The prevalence of autism spectrum disorder is not increasing in childhood

The title of this post is an excerpt from the paper by Sebastian Lundström and colleagues [1] (open-access) who set out to "compare the annual prevalence of the autism symptom phenotype and of registered diagnoses for autism spectrum disorder during a 10 year period in children" living in Sweden. Based on two datasets - the Child and Adolescent Twin Study in Sweden and the Swedish national patient register (NPR) - researchers analysed the records of well over a million children "born in Sweden over a 10 year period from 1993 to 2002."

Lundström et al. 2015. BMJ

As well as looking at the annual numbers of children with a reported diagnosis of autism spectrum disorder (ASD), researchers also looked at data that had assessed for "the autism symptom phenotype" over each year based on parental responses to the Autism-Tics, ADHD and other Comorbidities inventory (A-TAC). I've talked about the A-TAC quite recently (see here) and it's usefulness in assessing the 'ESSENCE' of autism. A-TAC by the way, should not be confused with the ATEC (see here).

Results, and a long quote coming up: "Using unique, large Swedish population based resources, we found that the annual prevalence of the autism symptom phenotype was stable over a 10 year period when investigating 9 and 12 year old children, while simultaneously the annual prevalence of clinically diagnosed autism spectrum disorder in a service based register steadily increased."

What this translates into is that the numbers of children presenting with a profile that looks like the autism phenotype based on the A-TAC results remained pretty steady year on year over the investigated period. When it came however to the numbers of children being diagnosed with autism or an ASD, there was "an almost linear increase over the examined years." The authors translate this as providing support for the idea "that administrative factors that affect the registered prevalence may account for much of the rise in the reported prevalence of autism spectrum disorder" quashing the notion of any major actual increase in the rate of autism. Not every piece of previous research has wholeheartedly agreed with that last sentence (see here and see here).

These are quite compelling data insofar as the numbers of participants included for study and the comprehensiveness of the various Scandinavian patient registers. The authors do however point out that the A-TAC "does not have perfect sensitivity or specificity, meaning that some degree of “diagnostic misclassification” should be expected" albeit probably not greatly affecting the results obtained given also it's equal use over the study years. I might also reiterate that this study looked at prevalence between birth years of 1993 and 2002 so subsequent study using the same methods should provide a clearer picture of more contemporary times also.

Without wishing to argue with the conclusions reached by Lundström et al, I did decide to have a closer look at some of the data presented in the paper. As per the graph presented above based on the information presented in Table 2 of the paper showing the calculated prevalences of registered diagnoses from the NPR data over the period of study and the "clinically validated cut-off for autism spectrum disorder of ≥8.5 to define the autism symptom phenotype" for the same period, there are some interesting details. I've not included the confidence interval (CI) data included in the original figures so one has to be a little guarded about drawing too many conclusions but the point raised by the authors about A-TAC (autism symptom phenotype) scores being "stable over a 10 year period" is not something necessarily as straight-forward as one might first think (follow the blue line).

"Research and clinical practice need to refocus on the child’s overall clinical situation and to acknowledge that autism is but one of the many Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations (ESSENCE)." I would very definitely agree with the authors' sentiments here and how the presentation of autism as part of a wider spectrum of issues (some perhaps at times even more 'disabling' than core autism symptoms) is something requiring much greater prominence in these days of overlapping comorbidity (see here). That some of that comorbidity might also extend into more 'somatic' features (see here) is also an important point to make with various implications for identification and appropriate management.

Update: 30 April 2015: I'll also draw your attention to the paper from Van Naarden Braun et al [2] (open-access) also providing some rather relevant data.

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[1] Lundström S. et al. Autism phenotype versus registered diagnosis in Swedish children: prevalence trends over 10 years in general population samples. BMJ 2015; 350.

[2] Van Naarden Braun K. et al. Trends in the Prevalence of Autism Spectrum Disorder, Cerebral Palsy, Hearing Loss, Intellectual Disability, and Vision Impairment, Metropolitan Atlanta, 1991–2010.  PLoS ONE. 2015; 10(4): e0124120.

