"parental asthma was associated with slightly elevated risk of ASD in offspring"

The paper by Tong Gong and colleagues [1] provides the blogging fodder today and the finding that "parental asthma was associated with slightly elevated risk of ASD [autism spectrum disorder] in offspring."

As unusual as it might sound to some people that a condition primarily affecting the lungs *might* show a connection to a developmental diagnosis in offspring, this is not the first time that asthma and autism has been talked about on this blog (see here and see here). Granted, much of that previous peer-reviewed research has been looking at the possible *connection* between asthma and autism diagnosed in the same person (albeit not necessarily always describing a link). But there is some research history connecting the two labels. Indeed, one of the primary comorbidities that can follow a diagnosis of autism - attention-deficit hyperactivity disorder (ADHD) - seems to have an even stronger *association* with asthma (see here).

Gong et al set out to investigate a few important issues: "the association between (a) maternal/paternal asthma and offspring ASD, and (b) prenatal exposures to β2-agonists, other asthma medications and offspring ASD." It would be difficult to describe the Gong study as 'underpowered' given that their use of those fabulous Scandinavian population registries - this time in Sweden - covering "all children (N=1,579,263) born in Sweden 1992-2007." From the total population, researchers identified some 22,000 children diagnosed with an ASD. They looked at their exposure to "parental asthma or prenatal asthma medications" and compared the data with other populations (not diagnosed with autism) including various degrees of siblings and extended family members.

As per the title of this post, a possible *association* was revealed between parental medical history of asthma and offspring risk of a diagnosis of ASD. Asthma in either parent seemed to show a connection, but maternal asthma showed the stronger connection. Also: "The risk of offspring ASD in mothers with asthma showed similar estimates when adjusting for shared familial factors among paternal half-siblings... full-cousins... and half-cousins." This suggests that familial factors were not 'confounding' factors. Another detail is important to mention: "Prenatal exposure to asthma medications among subjects whose mothers had asthma was not associated with subsequent ASD." This is an important detail. It mirrors the findings reported in the paper by Su and colleagues [2] looking at another Scandinavian cohort, and their conclusion: "children born to women who used β2AA [β2-adrenoreceptor agonist] during pregnancy have an increased risk of ASDs in later life" with the caveat that risk of offspring autism was "more likely due to underlying maternal diseases rather than the exposure to β2AA itself."

Implications? Well, several. Not least that more study is required looking at the biological and genetic links between autism and asthma. Y'know, something along the lines of the fact that 'autism genes are probably not just genes for autism' (see here) and how autism has been previously studied in the context of lung architecture too (see here).

What else? How about examining the possibility of some shared biological mechanisms also at work? Perhaps start with inflammation for example [3] and work through other potential immune-related issues as well (see here). And how about also thinking about the possibility of shared 'exposure' events being potentially important? Asthma is a condition affecting the lungs. Something like air pollution is therefore a prime suspect when it comes to the development and continuation of the condition. Likewise, air pollution is no stranger to the autism peer-reviewed research landscape (see here for example). Is it possible that air pollution might be implicated in asthma and autism?

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[1] Gong T. et al. Parental asthma and risk of autism spectrum disorder in offspring: a population and family based case-control study. Clin Exp Allergy. 2019 Feb 11.

[2] Su X. et al. Prenatal exposure to β2-adrenoreceptor agonists and the risk of autism spectrum disorders in offspring. Pharmacoepidemiol Drug Saf. 2017 Jul;26(7):812-818.

[3] Murdoch JR. & Lloyd CM. Chronic inflammation and asthma. Mutat Res. 2010;690(1-2):24-39.

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Vitamin D supplementation and autism: more work needed on the biochemistry of vitamin D metabolism

The findings reported by Conor Kerley and colleagues [1] provide the brief blogging fodder today. Researchers, who are no stranger to the research area that is vitamin D and autism (see here), decided to conduct a 'post-hoc analysis' of data from two controlled trials where vitamin D supplementation was experimentally tested for children with autism and children with asthma. They were specifically looking at the "serum response to vitamin D supplementation" rather that the amount of vitamin D supplemented as potentially being important to the clinical results obtained. They concluded that "children with ASD [autism spectrum disorder] had a lower increase in 25(OH)D levels with supplementation." Further: "Potential mechanisms include altered absorption/metabolism as well as well genetic factors."

Bearing in mind the relatively small participant group numbers used and comparisons between kids with autism and kids with asthma without any other 'asymptomatic' group involvement, I was really rather interested in the Kerley findings. This was a research group who previously concluded that vitamin D supplementation did little for their cohort of autistic children under experimental conditions [2]. Now they're perhaps suggesting that there may have been valid biological reasons behind such results with respect to the biochemistry/metabolism behind vitamin D with such issues potentially affecting how much vitamin D supplementation is required to suitably raise vitamin D levels.

Of course this is not necessarily a new finding. Science has already started to look at the genetics/biology of vitamin D metabolism in relation to autism (see here and see here) and continues to do so [3]. It also converges with the idea that a deficiency/insufficiency of vitamin D is an important clinical finding but does not necessarily mean that a universal dose of vitamin D supplementation will 'fix anything' (see here for another example in another label).

"Clinical and research work relating to vitamin D is ASD should measure 25(OHO)D response to supplementation to assess therapeutic doses." I can't argue with such sentiments on the basis of the results observed. Working back from sayings such as 'the dose makes the poison', it appears that for some on the autism spectrum, that dose may not be the same as everyone else...

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[1] Kerley CP. et al. Blunted serum 25(OH)D response to vitamin D3 supplementation in children with autism. Nutr Neurosci. 2018 Oct 10:1-6.

[2] Kerley CP. et al. Lack of effect of vitamin D3 supplementation in autism: a 20-week, placebo-controlled RCT. Arch Dis Child. 2017 Nov;102(11):1030-1036.

[3] Biswas S. et al. Fok-I, Bsm-I, and Taq-I Variants of Vitamin D Receptor Polymorphism in the Development of Autism Spectrum Disorder: A Literature Review. Cureus. 2018 Aug 29;10(8):e3228.

