"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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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

Language disorder and '2 children in every class'

I read with great interest the paper by Courtenay Frazier Norbury and colleagues [1] concluding that: "At school entry, approximately two children in every class of 30 pupils will experience language disorder severe enough to hinder academic progress."

With the aim of characterising "the impact of varying NVIQ [nonverbal IQ] criteria on prevalence, clinical presentation and functional impact of language disorder in the first UK population study of language impairment at school entry", the authors have generated quite a bit of food for thought as a consequence of their findings (see here) based on data derived from The Surrey Communication and Language in Education Study (SCALES).

Readers can peruse the hows and whys of the study design themselves, but some of the primary details were that based on an initial sample of some 7000 "who began a reception class (similar to kindergarten or school entry) in 2011" some 529 children were "selected for in-depth assessment in Year 1 (first grade, ages 5;1 – 6;10)" pertinent to issues such as language, NVIQ and other signs of emotional or behavioural problems.

After assessment(s) and some number-crunching, authors reported on a prevalence estimate of 7.5% when it came to "a clinically significant language disorder of currently unknown cause that adversely impacts learning." With class sizes of approximately 30 children in mind, we arrive at that opening sentence of 2 children in every class at Year 1 (5-6 year olds) potentially being affected. Further: "estimates are based on a population of children in mainstream classrooms and do not include children in special schools for children with complex learning needs or children with English as an additional language." Other details are also mentioned including the fact that the geographical area under study (Surrey) is a relatively affluent area (apparently having 'the highest proportion of millionaires in the UK') and so differing factors such as socio-economic status (SES) in other regions of the UK might actually mean the results are an 'under-estimate' of the true position.

There are a number of important implications from these findings, not least in terms of appropriate identification and support to be offered and "the need to raise awareness among education and health services regarding language disorder and its functional impact on children's daily lives." I note the authors have also zoomed in on the fact that language disorder had implications for "curriculum targets in the first year of school" (only 11% of those with a language disorder achieved those targets) and what that might mean in the wider context of schools being charged with 'raising standards, improving lives'. That also a greater number of children with a language disorder already had additional school support in place (39% vs. 6%) suggests that more needs to be done examining the impact of that support and whether it is actually helping children to achieve those 'curriculum targets' and more.

I appreciate that there are still various conversations on the nature of language disorder and what it actually means in the context of both available diagnostic criteria and in relation to its presence alongside other developmental/behavioural labels. No doubt debates will continue in these areas. For now however, the realisation that at least two children in every infant class will present with such issues is a wake-up call for quite a bit more research on both the hows and whys but also the best strategies to manage such issues and enable a child to achieve to their full academic potential...

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[1] Norbury CF. et al. The impact of nonverbal ability on prevalence and clinical presentation of language disorder: evidence from a population study. Journal of Child Psychology and Psychiatry. 2016. May 16.

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Norbury, C., Gooch, D., Wray, C., Baird, G., Charman, T., Simonoff, E., Vamvakas, G., & Pickles, A. (2016). The impact of nonverbal ability on prevalence and clinical presentation of language disorder: evidence from a population study Journal of Child Psychology and Psychiatry DOI: 10.1111/jcpp.12573

Immigrant background and risk of offspring ADHD

"The likelihood of being diagnosed with ADHD [attention-deficit hyperactivity disorder] was significantly increased among children of two immigrant parents... and children of an immigrant father."

So said the findings published by Venla Lehti and colleagues [1] continuing a research theme from this authorship group (see here) on how immigration might, for various reasons, bring about an increased or decreased risk of certain behavioural and/or psychiatric outcomes. This time around ADHD was in the research spotlight and how analysis "based on a national birth cohort" numbering in the tens of thousands suggested there may be more to see when it comes to a diagnosis in light of parental immigration status.

The records of over 10,000 children/young adults born between 1991 and 2005 and diagnosed with ADHD by 2011 were compared with matched - not ADHD - controls (n=39,124) taking into account "parents' country of birth and native language." Various other variables were added into the subsequent statistical mix including "time since maternal migration." As per that opening sentence, there did appear to be more to see when it came to immigration status and offspring outcome; where a child was born to two immigrant parents, the adjusted odds ratios were not to be sniffed at (4.7, 95% CI 3.4-6.6) insofar as an increased risk of offspring ADHD diagnosis.

I was also taken by another finding reported by Lehti et al: "Children, whose parents were born in countries with low Human Development Index (HDI), were more often diagnosed with ADHD." The HDI is a sort of summary measure taking into account variables such as education, life expectancy and income ranking countries in terms of their human development. Quite a few of the countries in places like sub-Saharan Africa, North Africa and Latin America rank 'low' on the HDI and also seemed to tally with the specific data on country of origin when it came to the Lehti findings.

As interesting as the current findings are, the universal idea that ADHD risk might be elevated in children of immigrant families is by no means a settled issue [2]. As per my sentiments on quite a few issues covered on this blog, sweeping generalisations are not required. I would however like to see a lot more research done on this issue focused not just on 'risk' of diagnosis but also around the possible factors that might contribute to immigrant offspring being more readily diagnosed with something like ADHD. Lehti et al suggest that their results might indicate "increased exposure to environmental risk factors, differences in the use of health services, or challenges in diagnosing immigrants' children" as being relevant. Certainly one could draw on work in other clinical areas as being potentially relevant (see here for example) to the current findings including potential biological correlates too (see here and see here).