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Lundstrom, S., Reichenberg, A., Anckarsater, H., Lichtenstein, P., & Gillberg, C. (2015). Autism phenotype versus registered diagnosis in Swedish children: prevalence trends over 10 years in general population samples BMJ, 350 (apr28 2) DOI: 10.1136/bmj.h1961

The International Classification of Functioning, Disability and Health (ICF) core sets for autism

"The International Classification of Functioning, Disability and Health (ICF) is a framework for describing and organising information on functioning and disability. It provides a standard language and a conceptual basis for the definition and measurement of health and disability."

That is the US CDC - Centers for Disease Control and Prevention - definition of the ICF (from WHO) and how, among other things, the ICF offers a "scientific basis for understanding and studying health and health-related states, outcomes, determinants, and changes in health status and functioning."

Bearing in the mind the utility of the ICF, one might start to appreciate how useful a schedule it might be if applied to autism. Say for example, you wanted to develop "useful standards for research and clinical practice and generating a common language for functioning and impairment in ASD in different areas of life and across the life span" [1]?

Well, the paper from Sven Bölte and colleagues [1] detailing the initial foray into developing "Comprehensive and Brief ICF Core Sets for ASD [autism spectrum disorder]" has now been joined by a further publication from Elles de Schipper and colleagues [2] (open-access here) adding further flesh to the scientific bones in applying the the ICF to autism. The de Schipper paper represents stage one of this four stage project - "a systematic review, an expert survey, a patient and caregiver qualitative study, and a clinical cross-sectional study" - and an initial look at "relevant functional ability and disability concepts" which could be mapped onto "the ICF-CY (Children and Youth version of the ICF, covering the life span)."

The de Schipper paper is open-access so it doesn't need any grand discussions from me. I will draw your attention to a few details however covering some idea of the size of the task facing researchers in this area: "The broad variety of ICF-CY categories identified in this study reflects the heterogeneity of functional differences found in ASD-both with respect to disability and exceptionality-and underlines the potential value of the ICF-CY as a framework to capture an individual's functioning in all dimensions of life." That also: "Twenty-two percent of the [autism relevant] concepts identified could not be linked to ICF-CY categories" means that the ICF-CY might not necessarily be as comprehensive as one would wish when [eventually] specifically applied to autism.

I am going to keep my eyes open for further developments of the ICF-CY with autism in mind. Assuming that this project gets it 'roughly right' when it comes to mapping the nature of autism onto the schedule, the potential benefits to autism research and practice are considerable when one takes into account ideas such as outcome and autism and its objective measurement including the analysis of things like daily living skills [3]. Move over Autism Impact Measure?

Music: Yeah Yeah Yeahs - Zero.

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[1] Bölte S. et al. Classification of functioning and impairment: the development of ICF core sets for autism spectrum disorder. Autism Res. 2014 Feb;7(1):167-72.

[2] de Schipper E. et al. Ability and Disability in Autism Spectrum Disorder: A Systematic Literature Review Employing the International Classification of Functioning, Disability and Health-Children and Youth Version. Autism Res. 2015 Mar 28.

[3] Bal VH. et al. Daily living skills in individuals with autism spectrum disorder from 2 to 21 years of age. Autism. 2015. April 28.

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de Schipper E, Lundequist A, Coghill D, de Vries PJ, Granlund M, Holtmann M, Jonsson U, Karande S, Robison JE, Shulman C, Singhal N, Tonge B, Wong VC, Zwaigenbaum L, & Bölte S (2015). Ability and Disability in Autism Spectrum Disorder: A Systematic Literature Review Employing the International Classification of Functioning, Disability and Health-Children and Youth Version. Autism research : official journal of the International Society for Autism Research PMID: 25820780

Melatonin and leaky gut continued

The paper from Garth Swanson and colleagues [1] reporting findings suggesting that "suppression of melatonin in AD [alcohol use disorder] may promote gut leakiness and endotoxemia" make for the discussion point today.