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ADHD and asthma meta-analysed

So, the paper by Samuele Cortese and colleagues [1] kinda continues a theme from my last post (see here) on how those in receipt of various developmental and/or psychiatric diagnoses might also be more 'prone' to physical or somatic issues appearing alongside.

The headline this time around: "The combined results of the meta-analysis and the population-based study support a significant association between asthma and ADHD [attention-deficit hyperactivity disorder], which remained even after simultaneously controlling for several possible confounders in the population-based study."

The possibility of an 'overlap' between ADHD and asthma is a theme that has been explored numerous times on this blog (see here for example). What sets the Cortese results apart from the previous peer-reviewed research is the focus on using a meta-analysis (where results from multiple studies are 'boiled down' to form a statistical opinion) to provide a 'where we're currently at statement' on any possible relationship.

Taking into account information from almost 50 datasets covering "a total of 210 363 participants with ADHD and 3 115 168 without" researchers looked to estimate the magnitude of any relationship between ADHD and asthma, having previously published their intention to undertake such an analysis (see here). They did try and take into account potentially important influencing variables such as year of birth and sex/gender. They concluded that there was something to see when it came to a possible relationship between ADHD and asthma, and that: "Awareness of this association might help to reduce delay in the diagnosis of both ADHD and asthma."

What's more to say? Well, aside from advancing the idea that preferential screening should be more widespread as and when ADHD or asthma is diagnosed, the other important question should be: Why? Why should a diagnosis of ADHD increase the possibility that asthma would be present and vice-verse? Does this imply that there may be some shared mechanism(s) between the two conditions such as a role for the immune system for example? And then there is the possibility that when present together, there could be some rather novel approaches to managing both labels (see here and see here for example). No, I'm not giving anything that looks, sounds or smells like medical or clinical advice; merely suggesting that what's good for body might also be good for mind too.

And whilst mentioning the work of Cortese, I note that other recent meta-analysis results [2] from the same author might be important to ADHD too...

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[1] Cortese S. et al. Association between attention deficit hyperactivity disorder and asthma: a systematic review and meta-analysis and a Swedish population-based study. Lancet Psychiatry. 2018 Jul 24. pii: S2215-0366(18)30224-4.

[2] Cortese S. et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatry. 2018. Aug 7.

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"a high rate of physical problems in children with NDDs"

NDDs mentioned in the title of this post refers to neurodevelopmental disorders, pertinent to the important results published by Setareh Alabaf and colleagues [1] on how autism and various other NDDs rarely appear in some sort of diagnostic vacuum (see here).

Including a notable ESSENCE-related name on the authorship list (see here), authors focused on various physical (somatic) diagnoses - "epilepsy, migraine, asthma, cancer, diabetes, psoriasis, lactose intolerance, celiac disease, diarrhea, constipation, daytime enuresis, encopresis" - and their frequency in a nationwide population cohort of twins that has been mentioned before on this blog (see here). The participant number totalling data on some 28,000 twins (parent reported) is not to be sniffed at, including over 1000 children categorised as having a NDD.

Results: "The results indicate a high rate of physical problems in children with NDDs, particularly in those with indications of the presence of combinations of several NDDs." I was particularly drawn to a couple of the results mentioned by Alabaf et al that tally with other independent findings. So: "asthma had the highest prevalence (14.2%)" following other peer-reviewed results (see here and see here). The authors also highlight another important physical comorbidity as being important to some: "Of the GI [gastrointestinal] problems, the most prevalent was constipation (8.4%) and lactose intolerance (5.9%)" which again aligns with other findings (see here and see here). I should mention that the study relied on telephone interviews with parents of children asking specifically whether particular physical problems were diagnosed. Yet again also responses to a questionnaire were "used as clinical proxies for ASD [autism spectrum disorder], ADHD [attention-deficit hyperactivity disorder] and LD [learning disorders], which are included in the NDD group" so one has to bear this in mind.

Another aspect to the Alabaf findings is also noteworthy: "children with different constellations of NDDs more often had coexisting physical problems as compared to children with a single NDD." This is important. It suggests that alongside the idea that a diagnosis like autism or ADHD typically do not exist in some sort of diagnostic vacuum when it comes to other psychiatric and developmental psychopathology, so the frequency of physical or somatic issues seems also to cumulative. The first thing that sprung to my mind when reading about this was the idea that 'autism genes' are probably not just 'genes for autism' (see here). And that probably goes for the presentation of somatic issues too. By saying that I don't belittle the contribution of the 'functional' immune system to autism and the various links that have been made there too [2] in a 'non-genetic' capacity.

It also means that yet again, as and when a diagnosis of something like autism or ADHD is given, professionals should be mindful that other 'preferential' screening should also be provided alongside...

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[1] Alabaf S. et al. Physical health in children with neurodevelopmental disorders. J Autism Dev Disord. 2018 Jul 24.

[2] Croen LA. et al. Family history of immune conditions and autism spectrum and developmental disorders: Findings from the study to explore early development. Autism Res. 2018 Aug 10

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Allergic disease and ADHD yet again...

Although words like 'first' and 'largest' were used in the paper by Chia-Feng Yang and colleagues [1] (open-access available here) observing that "AD [atopic dermatitis] and asthma with allergic sensitization are associated with ADHD [attention-deficit hyperactivity disorder] in children", I'm minded to be a little cautious with such 'we're the first/best' assertions.

Cautious because, on quite a few peer-reviewed research occasions (see here for example), a possible *link* between various allergic disease and ADHD has already been noted; even potentially extending to studies talking about how treatment for allergic disease might on some occasions also impact on presented ADHD symptoms (see here) (with no medical advice given or intended).

Yang et al relied on data from a research favourite country, Taiwan, derived from an initiative called the Childhood Environment and Allergic diseases Study (CEAS). The clue is in the name of the initiative in terms of what they were looking for/at, as per other publications derived from the initiative [2]. From the 3200-odd participants eligible for participation, researchers relied on data from over 2700 children. Questions about allergic disease history were asked to parents of said participants, alongside other 'environmental' factors such as family income, tobacco exposure and breastfeeding history. I note also a question about 'incensing at home' is also included relating to the use of burning incense typically linked to religious practices in certain cultures.