One further point that might also be particularly important to the Lehti findings: that linked to socio-economic status (SES) and how that seems to affect risk of a diagnosis of ADHD more generally (see here). Without generalising about any relationship between immigration status and SES, it is not outside the realms of possibility that at least for some migrants, entry to places like Finland where the current research was carried out, might not be accompanied by significant wealth for example. SES deprivation and ADHD diagnosis is an area of continuing interest [3]; indeed, with recent political situations in mind, one wonders whether future surveillance may be very much indicated.

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[1] Lehti V. et al. Association between immigrant background and ADHD: a nationwide population-based case-control study. J Child Psychol Psychiatry. 2016 May 2.

[2] Tan TX. Emotional and Behavioral Disorders in 1.5th Generation, 2nd Generation Immigrant Children, and Foreign Adoptees. J Immigr Minor Health. 2016 Mar 14.

[3] Russell AE. et al. The Association Between Socioeconomic Disadvantage and Attention Deficit/Hyperactivity Disorder (ADHD): A Systematic Review. Child Psychiatry Hum Dev. 2016 Jun;47(3):440-58.

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Lehti V, Chudal R, Suominen A, Gissler M, & Sourander A (2016). Association between immigrant background and ADHD: a nationwide population-based case-control study. Journal of child psychology and psychiatry, and allied disciplines PMID: 27133554

Age at autism diagnosis has not decreased in the UK over the past decade

"This study of over 2000 children shows that the median age of ASD [autism spectrum disorder] diagnosis in the UK has not reduced in the last decade."

That was the rather important message included in the study by Denise Brett and colleagues [1] (open-access) reporting combined results from the Daslne (Database of Children with ASD Living in the North East of England) and ASD-UK (Autism Spectrum Database-UK) initiatives. Including data from over 2100 children and families, researchers set about examining the mean and median age at diagnosis according to year from 2004 to 2014.

Alongside looking at the number and proportion of children per year who were diagnosed below 3 years and 5 years of age, they suggested that "increased publicity, clinical initiatives and awareness of ASD, and the knowledge that some phenotypes are strongly associated with ASD" has seemingly done little to reduce the age at diagnosis for this cohort. As a result, there are consequences: "For children, delayed diagnosis can result in lack of early intervention, suboptimal school placement, and lack of access to the strategies helpful for children with ASD" and "For parents, delays in diagnosis mean they are missing out on understanding their child’s difficulties, and receiving the appropriate support, help and management strategies they need." Indeed, there may be lots of consequences (see here).

There are some other important findings reported by Brett et al that also require comment. So: "Children with additional diagnoses were diagnosed with ASD later than children without other diagnoses" as over-represented diagnoses such as attention-deficit hyperactivity disorder (ADHD) are mentioned (see here). In light of the diagnostic 'interference' suggested by conditions such as ADHD, I might direct your attention to the important work coming out of the Wall/Duda lab as being potentially relevant (see here).

Also: "Contrary to our hypothesis, and previous research... having a sibling with ASD did not result in an earlier age at diagnosis." This is an odd finding given the wealth of knowledge on the topic of autism familial recurrence (see here) and idea that observation and perhaps even preferential screening might follow when one diagnosis is received. The authors explain this by suggesting that the presentation of autism can (and does) differ from one child (person) to the next. "For example, the first child may have autism and language regression, whereas the sibling’s language may have developed in line with age expectations but social communication difficulties only become clearer at school age." Appreciating the concepts such as the broader autism phenotype (BAP) can fuzzy the boundaries of what is and isn't [clinically] autism (see here), it seems that still there are lessons to be learned here. I'd also suggest that the issue of regression when it comes to the onset of autism is still deserving of a lot more scrutiny (see here).

"Factors associated with earlier age of diagnosis were autism diagnosis (compared with other ASD), language regression, language delay, lower socioeconomic status, and greater degree of support required." The authors provide some important details about which factors might affect age at diagnosis that should be added to what is already known (see here). That 'lower socioeconomic status' (SES) was associated with an earlier age of diagnosis might also seem surprising to some readers. The authors rightly highlight our National Health Service ('free at the point of use') and how this "may lessen the impact of SES on access to services in comparison with the US and some other countries." But still, the suggestion that lower SES might facilitate an earlier age of diagnosis does require more study, particularly when conditions like ADHD have also been linked to SES status in the UK (see here). I'm also wondering whether factors such as all that extra pupil premium money (when you can get it) given to schools/academies might also be contributory to earlier identification and diagnosis as a function of SES?

The findings from Brett et al suggest that here in the UK, we still have some way to go in order to progress early identification and diagnosis when it comes to autism. I'd like to think that changes are being made to elements contributory to earlier diagnosis as per the introduction of the ASQ-3 to the Healthy Child Program (see here) for example. But, and it is an important point, earlier diagnosis is really only going to be achieved when more money and resources are put into the mechanisms of screening and assessment (see here) and when headlines like 'we waited 6 years for an autism diagnosis' are seen no longer. Indeed, with all the talk about increasing autism awareness (which have been going on for quite a few years now), that awareness counts for nothing if the systems aren't in place to cope with the increasing numbers of people waiting for assessment (see here). And when it comes to autism screening and assessments, we might also want to listen to parents and primary caregivers a little more too (see here).