Continuing a theme from previous times on this blog that "melatonin may serve important gastrointestinal barrier functions" [2] and specifically those related to the concept of intestinal permeability and the so-called 'leaky gut' (see here), these are potentially important findings outside of the more traditional sleep-melatonin link. Swanson et al measured plasma melatonin levels and intestinal permeability via a urine sample in their small participant group of people (as opposed to the previous studies looking at rats). Participants included "20 subjects with alcohol use disorder (AD) and 17 healthy controls (HC, 6 day workers, 11 night workers)."

Authors reported less total sleep time in participants with AD and "and increased fragmentation of sleep." They also suggested that those with AD had lower levels of melatonin and said lower levels "correlated with increased intestinal permeability and a marker of endotoxemia" (i.e. lipopolysaccharide binding protein). Ergo, there may be quite a bit more to see when it comes to melatonin outside of just sleep with the gut in mind.

Wearing my autism research blogging hat and without wishing to equate alcohol use disorder with autism (bearing in mind a diagnosis of autism is in no way protective of such issues developing) I'd like to think that there may be some important science to do in this area on the back of the very preliminary results from Swanson et al. Melatonin as a management agent for sleeping problems in autism [3] is in the ascendancy these days albeit not necessarily working by "simply replacing melatonin" [4]. The various 'molecular handyperson' abilities of melatonin [5] kinda hint that, as one metabolite of the wonderful tryptophan cascade (see here), melatonin might be doing so very much more when taken.

Gastrointestinal or bowel issues being 'over-represented' when it comes to autism is a topic that is becoming less and less argued about these days as a result of the volumes of data being produced on this issue (see here for example). Part of the research question that still needs answering about functional bowel issues and autism is whether or not they are reflective of more 'pathological' states with the gut and in particular, their association (or not) with underlying problems that may well impact on gut barrier function and integrity (see here). The implication being that where present, alterations to gut permeability (leaky gut) may have the ability to do various 'things' to a person including potentially impacting on behaviour and development.

If we assume that melatonin might have some 'gut healing' properties [6] as part of it's repertoire of proposed actions [7] and considering it's growing use with autism in mind, the intriguing prospect that leaky gut is already being 'treated' in cases of autism is opened up. I say this with the understanding that science has yet to fully understand leaky gut or fully corroborate the idea that leaky gut can be treated where present in relation to autism (outside of the data from de Magistris et al [8] suggesting that those with autism "on a reported gluten-casein-free diet had significantly lower IPT [intestinal permeability] values compared with those who were on an unrestricted diet and controls").

So, once again the research gauntlet is thrown down: who will be first to apply some science to this area and measure melatonin vs. placebo in terms of sleep and gut barrier function when it comes to outcome in relation to autism?

Music: The Streets - Dry your eyes.

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[1] Swanson GR. et al. Decreased Melatonin Secretion is Associated with Increased Intestinal Permeability and Marker of Endotoxemia in Alcoholics. Am J Physiol Gastrointest Liver Physiol. 2015 Apr 23: ajpgi.00002.2015.

[2] Sommansson A. et al. Melatonin inhibits alcohol-induced increases in duodenal mucosal permeability in rats in vivo. Am J Physiol Gastrointest Liver Physiol. 2013 Jul 1;305(1):G95-G105.

[3] Veatch OJ. et al. Sleep in Autism Spectrum Disorders. Current Sleep Medicine Reports. 2015. April 24.

[4] Goldman SE. et al. Melatonin in children with autism spectrum disorders: endogenous and pharmacokinetic profiles in relation to sleep. J Autism Dev Disord. 2014 Oct;44(10):2525-35.

[5] Boga JA. et al. Beneficial actions of melatonin in the management of viral infections: a new use for this "molecular handyman"? Rev Med Virol. 2012 Sep;22(5):323-38.

[6] Eliasson L. Melatonin heals the gut. Acta Physiol (Oxf). 2014 Oct;212(2):120-1.