When it came to a diagnosis of ADHD, it's not entirely clear about how this was ascertained but it looks like diagnosis was given by a clinician: "The conditions of disease in children were confirmed by board-certified child psychiatrists or pediatric neurologists, according to the clinical evaluation." I should also mention that participants also received skin prick tests (SPTs) covering a range of potential allergens: "house dust mites (HDMs mix, including Der p, Der f, Der m, and Blot allergens), cockroaches, dog dander, milk, egg, and crab allergens" as way of defining allergic sensitisation.

Results: there was a "strong positive association between ADHD and allergic sensitization as diagnosed by positive SPTs." In other words, despite finding a fairly low level of ADHD in their sample (1%), those who 'reacted' to one or more of the allergens tested for via the skin prick test seemed to be at some increased risk of ADHD. Such an enhanced risk spanned both those presenting with "AD with allergic sensitization and asthma with allergic sensitization."

The authors provide some further results and details on the possible hows-and-whys of their results. Obviously the immune system figures quite strongly given what for example, they were testing for with the SPT and their focus on AD and asthma. The word 'inflammation' also figures quite heavily. I note too that the authors reiterate previous suggestions that: "Control of allergens exposure might be a critical factor influencing the development of ADHD."

There is a further scheme of work to follow in this area, not just dealing with mechanisms but also in relation to 'treating' allergies also potentially 'treating' [some] ADHD. I say this on the basis that other independent research has observed that before reaching for the antihistamine as a potential ADHD-modifier, there may actually be a connection between early antihistamine exposure and the development of ADHD [3] (albeit with potential confounders) to keep in mind. Other work also supporting a link between ADHD and atopic disease [4] provides some other 'clues' that may require further investigation; not least "cow's milk intolerance", which ties into similar findings (see here) and could also be one route from which ADHD heightens the risk of subsequent future psychiatric disorder (see here) in light of other 'milk' associations (see here).

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[1] Yang CF. et al. Association between allergic diseases, allergic sensitization and attention-deficit/hyperactivity disorder in children: A large-scale, population-based study. J Chin Med Assoc. 2017 Nov 24. pii: S1726-4901(17)30304-0.

[2] Wang IJ. et al. Allergens, air pollutants, and childhood allergic diseases. Int J Hyg Environ Health. 2016 Jan;219(1):66-71.

[3] Schmitt J. et al. Increased attention-deficit/hyperactivity symptoms in atopic dermatitis are associated with history of antihistamine use. Allergy. 2017 Oct 4.

[4] Hak E. et al. Association of childhood attention-deficit/hyperactivity disorder with atopic diseases and skin infections? A matched case-control study using the General Practice Research Database. Ann Allergy Asthma Immunol. 2013 Aug;111(2):102-106.e2.

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Allergy and ADHD meta-analysed and guess what...

"Reports of frequent manifestation of allergic diseases in children with attention deficit hyperactivity disorder (ADHD) have been the subject of mounting clinical interest."

OK, go on.

"The objective of this study was to compile and assess available studies on the association between ADHD and allergic diseases in children."

And your findings... "children with ADHD are more likely to have asthma, allergic rhinitis, atopic dermatitis, and allergic conjunctivitis than their counterparts. Interventions including strategies for managing allergies in children with ADHD would be beneficial."

So said the systematic review and meta-analysis published by Celine Miyazaki and colleagues [1] (open-access) who provide quite a good 'where we're at' update when it comes to a potentially important intersection between a developmental condition (ADHD) and a series of somatic, immune-based conditions (allergy).

Regular readers of this blog might already know that I have a blogging interest in all-things immune system and behaviour (see here for example). Indeed, acknowledging that the immune system may be doing so much more than protecting us from the multitude of viral, bacterial and other insults we face each day is gaining some real [peer-reviewed] scientific momentum.

Boiling down the peer-reviewed literature to five studies meeting the meta-analysis criteria laid out by authors, cumulatively including some 60,000 research participants (including data derived from that wonderful Taiwanese research registry that I keep going on about), researchers set to work on the examining the various findings. Nearly 8,000 of the 61,811 children included for study were diagnosed with ADHD and various allergic diseases were 'examined' in the context of the ADHD label or without the label. The results were as mentioned in the first paragraph.

When it came to looking at which specific allergic disease diagnoses were most strongly linked to ADHD a familiar theme emerged: "children with ADHD have an 80% increased odds of asthma compared with children without ADHD." I'm beginning to lose track of the number of times I've covered this association down the blogging years (see here and see here and see here). Indeed, these results add to other reviews on this topic [2] previously covered on this blog (see here).

The nature of the association? Well, more studies are still required. The authors talk about some work looking at possible overlapping genetic issues with autoimmunity in mind, and that is probably going to be quite important. More than that however is the idea that other less-genetic factors might also play a role. Y'know how social factors such as poverty might figure (see here) for example. I'm also minded to bring in the possibility of an 'association' between food allergy and behavioural symptoms (see here) in light of other work. Such a connection might also implicate all-manner of other bodily systems including the [hyped-up] field of microbiomics for example. Suffice to say that connections are likely to be complex and potentially numerous.

The other implication from the Miyazaki results is another thing I've been going on about for some years on this blog: preferential screening. Y'know, when a diagnosis of asthma for example, is received, how about screening for ADHD and related developmental issues? Or, the other way around, screen for allergic diseases when a diagnosis of ADHD is received? And then there's the intervention angle, and some potentially useful data from both other developmental/behavioural diagnoses and allergy symptoms (see here) and some rather more direct evidence (see here)?

To close, my brood have just discovered Little Britain and the laughter has gone on and on and on...

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[1] Miyazaki C. et al. Allergic diseases in children with attention deficit hyperactivity disorder: a systematic review and meta-analysis. BMC Psychiatry. 2017; 17: 120.

[2] Schans JV. et al. Association of atopic diseases and attention-deficit/hyperactivity disorder: A systematic review and meta-analyses. Neurosci Biobehav Rev. 2017 Mar;74(Pt A):139-148.