Now, how about also looking at the state of diagnosis and diagnostic delays when it comes to adults too including how 'self-diagnosis' might fit into the picture [2]? Y'know, among the various other changes that could improve the lives of those with autism...

To close, for those of us who understand the context of the words 'It's a trap!' it is indeed a sad day...

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[1] Brett D. et al. Factors Affecting Age at ASD Diagnosis in UK: No Evidence that Diagnosis Age has Decreased Between 2004 and 2014. Journal of Autism and Developmental Disorders. 2016. March 31.

[2] Foran Lewis L. Exploring the Experience of Self-Diagnosis of Autism Spectrum Disorder in Adults. Archives of Psychiatric Nursing. 2016. 1 April.

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Brett, D., Warnell, F., McConachie, H., & Parr, J. (2016). Factors Affecting Age at ASD Diagnosis in UK: No Evidence that Diagnosis Age has Decreased Between 2004 and 2014 Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-016-2716-6

2% of UK 16-year olds with chronic fatigue [syndrome]?

"CFS [chronic fatigue syndrome] affected 1.9% of 16-year-olds in a UK birth cohort and was positively associated with higher family adversity. Gender was a risk factor at age 16 years but not at age 13 years or in 16-year-olds without high levels of depressive symptoms."

So said the findings reported by Simon Collin and colleagues [1] which also gained some media interest as per an entry on the BBC news website for example (see here). Based on data generated by the Children of the 90s research initiative (ALSPAC to you and me), researchers looked to estimate the prevalence of the condition in some 5,700 youth participants.

I say looked to 'estimate the prevalence' of CFS but I don't think they formally screened/assessed for the condition on this occasion; rather sending out questionnaires to parents and youth regarding "unexplained disabling fatigue lasting ≥6 months." As per the introduction of SEID (see here) to CFS (and ME) such questioning addresses one aspect of CFS but not necessarily all. One also has to be slightly careful about spreading the label too liberally [2] so as not to dilute what CFS means to many, many people and potentially including many presentations under the current banner [3]. I'll say something further about this shortly.

Authors reported an overall prevalence of chronic fatigue of ~2% in their cohort. This figure fell somewhat when "excluding children with high levels of depressive symptoms" to something like 0.6%. Further, when also looking at data "obtained from the National Pupil Database" and cross-linking it to findings, they found that authorised school absences were higher for those with CFS. This follows previous work from this research group already covered on this blog (see here). Finally, the authors talk about how being female and "family adversity" seemed to be more frequently associated with chronic fatigue. As far as I can ascertain however, no other measure (biological or genetic) was included in the study as it stands.

Set within the context of 2015 seeing a real ramping up of research into CFS/ME (see here) and some rather public discussions on what may (or may not) be the best way to manage/treat the condition (see here), the Collin findings are an interesting addition to the research base. As per the accompanying press release, the idea that family adversity - that "included poor housing, financial difficulties and a lack of practical and/or emotional support for the mother" - seemed to play something of a role in the findings goes some way to "dispelling the commonly held view that CFS is a 'middle-class' illness or 'yuppie-flu'." The same authors have also talked about other factors linked to adolescent fatigue in other publications [4] but I'm minded to be a little careful around suggested ideas like "children whose mothers experience anxiety and/or depression between pregnancy and child's age 6 years have an increased risk of developing chronic disabling fatigue in early adolescence." I think many people have had quite enough of hearing about 'psychosomatic explanations' of CFS/ME (see here) and would perhaps prefer further concentration on more pertinent biological and/or genetic processes. I'd also like to see the term 'yuppie flu' stricken from any text where CFS/ME is also mentioned.

Significantly more resources need to be put into looking at CFS/ME (including identification [5]) and what can be done to alleviate the condition particularly when one sees how much it can affect a person (see here and see here) and those around them. As per my previous ramblings on the topic (see here and see here) I'm pretty firmly sold on the idea that whilst psychology will (inevitably) be affected by a diagnosis, targeting the underlying genetics [6] and biology of the condition is the way forward (see here for example) mindful that there probably is no universal one-size-fits-all intervention for this 'spectral' condition.

Just before I go, I do want to return to that point about what exactly comes under the banner of CFS/ME based on the Collin study findings and some other goings on. As per the example detailed by Jason et al [3], one has to be a little cautious about what one includes under labels such as SEID. To quote: "many individuals from major depressive disorder illness groups as well as other medical illnesses were categorized as having SEID" based on the lack of exclusionary criteria applied to this new label. I kinda get the impression that set within the viewpoint of CFS/ME being a 'psychological condition' still unfortunately prevalent in some quarters, conflating certain depressive illnesses with CFS/ME could be used to serve an important purpose when it comes to things like presenting certain intervention options above others. At the very least, it provides a handy distraction from looking at more objective biological information potentially pertinent to at least some of this patient group. We need to be very careful...

I foresee 2016 as being another important year for CFS/ME and yes, I will be blogging about the recent Roberts study on mortality statistics and CFS/ME soon enough...

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[1] Collin SM. et al. Chronic Fatigue Syndrome at Age 16 Years. Pediatrics. 2016 Jan 25. pii: peds.2015-3434.

[2] Friedberg F. et al. Prolonged fatigue in Ukraine and the United States: Prevalence and risk factors. Fatigue. 2015;3(1):33-46.