[7] Romo-Nava F. et al. Melatonin attenuates antipsychotic metabolic effects: an eight-week randomized, double-blind, parallel-group, placebo-controlled clinical trial. Bipolar Disord. 2014 Jun;16(4):410-21.

[8] de Magistris L. et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr. 2010 Oct;51(4):418-24.

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Swanson GR, Gorenz A, Shaikh M, Desai V, Forsyth CB, Fogg L, Burgess HJ, & Keshavarzian A (2015). Decreased Melatonin Secretion is Associated with Increased Intestinal Permeability and Marker of Endotoxemia in Alcoholics. American journal of physiology. Gastrointestinal and liver physiology PMID: 25907689

When optimal outcome in autism meets ESSENCE

I recently came across the paper by Martina Barnevik Olsson and colleagues [1] (open-access) and their rather interesting take on the issue of optimal outcome and autism (see here for some background on this concept).

Based on the idea that a diagnosis of autism or autism spectrum disorder (ASD) might not be as immutable as perhaps once thought (as in 'no longer meeting the diagnostic criteria for the condition'), Barnevik Olsson et al reported that loss of the autism/ASD label does not necessarily translate into typical developmental service being resumed. Indeed, that the concept of ESSENCE (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations) or autism+ if you prefer, might still influence clinical presentation and the subsequent continued "need of support, educationally, from a neurodevelopmental and a medical point of view."

Following 17 children originally diagnosed with ASD who "recovered from autism" after behavioural intervention, researchers took various 'readings' at follow-up points covering "the child’s daily functioning, school situation, and need of support." Alongside a parental interview, authors also used the Vineland Adaptive Behavior Scales (VABS) and the "Autism – Tics, Attention-deficit/hyperactivity disorder (AD/HD), and other Comorbidities (A-TAC) telephone interview" to see whether loss of the ASD label meant 'symptom-free'.

Results, and a long quote coming up:

"At the new follow-up around age 10 years, all the children had major behavioral and/or academic problems. Of the 13 children with social interaction problems in the semistructured parental interview, 12 also had repeated tantrums, nine had difficulties with hyperactivity or impulsivity, and two with passivity. Eleven of the children had difficulties concentrating, and ten had speech problems. Hence, it was evident that a majority of the children had problems in several different domains." The authors note that many of these presented symptoms fall under the umbrella term of ESSENCE. Further, that of the 14 children who's parents were available for the A-TAC interview, three of them were again considered to meet the criteria for ASD and "another six had pronounced subthreshold ASD symptoms."

Hopefully without the 'I told you so' attitude coming out to much, I have covered the issue of optimal outcome not necessarily translating into 'symptom-free' before on this blog (see here). Once again, I'm not trying to reverse my excitement about the original results from Deborah Fein and colleagues [2] but rather pushing the idea that autism is very often much more than the sum of the triad/dyad of characteristics which we use (see here). Further research from Fein and colleagues [3] has also hinted that functioning outside of the label of autism does not necessarily translate into a complete loss of certain issues too as has data from other groups.

Fluidity in the presentation of autistic traits is still something of real interest to autism research including that reaching into adulthood (see here). The Barnevik Olsson results add to that interest, incorporating the idea that quite a bit of the heightened comorbidity potentially present alongside a diagnosis of ASD may very well have some pretty significant effects on a person in terms of daily functioning and onwards issues affecting quality of life [4]. In policy terms, what this means is that just because a child (or adult) drops off the autism spectrum symptom threshold wise, may not necessarily translate into no additional help and support being required. Indeed, as per the increasing interest in the DSM-5 criteria change for autism (see here) and the rise and rise of labels such as social communication disorder (SCD) one wonders how many optimal outcomers will merely fall out of the autism/ASD label and into the SCD category?

Music: Seasick Steve - Summertime Boy.

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[1] Barnevik Olsson M. et al. “Recovery” from the diagnosis of autism – and then?  Neuropsychiatric Disease and Treatment. 2015. 11: 999-1005.