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Miyazaki, C., Koyama, M., Ota, E., Swa, T., Mlunde, L., Amiya, R., Tachibana, Y., Yamamoto-Hanada, K., & Mori, R. (2017). Allergic diseases in children with attention deficit hyperactivity disorder: a systematic review and meta-analysis BMC Psychiatry, 17 (1) DOI: 10.1186/s12888-017-1281-7

"Asthma was associated with increased risk for schizophrenia"

'Big data' Taiwan is once again the topic of a post on this blog as the results published by Wei-Chen Wang and colleagues [1] (open-access available here) receive an airing, specifically that: "Asthma was associated with increased risk for schizophrenia."

There are some common themes attached to these findings. Taiwan is already a research-favourite place on this blog as a result of their use of the National Health Insurance Research Database (NHIRD) for various research purposes. I can't name all the occasions I've talked about research from Taiwan based on the NHIRD but a few of them can be seen here and here. Another commonality of this latest research from Wang et al is the idea that physical illness with a substantial immune system component to it *might* show an important connection to a behavioural/psychiatric disorder. Asthma and related atopic diseases has been mentioned on a few other occasions (see here and see here). Hold those thoughts for now...

This time around Wang and colleagues "aimed to investigate the association between asthma, corticosteroid use, and schizophrenia." Comparing 'measures of schizophrenia' in some 25,000 participants diagnosed with asthma and 50,000 without asthma over 7 years, and adjusting for various potentially confounding variables - "sex, age, residence, socioeconomic status, corticosteroid use, outpatient and emergency room visit frequency, Charlson comorbidity index, and total length of hospital stays days for any disorder" - the results were interesting. Not least that "asthma was associated with significantly greater hazard ratio for incident schizophrenia." Researchers also noted that various other confounding variables also showed a relationship with schizophrenia such as rural residence, poor general health and lower economic status. "Corticosteroid use was not associated with increased risk for schizophrenia" we are also told.

Whilst interesting, the results do not say that everyone with asthma is at risk of developing schizophrenia. Not even close. The rates of schizophrenia identified in the Wang study were also quite low overall despite the large starting populations studied: "Of the total 75,069 subjects, 238 were diagnosed with schizophrenia during the study period: 100 (0.40%) of subjects were in the asthma cohort and 138 (0.28%) in the non-asthma cohort."

But, set within the context of other independent datasets [2] observing "the existence of an association between atopic disorders in general and asthma in particular and the risk of developing schizophrenia" there is cause for further investigation into any association. Not least that Wang et al describe their results in the context that: "a convergent disturbance in the immune-inflammatory system may contribute to the pathoetiology of asthma and schizophrenia." Y'know, all that talk that among the [plural] schizophrenias, one or two phenotypes might, to some quite large extent, be linked to immune function or dysfunction. Well, it's not as if we haven't got some quite reliable research clues already (see here). There may also be some subsequent discussions on the requirement for enhanced screening for something like schizophrenia as and when a diagnosis of asthma (or other atopic disease) is diagnosed as per other data (see here).

Finally, going back to the previous research occasions when asthma has been *correlated* with labels such as attention-deficit hyperactivity disorder (ADHD) and even autism, I'm wondering whether there could be wider links present when it comes to immune-related conditions and behavioural presentations. It's pretty well known that various behavioural/developmental/psychiatric labels tend to 'club together' (see here and see here for examples). There is also a growing realisation that alongside overlapping genetics and biology when it comes to such labels, the days of autism genes for example, just being genes for autism are beginning to drift off (see here); something probably relevant to conditions such as ADHD and schizophrenia too. So, could it be that immune system related conditions such as asthma and atopic disease, might have lots and lots of implications in relation to many developmental/behavioural/psychiatric labels? Even more intriguing, are there clues to possible intervention avenues too? (with no medical or clinical advice given or intended).

We await further investigations...

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[1] Wang WC. et al. Asthma, corticosteroid use and schizophrenia: A nationwide population-based study in Taiwan. PLoS One. 2017 Mar 28;12(3):e0173063.

[2] Pedersen MS. et al. Schizophrenia in patients with atopic disorders with particular emphasis on asthma: a Danish population-based study. Schizophr Res. 2012 Jun;138(1):58-62.

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Wang WC, Lu ML, Chen VC, Ng MH, Huang KY, Hsieh MH, Hsieh MJ, McIntyre RS, Lee Y, & Lee CT (2017). Asthma, corticosteroid use and schizophrenia: A nationwide population-based study in Taiwan. PloS one, 12 (3) PMID: 28350822

Poverty status and autism, ADHD and asthma

The paper by Christian Pulcini and colleagues [1] talking about poverty status potentially influencing "parent-reported lifetime prevalence and comorbidities" when it comes to three target conditions (autism, attention-deficit hyperactivity disorder [ADHD] and asthma) should have been a call to action. Concluding that "poor and near poor children had a higher lifetime prevalence of asthma and ADHD, but not ASD [autism spectrum disorder]" [2], some of the findings have instead attracted criticism based on the content of the abstract (see here); specifically the line: "the lifetime prevalence of ASD rose almost 400%."

Poverty and diagnosis is a topic that I've covered before on this blog (see here for example) and how not every research study has linked poverty (measures of poverty) to something like autism and/or ADHD. At least that is, when taking into account "elevated emotional problems among children with ASD + ADHD" [3].

On this most recent occasion, Pulcini et al drew on data derived from the "National Survey of Children's Health [NSCH] for years 2003, 2007, and 2011-2012" and specifically "trends in parent reported lifetime prevalence and comorbidity among children with asthma, ADHD, and ASD" taking into account variables like poverty status. The NSCH initiative has again, been talked about previously on this blog (see here and see here) in terms of parent-reported prevalence of autism and parent-reported epilepsy appearing alongside autism. It's a good rough-and-ready measure of what estimated prevalence rates might look like (with the need for further, more detailed study).