[3] Jason LA. et al. Unintended Consequences of not Specifying Exclusionary Illnesses for Systemic Exertion Intolerance Disease. Diagnostics (Basel). 2015 Jun 23;5(2):272-86.

[4] Collin SM. et al. Maternal and childhood psychological factors predict chronic disabling fatigue at age 13 years. J Adolesc Health. 2015 Feb;56(2):181-7.

[5] Collin SM. et al. Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME) is different in children compared to in adults: a study of UK and Dutch clinical cohorts. BMJ Open. 2015 Oct 28;5(10):e008830.

[6] Schlauch KA. et al. Genome-wide association analysis identifies genetic variations in subjects with myalgic encephalomyelitis/chronic fatigue syndrome. Translational Psychiatry. 2016; 6: e730.

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Collin, S., Norris, T., Nuevo, R., Tilling, K., Joinson, C., Sterne, J., & Crawley, E. (2016). Chronic Fatigue Syndrome at Age 16 Years PEDIATRICS, 137 (2), 1-10 DOI: 10.1542/peds.2015-3434

ADHD in the UK

I don't want to keep you too long today but thought it worthwhile to bring the paper by Adrian Hire and colleagues [1] to your attention and the suggestion that "socioeconomic deprivation" may play a role when it comes to ADHD (attention-deficit hyperactivity disorder).

Based on data derived from the "Clinical Practice Research Datalink (CPRD)" - a UK based resource "providing anonymised primary care records for public health research since 1987" - researchers set about looking at those children/young adults diagnosed with ADHD between 2004 and 2013. This information was stratified according to the region where the general practice (GP) surgery was based added to which a measure of deprivation status was calculated ("Practice Index of Multiple Deprivation (IMD) score").

The results: well, aside from something of quite a stable incidence (that's incidence not prevalence) of ADHD apart from the last 2 years studied (interestingly), Hire et al also reported that: "In almost every year studied, incidence rates were highest among the most deprived patients and lowest among the least deprived patients." They concluded that there may be quite a bit more to see when it comes to socioeconomic deprivation (i.e. poverty etc.) and the label ADHD.

Obviously one has to be a little guarded in making too many sweeping generalisations from this data (including the use of "a surrogate measure" for deprivation status) but there is quite a bit more work to do in this area. Other statistics for example, have come to similar conclusions about socioeconomic disparities and ADHD diagnosis [2] crossing different geographies as well. That and the suggestion that ADHD + other diagnoses might show important effects as a function of societal variables such as poverty (see here) and one has some intriguing hypotheses to test with some potentially important conclusions reflective of lots of variables including social policy.

Music: Coldplay - Adventure Of A Lifetime (and a great video).

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[1] Hire AJ. et al. ADHD in the United Kingdom: Regional and Socioeconomic Variations in Incidence Rates Amongst Children and Adolescents (2004-2013). J Atten Disord. 2015 Nov 23. pii: 1087054715613441.

[2] QuickStats: Percentage of Children Aged 5-17 Years with Diagnosed Attention Deficit/Hyperactivity Disorder (ADHD),by Poverty Status and Sex - National Health Interview Survey, 2011-2014. MMWR Morb Mortal Wkly Rep. 2015 Oct 16;64(40):1156.

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Hire AJ, Ashcroft DM, Springate DA, & Steinke DT (2015). ADHD in the United Kingdom: Regional and Socioeconomic Variations in Incidence Rates Amongst Children and Adolescents (2004-2013). Journal of attention disorders PMID: 26604267

Prenatal air pollution and autistic traits NOT linked (in Europe)

"Prenatal exposure to NO2 [nitrogen oxide] and PM [particulate matter] was not associated with autistic traits in children from four to ten years of age in four European population-based birth/child cohort studies."

That was the conclusion reached in the study published by Mònica Guxens and colleagues [1] (open-access available here) crossing various European population-based cohorts as part of the "European Study of Cohorts for Air Pollution Effects (ESCAPE)" and looking at some 8,000 children in total. Outside of the grand study design and large participant number included in the Guxens study, I wanted to talk about this study to provide a little balance to the previous discussions on this blog about autism and air pollution which seemed to be coming to rather different conclusions (see here and see here for example).

The Guxens paper is open-access but here are a few pointers:

• First, take three population-based birth cohorts (GENERATION R, GASPII & INMA) and one "European longitudinal child and adolescent twin study: CATSS". 
• Follow a well-trodden path of estimating air pollution exposure based on birth home addresses and looking at air pollution levels "in the study areas" and "estimate annual average air pollution concentration at the participants’ birth home addresses."
• Next, assess your cohort(s) for the presence of autistic traits (not actual diagnoses) using various instruments (though not necessarily the same instrument for every country included for study). Control for possible confounders including urbanicity and various maternal characteristics including those during birth and apply statistics.
• Results: anywhere between 3-12% of children studied showed "autistic traits within the borderline/clinical range." Further: "between 0.7% and 3.6% were classified as having autistic traits within the clinical range." These were mostly boys and "had a higher proportion of mothers with low educational level and mothers who smoked during pregnancy compared to children without autistic traits."
• "We found no evidence for an association between prenatal air pollution exposure and autistic traits in children aged 4 to 10 years." Further: "These results were consistent for all air pollutants assessed, across countries, using different cut-offs of autistic traits, examining autistic traits as continuous variables, and after adjusting for several socioeconomic status variables and urbanicity."