[2] Fein D. et al. Optimal outcome in individuals with a history of autism. J Child Psychol Psychiatry. 2013 Feb;54(2):195-205.

[3] Orinstein AJ. et al. Social Function and Communication in Optimal Outcome Children and Adolescents with an Autism History on Structured Test Measures. J Autism Dev Disord. 2015 Mar 11.

[4] Gotham K. et al. Depressive and anxiety symptom trajectories from school age through young adulthood in samples with autism spectrum disorder and developmental delay. J Am Acad Child Adolesc Psychiatry. 2015 May;54(5):369-376.e3.

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Barnevik Olsson, M., Westerlund, J., Lundström, S., Giacobini, M., Fernell, E., & Gillberg, C. (2015). “Recovery” from the diagnosis of autism – and then? Neuropsychiatric Disease and Treatment DOI: 10.2147/NDT.S78707

Kids with autism: a highly [psychotropic] medicated group?

"In keeping with international studies this sample of children with ASD [autism spectrum disorder] was a highly medicated group."

So said the results of the study reported by Kerry-Ann Louw and colleagues [1] back in 2013 who noted that approximately one quarter of their cohort were currently in receipt of "psychotropic medications". I don't want to linger too much on this topic given that such findings tally with other peer-reviewed reports including those with much larger participant numbers [2].

I am slightly concerned that "Antipsychotics were the most common reportedly used psychotropics" according to Louw et al given that this is a paediatric group we are talking about and the special caution that is perhaps required (see here). I'm not pharma-bashing by saying that, just being mindful of issues like side-effects and the whole developing infant/child brain bit.

I've covered the area of 'challenging behaviour' - one of the main reasons for medication - in the context of autism before on this blog (see here for example). In that post as in this, I can see that as a last resort and in very specific cases (accompanied by the correct medicines management and monitoring) certain psychotropic pharmaceutics can potentially bring some very positive benefits to quality of life. One only needs to look at how destructive challenging behaviours can be in the context of self-injury for example (see here) to see how medication for the right group can be a life-transformer. That being said, a careful and managed approach to medication is always the way forward, alongside treating such pharmaceutic use as a time-limited experiment...

Music: Manish Boy by Muddy Waters.

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[1] Louw KA. et al. Prevalence and patterns of medication use in children and adolescents with autism spectrum disorders in the Western Cape, South Africa. J Child Adolesc Ment Health. 2013 Jul;25(1):69-79.

[2] Coury DL. et al. Use of psychotropic medication in children and adolescents with autism spectrum disorders. Pediatrics. 2012 Nov;130 Suppl 2:S69-76.

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Louw KA, Bentley J, Sorsdahl K, & Adnams CM (2013). Prevalence and patterns of medication use in children and adolescents with autism spectrum disorders in the Western Cape, South Africa. Journal of child and adolescent mental health, 25 (1), 69-79 PMID: 25860309

DSM-5 impacting on autism numbers

"Consistent with previous reviews, the majority of included studies indicated between 50 and 75 % of individuals will maintain diagnoses."

That was one of the conclusions reached by Isaac Smith and colleagues [1] following their systematic review of studies comparing DSM-IV and DSM-5 criteria for autism spectrum disorder (ASD) and what the changes mean for eligibility for the label.

Authors further reported that: "the greatest decreases [were] among high-functioning populations with IQs over 70 and/or previous diagnoses of PDD-NOS or Asperger's disorder" when it came to those not fitting the latest autism description in DSM.

I've got little more to say on this topic over what has been discussed previously on this blog with DSM-5 in mind (see here). The newly appointed catch-all category of social communication disorder (SCD) remains a label to watch, not just with respect to how many people will be diagnosed and what level of services/support will be offered, but also with the idea that the broader autism phenotype (BAP) might also gain some clinical recognition.

Music: Nirvana - Drain You.

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[1] Smith IC. et al. The Effects of DSM-5 Criteria on Number of Individuals Diagnosed with Autism Spectrum Disorder: A Systematic Review. J Autism Dev Disord. 2015 Mar 22.