This time around the authors illustrated that - yet again - the only way is up when it comes to estimated prevalence rates for all the 'target' conditions examined. I don't think anyone should be too surprised at such findings given data from other studies in other geographic areas (see here) specifically with the autism spectrum in mind. I'm not going to head into the debate about whether the 400% increase figure is right or wrong but will note previous findings [4] that suggested that: "differential survey measurement error over time was not a major contributor to observed changes in the prevalence of parent-reported ASD. Rather, much of the prevalence increase from 2007 to 2011–2012 for school-aged children was the result of diagnoses of children with previously unrecognized ASD." This for when data from the 2007 and 2011-2012 surveys were contrasted (not the 2003 survey).

The contribution of poverty or near poverty was not to be sniffed at when it comes to those ADHD and asthma diagnoses. This is perhaps even more important when one considers that these two labels might be rather more 'entangled' than many people might have previously realised (see here). That a poverty and ADHD link might also generalise to somewhere like here in the UK is also worth noting (see here) and implies that quite a bit more research is needed to answer the question: why? With regards to autism (ASD), the observation that the "rise in ASD was associated with being nonpoor"adds to an on-going debate, with some studies saying yes, we agree, and other studies saying no, we don't (see here). In short, it is slightly more complicated when it comes to how social factors might affect autism rates.

Music: Three steps to heaven.

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[1] Pulcini CD. et al. Poverty and Trends in Three Common Chronic Disorders. Pediatrics. 2017 Feb 13. pii: e20162539.

[2] Dreyer BP. Congress Should Adopt a “Do No Harm to Children” Standard in Changes to Public Health Insurance. Pediatrics. 2017. Feb 2017.

[3] Flouri E. et al. Poverty and the Growth of Emotional and Conduct Problems in Children with Autism With and Without Comorbid ADHD. J Autism Dev Disord. 2015 Sep;45(9):2928-38.

[4] Blumberg SJ. et al. Changes in Prevalence of Parent-reported Autism Spectrum Disorder in School-aged U.S. Children: 2007 to 2011–2012. Natl Health Stat Report. 2013 Mar 20;(65):1-11.

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Pulcini CD, Zima BT, Kelleher KJ, & Houtrow AJ (2017). Poverty and Trends in Three Common Chronic Disorders. Pediatrics PMID: 28193790

Particulate matter exposure and autism risk systematically reviewed?

"To conclude, the evidence from the studies allows us to conclude that there is an association between PM [particulate matter] exposure and ASD [autism spectrum disorder] whose strength varies according to the particle size studied with the association with PM2.5 and diesel PM being stronger."

Although probably not great sentence structure to begin a post with a conclusion, the 'bottom line' reported by María Morales-Suárez-Varela and colleagues [1] summarises the current research looking at particulate matter (a.k.a pollution) and risk of autism. Surveying the current research literature - well, a window "from November 2015 up to January 2016" - authors reported finding a majority of studies showing "positive associations restricted to specific exposure windows which however do not reach statistical significance at times." This adds to other reviews of the research in this area [2].

I don't want to dwell too much on this paper and topic because it's something that has already received quite a bit of attention on this blog (see here and see here for examples). As with most research areas focused on autism, there is evidence for and evidence against any association/correlation between air pollution exposure and risk of autism. Given the various factors included under the heading of pollution (type, particle size, how exposure is measured) it's perhaps not surprising that there is not yet any 'smoking gun' (pardon the pun) when it comes to any possible association.

I however, am taken by the ideas that (a) genes probably play a hand in translating air pollution exposure to a heightened risk of [offspring] autism and (b) other conditions linked to air pollution such as asthma might also feature in any connection (see here for example). Indeed, in these times of seemingly ever-increasing air pollution (see here) and lots of possible connections, further investigations are very much indicated.

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[1] Morales-Suárez-Varela M. et al. Systematic review of the association between particulate matter exposure and autism spectrum disorders. Environ Res. 2016 Dec 13;153:150-160.

[2] Lam J. et al. A Systematic Review and Meta-Analysis of Multiple Airborne Pollutants and Autism Spectrum Disorder. PLoS One. 2016 Sep 21;11(9):e0161851.

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Morales-Suárez-Varela M, Peraita-Costa I, & Llopis-González A (2016). Systematic review of the association between particulate matter exposure and autism spectrum disorders. Environmental research, 153, 150-160 PMID: 27984759

Atopy increases vulnerability to affective and anxiety issues?

In a year of impossible things...

I was rather interested to read the recent paper by Renee Goodwin and colleagues [1] observing that: "Atopy appears to be associated with increased vulnerability to affective and anxiety problems, compared to youth without atopy."

Atopy, referring to a predisposition to developing allergic diseases such as eczema, asthma and/or hayfever, is something on the 'up' in research terms when it comes to aspects of psychiatry and/or developmental outcomes (see here for example). Goodwin et al set about further testing the possibility of a link based on data "drawn from the Raine Study (N = 2868) [a favourite initiative on this blog], a population-based birth cohort study in Western Australia."

Looking at signs of atopy - "using parent report and objective biological confirmation (sera IgE)" - at ages 1-5 years and "the range of internalizing and externalizing mental health problems at ages 5-17 years" authors reported on some interesting patterns/correlations in relation to affective and anxiety problems potentially being linked. Authors also described how their results held strong even "after adjusting for a range of potential confounders."

Whilst there are always going to be issues associated with studies linking one or two variables across various years, the Goodwin paper represents yet another example of how further research resources need to be ploughed into the area of immune function and behaviour. Yes, I appreciate that we are entering the era of immunopsychiatry (if I can call it that) and that there is some good science emerging in this area (see here) but questions about the [various] hows and whys still need answering [2].

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[1] Goodwin RD. et al. Childhood atopy and mental health: a prospective, longitudinal investigation. Psychol Med. 2016 Oct 20:1-9.

[2] Hatfield SJ. et al. What's new in atopic eczema? An analysis of systematic reviews published in 2014. Part 1. Epidemiology, risk factors and outcomes. Clin Exp Dermatol. 2016 Nov 2.