Guxens et al note how their results are in direct contrast to the some of the previous and emerging research [2] in this area, citing some important references along the way. They explain this in a few ways including noting how: "previous case-control studies selected children with a diagnosis of ASD [autism spectrum disorder] whereas in our study we studied children with autistic traits from population-based birth/child cohorts." Further: "We hypothesize that prenatal exposure to air pollution could be related to ASD but not with broad autistic traits in children" but based on their data "found no indication of an association between prenatal air pollution exposure and autistic traits within the clinical range."

The idea that: "Further research including trace metal content of the PM such as lead or manganese is warranted to better understand the discrepant findings" is also banded about and I'm in agreement with them on this matter [3] given some of the previous findings on the metallome and autism (see here). Lead (Pb) and its health effects by the way, is also something that I've been interested in down the years of blogging (see here).

Without trying to turn null findings into positive findings, I'm also minded to bring another variable to the table that might be worth re-analysing for based on the findings from Heather Volk and colleagues [3] (one of the co-authors on the Guxens paper) who talked about gene x environment interactions when it comes to the possibility of a link between risk of autism and prenatal air pollution exposure (covered in a previous blog post). I say this bearing in mind that studying MET genotype on its own and without reference to the multitude of genetic and epigenetic factors that may also be involved, is but a drop in the scientific ocean; but at least it would be a start.

I end however with the statement that: "this study showed a null association between prenatal exposure to several air pollutants, including NO2 and PM, and autistic traits in children aged 4 to 10 years in four European population-based birth/child cohorts." Once again, autism research comes up with conflicting findings...

Music: AC/DC - Highway to Hell.

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[1] Guxens M. et al. Air Pollution Exposure during Pregnancy and Childhood Autistic Traits in Four European Population-Based Cohort Studies: The ESCAPE Project. Environ Health Perspect. 2015 Jun 12.

[2] Talbott EO. et al. Fine particulate matter and the risk of autism spectrum disorder. Environmental Research. 2015; 140: 414-420.

[3] Sanders AP. et al. Perinatal and Childhood Exposure to Cadmium, Manganese, and Metal Mixtures and Effects on Cognition and Behavior: A Review of Recent Literature. Current Environmental Health Reports. 2015. July 5.

[4] Volk HE. et al. Autism spectrum disorder: interaction of air pollution with the MET receptor tyrosine kinase gene. Epidemiology. 2014 Jan;25(1):44-7.

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Guxens M, Ghassabian A, Gong T, Garcia-Esteban R, Porta D, Giorgis-Allemand L, Almqvist C, Aranbarri A, Beelen R, Badaloni C, Cesaroni G, de Nazelle A, Estarlich M, Forastiere F, Forns J, Gehring U, Ibarluzea J, Jaddoe VW, Korek M, Lichtenstein P, Nieuwenhuijsen MJ, Rebagliato M, Slama R, Tiemeier H, Verhulst FC, Volk HE, Pershagen G, Brunekreef B, & Sunyer J (2015). Air Pollution Exposure during Pregnancy and Childhood Autistic Traits in Four European Population-Based Cohort Studies: The ESCAPE Project. Environmental health perspectives PMID: 26068947

Sick leave and income levels for parents of children with autism

"Parents of children with ASD [autism spectrum disorder] living in Stockholm, Sweden in 2006 were more likely to be on sick leave, not in the labor force, or earning low income when compared to parents who did not have a child with ASD and these results remained after adjusting for familial socioeconomic factors and parental psychiatric care."

That was the rather grim conclusion reached by Miranda McEvilly and colleagues [1] (open-access) following their analysis of families taking part in the Stockholm Youth Cohort (SYC) initiative [2] - "a record-linkage study comprising all individuals aged 0–17 years, ever resident in Stockholm County in 2001–2007 (N = 589,114)." From the huge number of participants, researchers identified 2,982 mothers/fathers with a child diagnosed on the autism spectrum: "1,207 had ASD with ID [intellectual disability] (or more than one child with ASD where at least one of the children had ASD with ID) and 1,685 had ASD without ID."

"Four outcomes, two for sick leave and two for work participation, were obtained using data from LISA in 2006." LISA by the way, refers to "the longitudinal integration database for health insurance and labor market studies (LISA)" based in Sweden and carries quite a bit of information about employment and related parameters. Participant data were analysed according to the presence of offspring autism and whether or not said autism was accompanied by ID or not. Various potential confounding variables were also added into the statistical mix as per the headline sentence above.

Results: well, we already know that parents with a child (or children) with autism were quite a bit more likely to be taking sick leave or not to be in work or to be on a low income compared to those without. This trend was particularly notable in mothers of children with autism. Researchers also reported that when comparing families with a child with autism and ID with those with a child with autism but no ID, several differences were also apparent. So: "Increased sick leave (15–365 days) is associated with parents of children with ASD without ID but not ASD with ID" (again, with mothers faring worse than fathers).