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Smith IC, Reichow B, & Volkmar FR (2015). The Effects of DSM-5 Criteria on Number of Individuals Diagnosed with Autism Spectrum Disorder: A Systematic Review. Journal of autism and developmental disorders PMID: 25796195

Does maternal asthma 'prime' for offspring neurodevelopmental disorder?

The paper from Jared Schwartzer and colleagues [1] (open-access) including a couple of familiar names on the authorship list (Charity Onore and Paul Ashwood) caught my attention recently. Based on mouse studies and the artificial induction of maternal allergy/asthma in pregnant mice, researchers reported that: "Activation of the maternal immune system with an allergy/asthma insult significantly perturbed developmental growth and species-typical behaviors in offspring." Further that their results: "support the notion that the maternal immune system has a crucial role in shaping fetal development and is an important factor contributing to the etiology of neurodevelopmental disorders" (in mice at least).

This is not the first time that maternal immune activation (MIA) has been looked at by this authorship group as per some of their other results on the development of "autism-like behaviors" in offspring mice of mother mice exposed to an agent leading to immune activation during pregnancy [2] (see here for my take on this). This following a whole area of research on MIA in relation to [some] autism and [some] schizophrenia (see here).

On this latest occasion, the authors report on their testing of the hypothesis that: "maternal allergy/asthma (MAA) imparts neurobehavioral alterations in brain and behavior of offspring reminiscent of the common endophenotypes observed in neurodevelopmental disorders." This involved the induction of "allergic airway inflammation" in pregnant mice - C57Bl/6J mice - via the use of an injection of ovalbumin (OVA) for initial sensitisation and then a further "aerosolized solution of 1% (wt/vl) OVA in PBS" or just PBS as a control when mother mice were pregnant corresponding to "early, middle and late gestation." OVA, by the way, is quite a typical way of experimentally inducing allergic reactions.

Offspring of MAA and control mice (39 PBS, 43 MAA) were then put through their behavioural paces to determine whether their were any consequences following said maternal immune stimulation during pregnancy. This involved looking at aspects such as marble-burying behaviour ("analogous to the restricted, repetitive patterns of behavior observed in neurodevelopmental disorders") and social approach behaviour among other things. A small number of mice were also sacrificed for the "analysis of serotonin transporter protein levels in the cortex."

Results: well, we already know that there were some differences between the MAA and PBS (control) group. "Offspring of MAA dams... exhibited increased marble-burying behavior, a perseverative behavior analogous to repetitive behaviors observed in neuropsychiatric disorders including obsessive compulsive disorder and ASD." Social approaches were also different in MAA offspring - "Mice born to mothers repeatedly exposed to allergy/asthma displayed significantly reduced sociability scores compared with control mice from PBS-treated dams." MAA offspring who were sacrificed (a small number) also "had a 33% increase in the expression of SERT compared with control offspring of PBS-exposed dams."  Ergo, a mouse model of immune activation during pregnancy may very well show effects on offspring mice.

Obviously we have to be a little cautious in interpreting these results and applying them to the very wide and very complex conditions that are autism and/or schizophrenia for example. As I've said before mice can make for good animal models of a condition/label but they will always be just models (see here). Likewise, when it comes to that SERT finding in the MAA vs control mice, we have to be slightly cautious about generalisation based on examination of one parameter in a very small number of mice.

That being said, one might be open to the idea that the Schwartzer results might translate into something like real life [3] as and when further investigations are undertaken. The authors use the example of air pollution as potentially mapping onto their results: "For example, exposure to air pollutants, such as diesel fuel and other particulate matter, can result in the development of asthma, and exposure to pollutants is associated with an increased risk of having a child with a neurodevelopmental disorder." There are a few generalisations made in that story but I was kinda interested in how they talked about asthma linking into neurodevelopmental disorders following my discussions on this topic in previous musings (see here). I might add that other agents have also been linked to asthma as per some discussions on paracetamol (acetaminophen) and offspring outcomes. Maybe these represent the next mouse studies in this area?