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Goodwin RD, Robinson M, Sly PD, & Holt PG (2016). Childhood atopy and mental health: a prospective, longitudinal investigation. Psychological medicine, 1-9 PMID: 27762174

One more time: asthma and autism

I'm actually getting a little bored of talking about the various peer-reviewed research looking at a possible connection between asthma and autism on this blog. It's not that it isn't an interesting topic but rather that the data is coming in thick and fast suggesting that behaviour and physiology are not completely separate anymore.

I did however want to direct you to the paper by Alessandro Tonacci and colleagues [1] who, following a systematic review "according to the PRISMA guidelines" suggested that "Autism Spectrum Disorder and asthma could be associated conditions, as evidenced by the higher prevalence of asthma in autistic children with respect to typically developed controls." I might add that this is not the first time that this authorship group have examined the coincidence of allergic disease with autism (see here).

The idea that asthma and autism might be connected is an important finding because not so long ago I talked about another paper [2] - a meta-analysis - that came up with a slightly different conclusion to that listed by Tonacci (see here). OK, a systematic review and a meta-analysis whilst related are not necessarily one and the same and so one has to be a little careful. That being said, I did raise a few 'issues' with that previous meta-analysis by Zheng and colleagues [2] around what they did and did not seemingly include in their paper. A meta-analysis or systematic review is only as good as the number and quality of the studies it includes.

The strength of the Tonacci review is that it followed those PRISMA guidance - the Preferred Reporting Items for Systematic reviews and Meta-Analyses - and also that "Methods for study selection and inclusion criteria were specified in advance and documented in PROSPERO protocol #CRD42014012851." In other words, much like when study protocols for clinical trials are pre-registered to avoid any 'massaging' of results or changing/switching outcomes, so their aims and objectives were on record for all to see.

Where next for the suggestion of a possible link between asthma and autism? Well, how about taking into account a role for comorbidity as per the increasingly strong evidence coming out about how asthma and attention-deficit hyperactivity disorder (ADHD) may be linked (see here) and what that means for the over-representation of ADHD in autism or vice-versa (see here). I might once again suggest that immune function (i.e. inflammation or inflammatory processes) could be a common variable requiring further study too (see here for example). Such research may wish to take into account overlapping genetics/epigenetics as being important as well as the more functional biochemistry of immune system processes.

Given also the specific focus on "allergic asthma" by Tonacci et al I'm also wondering whether the various research on allergy symptoms affecting autism presentation might be important for some (see here). Indeed, with no medical advice given or intended, the idea of treating allergic disease in cases of ADHD for example (see here) is perhaps an area ripe for further investigation when it comes to autistic presentation too...

To close: Guardians of the Galaxy is back (and the soundtrack will be as cool as ever I guess).

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[1] Tonacci A. et al. A systematic review of the association between allergic asthma and autism. Minerva Pediatr. 2016 Oct 5.

[2] Zheng Z. et al. Association between Asthma and Autism Spectrum Disorder: A Meta-Analysis. PLoS One. 2016 Jun 3;11(6):e0156662.

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Tonacci A, Billeci L, Ruta L, Tartarisco G, Pioggia G, & Gangemi S (2016). A systematic review of the association between allergic asthma and autism. Minerva pediatrica PMID: 27706122

Comorbidities surrounding paediatric chronic fatigue syndrome / myalgic encephalomyelitis (CFS / ME)

"This large nationwide registry linkage study confirms that the clinical picture in CFS/ME [chronic fatigue syndrome / myalgic encephalomyelitis] is complex."

That sentence, taken from the paper by Inger Bakken and colleagues [1] (open-access available here), is perhaps the under-statement of the year as authors sought to "describe comorbidities diagnosed in primary care in children diagnosed with CFS/ME in specialist health care" and "describe the timing of the diagnoses from primary care in relation to the timing of the CFS/ME diagnosis."

I grow tired of saying this but yet again, one of those very useful Scandinavian population registries was the starting point for the study - this time based in Norway - as some 1600 children diagnosed with CFS/ME were identified. Their data were compared against nearly 5000 children diagnosed with type 1 diabetes (T1DM) and a little over 1.3 million control - general child population - children. You could say that this was an adequately powered study.

A couple of important points were identified from the analysis of patient records. First: "Among children with CFS/ME, the most frequently observed primary care diagnosis was “weakness / general tiredness”." This is probably not unexpected given the nature of CFS/ME. Despite such weakness/general tiredness being initially identified in the vast majority of those with CFS/ME, sleep disturbances were also found more commonly among this group compared to other participants. Rather interestingly, asthma was also reported to be more common in the CFS/ME group than either of the control groups potentially reinforcing a role for atopy in the course/onset of at least some CFS/ME [2].

Next: "we found higher frequencies of depression and anxiety in the CFS/ME group." This is an important point that one has to be slightly careful with in terms of the introduction of psychological/psychiatric elements to a diagnosis of CFS/ME. I'll come back to this shortly.

Next: "Elevated frequencies of all diagnoses related to infection were observed in the CFS/ME group. In particular, infectious mononucleosis was far more frequent in this group (17.2 %) than in the control groups (T1DM: 3.7 %, general child population: 2.9 %). Influenza, acute tonsillitis, “strep throat”, and pneumonia were also more frequent in the CFS/ME group." Minus any sweeping generalisations, the suggestion that an infection illness might be part and parcel of at least some cases of CFS/ME is potentially borne out by this data. Infectious mononucleosis a.k.a glandular fever as a 'trigger' for CFS/ME is not unknown to the research [3] and other literature for example.

Finally: "The time span from the first primary care diagnosis of weakness / general tiredness to the specialist health care diagnosis of CFS/ME was 1 year or longer for 47.8 %." Whilst everyone would love to see a timely diagnosis of CFS/ME made, particularly when it comes to children, this data kinda suggest that diagnosis in Norway can still a long and drawn out process. Yes, I understand that many of the numerous diagnostic criteria used to diagnose CFS/ME rely on symptoms being present for an extended period of time but this does little to aid the child and their family and the important effects of such symptoms on things like schooling and other important facets of childhood.