"Parents who have a child with ASD are more likely to experience stress, depression, and fatigue. Therefore it is not surprising that these parents take sick leave more frequently or participate less in the work force." As per this excerpt, the authors frame their findings within the perspective that parenting a child diagnosed with an ASD can carry its own particular stresses and strains outside of those more generally associated with parenting. I've covered this topic before on this blog and how, without blaming or stigmatising, there is a growing recognition of the need for additional support services for those parents (see here). The fact that Sweden has specific policies "aimed at helping families of children with ASD, both with well-being and with ability to work" also seemed not to be as effective as perhaps initially thought as "these parents remain a vulnerable group for which additional support might be warranted."

This is valuable data that adds to previous discussions about how the presence of familial autism can [variably] impact well beyond individuals and contribute to some of the societal inequalities that have been noted. One might quibble with some of the study mechanics such as the inclusion of "parents with children with other disabilities" in the comparison group or the lack of emphasis on other autism-associated comorbidities (in these days of ESSENCE) outside of ID and how they may impact on parental employment and earnings, but this is perhaps research fodder for a different time.

"It can also be noted that being on sick leave, outside of the work force or earning a low income will have long reaching impact on these parents because of Sweden’s pension system which is based on an individual’s life time earnings." This is another potential outcome that the authors focus in on as a consequence of their findings. One might put forward the viewpoint that where noted both inside and outside of Sweden, further preferential economic policies could be put in place as and when a child is diagnosed to secure both their future and that of their parents too. Also: "It is recommended that further studies be done to see what support mothers and fathers would find most beneficial and what support they are lacking." I cannot disagree with that last sentiment.

Music: David Bowie - Five Years.

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[1] McEvilly M. et al. Sick Leave and Work Participation Among Parents of Children with Autism Spectrum Disorder in the Stockholm Youth Cohort: A Register Linkage Study in Stockholm, Sweden. Journal of Autism and Developmental Disorders. 2015; 45: 2381.

[2] Idring S. et al. Autism Spectrum Disorders in the Stockholm Youth Cohort: Design, Prevalence and Validity. PLoS One. 2012; 7(7): e41280.

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McEvilly M, Wicks S, & Dalman C (2015). Sick Leave and Work Participation Among Parents of Children with Autism Spectrum Disorder in the Stockholm Youth Cohort: A Register Linkage Study in Stockholm, Sweden. Journal of autism and developmental disorders PMID: 25697737

Autism, parental concerns and socioeconomic status

I'd like to think that there are some rather important messages to be taken from the paper by Xiang Sun and colleagues [1] on level of parental concern, socioeconomic status (SES) and risk of autism. Not only did the authors conclude that: "a higher SES was not associated with the risk of having ASC [autism spectrum conditions]" they also found that: "No child met ASC criteria where parents expressed no concerns".

Do you prefer "fashion victim" or "ensembly challenged"?

SES - including variables such as family income, parental educational attainment(s) and parental occupation(s) - has been something of a talking point in autism research down the years and the rather mixed messages which have come out of the research literature on SES and offspring autism risk (see here). The growing appreciation that children of those positioned in a higher SES bracket don't seem to be at any significantly greater risk of autism is something rather important as per other evidence, for example, noted by Fujiwara [2]. Whether this means previous contrary findings were in error or that there has been some shift in the factors linked to the onset of contemporary autism is unknown at this time.

Some of my first thoughts on the Sun SES findings were in relation to all the discussions about offspring autism potentially being associated with certain types of parental occupational choices [3]. Indeed, considering that the Sun study was both carried out in and originated from Cambridge (UK) and included Prof. Simon Baron-Cohen on the authorship team, it is coincidental that the findings could be construed as counter to such occupational links with autism (assuming that Physicists, Engineers and Mathematicians would be described as higher SES jobs).

Of course I'm not saying the research on any relationship between offspring autism and parental occupation choice is all bunk; the paper from Windham and colleagues [4] and other evidence is too strong to negate (including that of occupational exposures potentially being involved). Merely that there may be much more to see than just a spectrum of 'talent' genes overlapping with autism risk genes [5] when it comes to receipt of a diagnosis on the very wide autism spectrum. Oh, and assuming you believe talent is all in the genes...

The other finding from Sun et al discussing parental concern and potential diagnosis of autism in offspring also carries quite a bit of potential importance. Regular readers of this blog might already have picked up my respect for parents and carers as active agents both in terms of picking up the signs and symptoms of autism in their loved ones (see here) and also detecting and reporting other important comorbidity (see here). I see the Sun findings - "No child met ASC criteria where parents expressed no concerns" - as corroborating parents and caregivers as doing what they do best: knowing their own child. I might also suggest that the discussions on increasing autism rates solely being down to better awareness and greater diagnostic vigilance are not seemingly backed up by the Sun findings if we assume parental concerns represent the starting point of the diagnostic journey into autism.

Some music to close. Gershon Kingsley and Popcorn.

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[1] Sun X. et al. Parental concerns, socioeconomic status, and the risk of autism spectrum conditions in a population-based study. Res Dev Disabil. 2014 Sep 25;35(12):3678-3688.

[2] Fujiwara T. Socioeconomic status and the risk of suspected autism spectrum disorders among 18-month-old toddlers in Japan: a population-based study. J Autism Dev Disord. 2014 Jun;44(6):1323-31.

[3] Baron-Cohen S. Does Autism Occur More Often in Families of Physicists, Engineers, and Mathematicians? Autism. 1998; 2: 296-301.

