoms of autism, authors highlighted how "these disorders are difficult to differentiate early in life, which could reflect the presence of common developmental pathways or convergence in early behavioural manifestations of these disorders." In other words, there may be some intricate links between them.

Of course, lots more research is needed in this area, as authors mention about the use of "parent‐rated measures of early‐life predictors and mid‐childhood symptoms of ADHD, anxiety and ASD" and what that could mean for the quality of the information obtained. Personally, I'd be inclined to suggest that parents are often 'under-rated' in their contributions to autism research (see here for example) including on the specific issue of anxiety and autism (see here). But I guess every study can be improved in some respect.

What's more to say on this topic? Well, I'm minded to bring in some other, rather 'left-field' evidence for how autism and anxiety might be more intricately linked than hitherto suggested, in the form of some work looking at selective mutism and autism (see here). How, a condition centrally identifying with anxiety (selective mutism), also seemingly heightens the risk of autism being subsequently diagnosed well beyond what would be expected. I don't doubt that there other examples of anxiety-related conditions also potentially increasing the likelihood of autism presenting clinically further strengthening the 'beyond just comorbidity' sentiments.

And set within this emerging research/clinical picture [2], we then go back to the idea that some autistic traits might be 'promoters' of something like anxiety in the context of autism, and back to the important question of what to do about them...

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[1] Shephard E. et al. Early developmental pathways to childhood symptoms of attention-deficit hyperactivity disorder, anxiety and autism spectrum disorder. J Child Psychol Psychiatry. 2018 Jul 2.

[2] Spain D. et al. Social anxiety in autism spectrum disorder: A systematic review. Research in Autism Spectrum Disorders. 2018; 52: 51-68.

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