The Bakken findings provide an important research snapshot of CFS/ME in children. The themes of (i) infection being potentially important to quite a few cases and (ii) the quite long time lag between primary care (i.e. General Practitioner, GP) diagnosis of weakness / general tiredness and specialist diagnosis of CFS/ME are important ones that research and practice can/should perhaps learn some lessons from.

Insofar as the observation of depression and/or anxiety being more frequently present in cases of CFS/ME, the authors make reference to the paper by Winger and colleagues [3] (see this post for more information). Winger et al reported that depressive symptoms in their group did not seemingly link/explain the reduction of health-related quality of life scores they reported for their cohort of adolescents with CFS. Taken together with the Bakken results, the implication is that whilst more commonly reported in CFS/ME, depression (and anxiety) issues are important to cases. They cannot however at this point be described as anything more than comorbid. I say this because, unfortunately, there are still opinions out there that might see depression, anxiety and other psychiatric manifestations as 'causative' of CFS/ME rather than, as I see it, being a symptom stemming from the effects of CFS/ME. If you are bed-bound, not able to go to school, not able to socialise properly and not able to do all the things your peers are doing, it is highly likely that your psychology will eventually be affected to some degree.

"The long time spans observed from the first diagnosis of weakness / general tiredness in primary care to a specialist health care diagnosis of CFS/ME might indicate that the treatment of these patients is sometimes not optimal." I also struggle to disagree with that sentence.

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[1] Bakken IJ. et al. Comorbidities treated in primary care in children with chronic fatigue syndrome / myalgic encephalomyelitis: A nationwide registry linkage study from Norway. BMC Fam Pract. 2016 Sep 2;17(1):128.

[2] Yang TY. et al. Increased Risk of Chronic Fatigue Syndrome Following Atopy: A Population-Based Study. Medicine (Baltimore). 2015 Jul;94(29):e1211.

[3] Winger A. et al. Health related quality of life in adolescents with chronic fatigue syndrome: a cross-sectional study. Health Qual Life Outcomes. 2015 Jul 3;13:96.

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Bakken IJ, Tveito K, Aaberg KM, Ghaderi S, Gunnes N, Trogstad L, Magnus P, Stoltenberg C, & Håberg SE (2016). Comorbidities treated in primary care in children with chronic fatigue syndrome / myalgic encephalomyelitis: A nationwide registry linkage study from Norway. BMC family practice, 17 (1) PMID: 27590471

ALSPAC says maybe to link between prenatal paracetamol exposure and childhood behavioural difficulties

ALSPAC - the Avon Longitudinal Study of Parents and Children - continues to give in research terms as today I approach the findings reported by Evie Stergiakouli and colleagues [1]. They observed that: "Children exposed to acetaminophen [paracetamol] prenatally are at increased risk of multiple behavioral difficulties, and the associations do not appear to be explained by unmeasured behavioral or social factors linked to acetaminophen use insofar as they are not observed for postnatal or partner’s acetaminophen use." Some media attention for the study can be found here.

Continuing the research journey on a topic not unfamiliar to this blog (see here and see here for example) that exposure to paracetamol during the nine months that made us might not be a totally benign affair, Stergiakouli et al analysed data for some 7,700 mothers included in the initiative between 1991 and 1992. Questions about paracetamol use at 18 and 32 weeks of pregnancy were asked of mothers and maternal reports of child behaviour problems at 7 years using the Strengths and Difficulties Questionnaire (SDQ) were thrown into the research mix.

Results: those behavioural difficulties potentially associated with maternal paracetamol use at both 18 and 32 weeks of pregnancy included both conduct problems and hyperactivity symptoms. Researchers were also able to record no (significant) connection between post-natal paracetamol use nor partner paracetamol use and childhood behavioural problems. They concluded that "the timing of acetaminophen use might be important" and that "the association between prenatal acetaminophen exposure and childhood behavioral problems is not explained by unmeasured familial factors linked to both acetaminophen use and childhood behavioral problems and that the findings are consistent with an intrauterine effect."

Combined with the various other studies suggesting an association between prenatal exposure to paracetamol and offspring behavioural 'issues' the case for a possible link is growing. ALSPAC has a number of methodological strengths to its design, not least "the availability of prospective information on acetaminophen use during the second and third trimesters of pregnancy and postnatally by the mother and by her partner." The fact that numerous potentially confounding variables were also controlled for is another bonus for the study results: "maternal age at birth, parity, socioeconomic status, smoking and alcohol consumption during pregnancy, prepregnancy body mass index (BMI), maternal self-reported psychiatric illness, and possible indications for acetaminophen use." This is pretty strong data (or at least as strong as the other data published on this topic).

Mechanism(s) of effect? Still something that needs a little more work I'm afraid, before any precise information is revealed. The authors go with some ideas based on the "endocrine-disrupting properties of acetaminophen" for example, but let's wait and see before anyone makes too many sweeping generalisations. I might however suggest that the possibility of a link between paracetamol exposure and asthma (see here) could be important in light of what asthma might mean for the risk of presentation of ADHD (attention-deficit hyperactivity disorder) for example (see here). Just a thought and bearing in mind the evidence linking paracetamol use and asthma is not always all on-way.

Further studies are required on this increasingly important topic. Please also bear in mind no medical or clinical advice is given or intended on this blog. Speak to your physician if you need more information about pain relief during pregnancy.

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[1] Stergiakouli E. et al. Association of Acetaminophen Use During Pregnancy With Behavioral Problems in Childhood. JAMA Pediatrics. 2016. Aug 15.

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Stergiakouli, E., Thapar, A., & Davey Smith, G. (2016). Association of Acetaminophen Use During Pregnancy With Behavioral Problems in Childhood JAMA Pediatrics DOI: 10.1001/jamapediatrics.2016.1775

Autism and asthma meta-analysed.. or is it?

"In conclusion, the results of this meta-analysis do not suggest an association between asthma and ASD [autism spectrum disorder]. Further prospective studies ascertaining the association between asthma and ASD are warranted."