[4] Windham GC. et al. Autism spectrum disorders in relation to parental occupation in technical fields. Autism Res. 2009 Aug;2(4):183-91.

[5] Baron-Cohen S. Autism and the technical mind: children of scientists and engineers may inherit genes that not only confer intellectual talents but also predispose them to autism. Sci Am. 2012 Nov;307(5):72-5.

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Sun, X., Allison, C., Auyeung, B., Baron-Cohen, S., & Brayne, C. (2014). Parental concerns, socioeconomic status, and the risk of autism spectrum conditions in a population-based study Research in Developmental Disabilities, 35 (12), 3678-3688 DOI: 10.1016/j.ridd.2014.07.037

Weighing up genetics and environment in autism

"Environment as important as genes in autism, study finds" read the press release about the study by Sven Sandin and colleagues [1]. Even the authors seemed to be taken aback by the weighting their results gave to a role for non-genetic factors contributing to autism risk as per their comments: "We were surprised by our findings as we did not expect the importance of environmental factors in autism to be so strong... It's now clear we need much more research to focus on identifying what these environmental factors are".

And so the titanic battle between genes and environment continues in autism research as memories flood back about the paper by Joachim Hallmayer and colleagues [2] talked about in a previous post (see here).

Backing up slightly, there are a few points to make about the Sandin paper:

• Based on data derived from one of those very useful Scandinavian health registries, this time based in Sweden, the starting point for researchers were the records of over 2 million children born between 1982 and 2006. 
• Fourteen and a half thousand children diagnosed with an autism spectrum disorder (ASD) were included in those millions of records, 5689 of them diagnosed with autism up until the end of December 2009. One certainly can't say that it was an under-powered study in terms of the participant numbers examined despite the focus being on anonymised data from medical records. 
• As per another write-up of the study (see here) the authors looked at both heritability, "the proportion of risk in the population that can be attributed to genetic factors" and relative recurrence risk (RRR) which "measures individual risk for people who have a relative with autism".
• Results: "Autism risk rises 10 fold if first child has disorder" for full siblings reported one newspaper. So, having a full brother or sister with autism places a sibling at some significant risk of developing autism or ASD. Even a half brother or sister is associated with something like a 3-fold risk for autism, and a 2-fold risk if it is a cousin. Monozygotic twins.. well the RRR came in at 153 which I'm pretty sure speaks for itself.
• But... "The ASD heritability was estimated to be 0.50 (95% CI, 0.45-0.56) and the autistic disorder heritability was estimated to 0.54 (95% CI, 0.44-0.64)". This is the part of the Sandin paper that most media have gone with, suggesting that for autism "heritability is only half the story, with the other 50 percent explained by environmental factors such as birth complications, socio-economic status, or parental health and lifestyle". 

I don't think I need to tell you how important the Sandin paper might be to autism research. Not only because the findings further inform about the potential recurrence risk of autism [3] and the implications for genetic counselling, but also that they bring back to our attention how genes and environment might [variably] interact when it comes to autism risk. Certainly sweeping generalisations that I've heard down the years about 'autism being genetic' might have to be slightly tempered. Regular readers of this blog probably already know how I feel about generalisations when it comes to autism, sorry the autisms, and how aspects of environment (however you wish to describe this) are finding quite a bit of research favour in recent years (see here and see here).

I'd also like to think that the Sandin study might further stimulate some research interest and funding when it comes to looking at the bridges between genes and environment when talking about autism risk. I'm thinking about the recent genes and air pollution work (see here) as a template of where to start; understanding that although the door has been further opened to a role for environment in autism risk, this doesn't mean that genetic contributions are all bunk. Think BCKDK gene mutations as one example (see here) and keep in mind the heterogeneity of autism and its potential overlap with other conditions (see here).

And then there is epigenetics. I know that some people still see this upcoming area as a fad or distraction from work on more traditional structural changes to the genome such as all those SNPs, CNVs and other issues. I don't. I see it as very much complementary and how concepts such as DNA methylation or mention of words like histones might have some really important connections to conditions like autism. Think HERVs - human endogenous retroviruses - as one example (see here) under epigenetic control, and indeed, whether as the paper by Shuvarikov and colleagues [4] implied: "HERV-H elements as a mechanism of [genetic] deletion formation".

I could go on but I won't. Suffice to say the autism research wheels keep turning and science books about autism keep being rewritten...

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[1] Sandin S. et al. The Familial Risk of Autism. JAMA 2014; 311: 1770-1777.

[2] Hallmayer J. et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry. 2011 Nov;68(11):1095-102.

[3] Ozonoff S. et al. Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium study. Pediatrics. 2011 Sep;128(3):e488-95.

[4] Shuvarikov A. et al. Recurrent HERV-H-mediated 3q13.2-q13.31 deletions cause a syndrome of hypotonia and motor, language, and cognitive delays. Hum Mutat. 2013 Oct;34(10):1415-23.

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Sandin, S., Lichtenstein, P., Kuja-Halkola, R., Larsson, H., Hultman, C., & Reichenberg, A. (2014). The Familial Risk of Autism JAMA, 311 (17) DOI: 10.1001/jama.2014.4144

Increased rate of offspring autism among migrants

In the eternal search for the various potential factors (yes, there are probably going to be several) to account for the quite staggering increases in diagnosed cases of the autism spectrum conditions, no stone is seemingly being left unturned. Accepting the important and oft-cited sentence "correlation is not the same as causation" and accepting that the reasons for the increase in the autisms (plural) might differ from location to location, country to country and people to people, retrospective reviews of registries and case notes have featured quite a bit in this search for reasons.