Music: The Horrors - Sea Within A Sea.

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[1] Schwartzer JJ. et al. Allergic fetal priming leads to developmental, behavioral and neurobiological changes in mice. Translational Psychiatry. 2015; 5: e543.

[2] Schwartzer JJ. et al. Maternal immune activation and strain specific interactions in the development of autism-like behaviors in mice. Translational Psychiatry. 2013; 3: e240.

[3] Croen LA. et al. Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders: a case-control study. Arch Pediatr Adolesc Med. 2005 Feb;159(2):151-7.

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Schwartzer, J., Careaga, M., Chang, C., Onore, C., & Ashwood, P. (2015). Allergic fetal priming leads to developmental, behavioral and neurobiological changes in mice Translational Psychiatry, 5 (4) DOI: 10.1038/tp.2015.40

MMR vaccine was not associated with increased risk of autism

"In this large sample of privately insured children with older siblings, receipt of the MMR [measles-mumps-rubella] vaccine was not associated with increased risk of ASD [autism spectrum disorder], regardless of whether older siblings had ASD. These findings indicate no harmful association between MMR vaccine receipt and ASD even among children already at higher risk for ASD."

That was the conclusion reached in the study by Anjali Jain and colleagues [1] (open-access) based on an analysis of data for over 95,000 children with an older sibling held on "an administrative claims database associated with a large US health plan (the Optum Research Database)." With the aim of reporting "ASD occurrence by MMR vaccine status in a large sample of US children who have older siblings with and without ASD" researchers trawled through the collected data looking "for autistic disorder or other specified pervasive developmental disorder (PDD) including Asperger syndrome, or unspecified PDD (International Classification of Diseases, Ninth Revision, Clinical Modification 299.0x, 299.8x, 299.9x)" as a function of MMR vaccine receipt between birth and the 5 years of age.

They found that nearly 2000 of the 95,000+ children included for study had a sibling diagnosed with autism (2%). As per the results of quite a bit of research in this area, having an older sibling with autism was associated with an increased risk of autism among study participants compared with having an older sibling without autism (6.9% vs. 0.9%).

Then to the MMR...

Vaccination rates were lower for those with an older sibling with autism compared with those with an older sibling without autism (73% at 2 years & 86% at 5 years vs. 84% at 2 years & 92% at 5 years respectively). This difference was present despite similar rates of 'vaccination-associated allergies' being reported. The presence of seizures and the variable of preterm birth were somewhat different between the sibling with ASD and sibling without ASD groupings but the authors don't appear to be reporting such differences to be statistically significant. The issue of vaccine uptake as a function of having an older sibling with autism has been covered before on this blog (see here).

And then to the headlines: 'No association found between MMR vaccine and autism, even among children at higher risk'. This was based on the calculation of unadjusted relative risks (RRs) - "cumulative incidence rate ratios by taking the ratio of the proportion of children who had an ASD diagnosis in an exposed group (either 1 MMR dose or 2 MMR doses) to the proportion of children who had an ASD diagnosis in the unvaccinated group at a given age" and adjusted RRs - "hazard rate ratios estimated from a single Cox proportional hazard regression model that used age since birth as the time scale and included MMR receipt as a time-varying covariate ascribing follow-up time to either the unvaccinated group, the 1-dose group, or the 2-dose group, depending on immunization status at any given age." Further: "An interaction term between MMR receipt and older sibling ASD status was included to allow adjusted RRs to vary by older sibling ASD status." What this boiled down to based on either one dose of MMR received at age 2 or two doses of MMR by age 5 was pretty much nothing in terms of any elevated statistical risk of autism among cases as a function of either having an older sibling with autism or not.

The editorial from Bryan King [2] accompanying the Jain results is also quite illuminating specifically on the possibility that some of the results might be "arguing that MMR vaccine actually reduces the risk of ASD in those who were immunized by age 2 years." I tread very carefully in discussing this sentiment given the confidence intervals (CIs) reported and the idea that delayed MMR vaccination past some pervceived 'critical period' might artificially decrease the risk of autism being diagnosed. I'll come back to this shortly.