So said the results of the meta-analysis by Zhen Zheng and colleagues [1] (open-access available here) and with it some research that made me think a little. Think because, on more than one occasion, I've talked about research suggesting that there might be a link between autism and asthma (see here and see here for example) including some 'big data' coming out of the research powerhouse that is Taiwan. Indeed, keep Taiwan in mind for now...

In this latest meta-analysis, data for some 9,000 participants diagnosed with an ASD were included, alongside over 175,000 controls (not autism). Authors concluded that: "the prevalence of asthma in ASD was 20.4%, while the prevalence of asthma in controls was 15.4% (P < 0.001)" (a significant difference). They go on to suggest that whilst a link between autism and asthma was 'plausible' (i.e. both labels seem to include findings around immune function and/or inflammatory processes) any relationship is likely to be coincidental or at least non-significant.

I don't mind telling you that I was a little confused by the Zheng findings. Yes, I know that the possibility of a link between autism and asthma is not always represented in the peer-reviewed findings (see here) but the conclusions just didn't sit right with me in terms of the data currently out there...

So, I had a good look at the Zheng paper and the adage that a meta-analysis is only as good as the data it examines might perhaps ring true. So: "Studies were eligible for analysis if they met all of the following criteria: (1) they were about the association between asthma and ASD; (2) they were case-control or cohort studies or cross-sectional studies; and (3) they provided the raw data or odds ratio (OR) with associated 95% confidence interval (CI)." Using these criteria, some 10 studies made the grade: "Six studies were conducted in the United States..., one in Turkey..., one in Brazil..., one in Poland..., and one in China" and went into the meta-analysis.

Did you notice that one country was missing? Y'know, a country beginning with 'T'? Far be it from me to question methods and authors' decisions and the like, but I couldn't help but ask where were the studies from Taiwan on this topic? Specifically, I was thinking about the research from Po-Hsin Tsai and colleagues [2] which probably should have made the research grade for a meta-analysis in this area. To quote from the Tsai study: "This prospective study indicated a temporal relation between asthma and subsequent ASD diagnosis, supporting the immune hypothesis of ASD pathogenesis." Indeed, I might also bring to your attention other work from Taiwan [3] that might also have made the meta-analysis grade too (albeit focused on various atopic diseases including asthma).

I'm willing to accept that some of the Taiwanese research may have not met all the criteria laid down by Zheng and colleagues and as a result, was not included for analysis. I'm also willing to accept that certain comorbidities (if I can still call them that) that appear to be over-represented when it comes to a diagnosis of autism might also show a stronger relationship to something like asthma as per the attention-deficit hyperactivity disorder (ADHD) correlation (see here). But in these days of increasing meta-analysis and systematic reviews, the idea that 'what goes into such an analysis will influence what comes out of it' might have to be more prominently displayed when big conclusions are being made from such big data...

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[1] Zheng Z. et al. Association between Asthma and Autism Spectrum Disorder: A Meta-Analysis. PLoS One. 2016 Jun 3;11(6):e0156662.

[2] Tsai P-H. et al. Increased risk of autism spectrum disorder among early life asthma patients: An 8-year nationwide population-based prospective study. Research in Autism Spectrum Disorders. 2014; 8: 381-386.

[3] Chen MH. et al. Is atopy in early childhood a risk factor for ADHD and ASD? a longitudinal study. J Psychosom Res. 2014 Oct;77(4):316-21.

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Zheng Z, Zhang L, Zhu T, Huang J, Qu Y, & Mu D (2016). Association between Asthma and Autism Spectrum Disorder: A Meta-Analysis. PloS one, 11 (6) PMID: 27257919

The developmental correlates of asthma (again)

Can I just get it out of the way? May the 4th be with you.

OK. The results from Mark Strom & Jonathan Silverberg [1] caught my eye recently and further evidence of a 'correlation' between asthma and developmental and/or behavioural outcomes. This time around it was "caregiver-reported speech disorders in US children" and how the appearance of asthma, hay fever and/or food allergy might show some important relationships with something like speech disorder. This follows other, similar work from this research tag-team that has previously graced this blog (see here).

Based on the analysis of "cross-sectional data on 337,285 children aged 2-17 from 19 US population-based studies, including the 1997-2013 National Health Interview Survey and the 2003/4 and 2007/8 National Survey of Children's Health" researchers engaged in some number-crunching to ascertain how physiology and behaviour might be linked. When controlling for various other important variables such as age and a history of eczema, authors reported some interesting correlations based again on those household survey results. "Future prospective studies are needed to characterize the associations.

I've zoomed in on the specific condition called asthma as being tied into parent (caregiver) -reported speech disorders because I'm mighty interested in the behavioural correlates that might follow this inflammatory condition (see here and see here for example). As Strom & Silverberg mention: "In one study that assessed caregiver-reported asthma severity, mild (1.58 [1.20-2.08], P=0.001) and moderate (2.99 [1.54-3.41], P<0.0001) asthma were associated with increased odds of speech disorder, however severe asthma was associated with the highest odds of speech disorder (5.70 [2.36-13.78], P=0.0001)." The idea therefore that severity of asthma might correlate with the odds of reporting (caregiver-reporting) a speech disorder, is seemingly an important one.

I could speculate all-day as to what might be the important driver(s) in any association between asthma and speech disorder (genetics, immune function, gut bacteria, medication and/or pollutants) but I don't think it would be particularly helpful at this point. Not any more helpful than reiterating that we do need a lot more investigation into this proposed association and that preferential screening for one or other condition when the other has been diagnosed might be a rather good idea.

And while I'm on the topic of immune function and behavioural correlates, how about another recent paper from this research tag-team [2] and more scientific evidence for a possible important association between atopic dermatitis and ADHD...

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[1] Strom MA. & Silverberg JI. Asthma, hay fever and food allergy are associated with caregiver-reported speech disorders in US children. Pediatr Allergy Immunol. 2016 Apr 19.

[2] Strom MA. et al. Association between AD and attention deficit hyperactivity disorder in US Children and Adults. Br J Dermatol. 2016 Apr 23.

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Strom MA, & Silverberg JI (2016). Asthma, hay fever and food allergy are associated with caregiver-reported speech disorders in US children. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology PMID: 27091599