The paper by Suzanne Bolton and colleagues* follows in this methodological tradition, suggesting: "an observation of increased rates of ASD [autism spectrum disorder] among a migrant population derived particularly from children born to mothers originating in Sub-Saharan Africa" based on a review of some 366 children presenting at a child development service in Ireland (Éire).

Based on those 366 case reports, autism or rather an ASD, was diagnosed in 131 and speech and language issues in 132 children. This in itself is interesting data based on the proportion of children coming to use the child development services - I assume because someone, somewhere had observed something worthy of the referral - and those eventually diagnosed with autism. Even more interesting in light of further genetic connections being made between autism and language impairment**.

No mind, when looking at those born to mothers born themselves in Africa "a higher proportion of the African cohort 13/18 (72.2 %) presented with moderate/severe cognitive disability compared to the Irish group 9/55(16.3 %)". In other words, the presentation of autism and intellectual (learning) disability towards the more severe end of the spectrum seemed to be more pronounced in the migrant population than those born to mothers themselves born in Ireland.

This is not the first time such a finding has been reported. I hark back to my post on the work of Cecilia Magnusson and colleagues*** who also reported a similar trend in their registry-based study following on from similar suggestions from other work.

So, what might one surmise from this growing body of work. Well, if I were to use the paper by Rai and colleagues**** as my starting point (see a previous post here) I might say that we should be looking at factors such as socio-economic status (SES) among those families arrived from Africa compared to Irish families to see if they could account for the differences raised by Bolton et al. Rai concluded that "Lower, not higher, socioeconomic status was associated with an increased risk of ASD" and without making any sweeping generalisations, one has to wonder whether demographic disparities might exist on the basis of indigenous and naturalised status.

That all being said, Ireland has some pretty comprehensive measures when it comes to the screening and diagnosis of autism (see here) no matter what side of the border you are on. If we are talking about children presenting with "a more severely affected" type of autism, it's highly likely that if not parents, nursery or school or other services would pick up on the need for a referral for assessment even if not knowing that it might be autism. Language and cultural differences about autism (see here) may impact on this process but I'd hazard a guess that not as much as one might first think.

Other potential explanators please. Well, without getting too bogged down in the debate about different ethnicities and different genetics, one has to wonder whether the risk of autism might be somehow reduced or elevated among different peoples. At the moment, we can't say for sure because worldwide, not everyone has access to the same screening, assessment and diagnostic resources that we perhaps take for granted in the modern Western world (see here). Autism research is also not exactly thriving in some parts of the world. Throw in again those language and cultural issues - even in our supposedly developed world***** - and the big question mark on this area still remains.

Then to environment. Lots of potential factors here including the stress of moving to and integrating into a new country, the introduction of a very new environment and climate - Ireland vs. Sub-Saharan Africa, mmm? - new foods, new microbes/infections, etc. Take your pick of what might be important or not. With my current interest in all things sunshine and vitamin D, I'm minded to suggest that this might be a factor worth considering given all the research attention that has been paid to vitamin D and autism. That and the whole solar intensity and ADHD link (no, really).... Likewise, I'm sure lessons can be learned from other research highlighting a similar pattern of risk in relation to other conditions such as schizophrenia and its link to immigration status******.

Whatever the reasons for the disparity being highlighted by the studies by Bolton and others, from a practical point of view it is perhaps more important that measures are put in place to accommodate this potentially heightened risk of offspring autism in immigrant populations. This might mean additional screening and assessments being offered to communities (language-appropriate) as well as providing any advice and education that may be required about autism and raising a child with autism.

And while we're on the topic, I'll also throw the paper by Lehti and colleagues******* (open-access) into the mix and their suggestion that "In Finland, children who are born to immigrant mothers with or without an immigrant partner, have an increased risk of childhood autism".

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* Bolton S. et al. Autism in a recently arrived immigrant population. Eur J Pediatr. 2013 Oct 2.

** Bartlett CW. et al. A Genome Scan for Loci Shared by Autism Spectrum Disorder and Language Impairment. Am J Psychiatry. 2013.

*** Magnusson C. et al. Migration and autism-spectrum disorder: population-based study. British Journal of Psychiatry. February 2012. DOI: 10.1192/bjp.bp.111.095125

**** Rai D. et al. Parental socioeconomic status and risk of offspring autism spectrum disorders in a Swedish population-based study. J Am Acad Child Adolesc Psychiatry. 2012 May;51(5):467-476.e6.

***** Zuckerman KE. et al. Pediatrician Identification of Latino Children at Risk for Autism Spectrum Disorder. Pediatrics. 2013; 132: 445-453.

****** Cooper B. Immigration and schizophrenia: the social causation hypothesis revisited. Br J Psychiatry. 2005; 186: 361-363.

******* Lehti V. et al. The risk of childhood autism among second-generation migrants in Finland: a case--control study. BMC Pediatrics 2013, 13:171

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Bolton S, McDonald D, Curtis E, Kelly S, Gallagher L. (2013). Autism in a recently arrived immigrant population Eur J Pediatr DOI: 10.1007/s00431-013-2149-6