The Jain results add further weight to the idea that childhood vaccination is probably not going to be a significant risk factor for the subsequent development of autism. The impressive participant numbers included for study cannot be readily ignored. The data is however not perfect as per the authors critique and issues such as "children in our study who are considered unvaccinated may have received vaccines in settings such as schools or public health clinics in which claims were not submitted." MMR might also not mean MMR in terms of a single combined vaccine as per the comment: "The date of administration of the trivalent MMR (or the last-administered component of monovalent vaccines) was used to determine age at administration for each dose (first or second)."

Vaccination and autism has appeared before on this blog as per my mega-post back in 2014 (see here) and previous musings on the 'too many too soon' suggestion (see here). In both those posts, the data pointed towards no population wide link between vaccination and autism as well as reiterating the important public health message on the value of vaccination. Other subsequent studies have found similar things [3]. This does not rule out isolated events potentially temporally linked to vaccine administration (as per the sentiments of 'Four Kingdoms' post from Dr Tom Insel and past other high-profile cases [4]) but certainly does not mirror the narcolepsy - H1N1 influenza vaccine story for example (see here for some background).

Just before I go, I do want to go back to the issue of whether childhood MMR vaccination (or other vaccines) might actually reduce the risk of autism. Taking into account the research literature looking at something like congenital rubella with autism in mind (see here) one might make a case for suggesting that the rubella vaccine part of MMR vaccine has potentially impacted on the numbers of cases of autism down the years [5]. Whether vaccination with MMR or other immunisations might more directly confer some protection against the development of autism is something that perhaps needs further exploration alongside the possible mechanisms of effect. I'd also put forward the idea that variables such as post-vaccination paracetamol (acetaminophen) use might also require a little more study too [6].

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[1] Jain A. et al. Autism Occurrence by MMR Vaccine Status Among US Children With Older Siblings With and Without Autism. JAMA. 2015; 313: 1534-1540.

[2] King BH. Promising Forecast for Autism Spectrum Disorders. JAMA. 2015; 313: 1518-1519.

[3] Uno Y. et al. Early exposure to the combined measles-mumps-rubella vaccine and thimerosal-containing vaccines and risk of autism spectrum disorder. Vaccine. 2015 Jan 3. pii: S0264-410X(14)01689-2.

[4] Poling JS. et al. Developmental regression and mitochondrial dysfunction in a child with autism. J Child Neurol. 2006 Feb;21(2):170-2.

[5] Berger BE. et al. Congenital rubella syndrome and autism spectrum disorder prevented by rubella vaccination--United States, 2001-2010. BMC Public Health. 2011 May 19;11:340.

[6] Schultz ST. et al. Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: the results of a parent survey. Autism. 2008 May;12(3):293-307.

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Jain, A., Marshall, J., Buikema, A., Bancroft, T., Kelly, J., & Newschaffer, C. (2015). Autism Occurrence by MMR Vaccine Status Among US Children With Older Siblings With and Without Autism JAMA, 313 (15) DOI: 10.1001/jama.2015.3077

Jessica Biesiekierski on non-coeliac gluten sensitivity (NCGS)

It's not often that I dedicate a blog post to a specific individual and their views and opinions on a particular topic. Today however, I'm doing just that to provide you with a link to the paper from Jessica Biesiekierski on the topic of non-coeliac gluten sensitivity (NCGS) [1] (open-access).

The reason? Well, aside from being one of the primary protagonists in the research topic of gluten-related ills outside of the autoimmune condition known as coeliac (celiac) disease (itself the topic of some considerable bafflement to me), the work from Dr Biesiekierski and others has also invited quite a bit more inspection of other dietary components ("FODMAPs: Fermentable Oligo-, Di-, and Mono-saccharides And Polyols") as potentially taking the strain off just gluten/wheat when it comes to ideas about health and wellbeing.

The review paper is open-access so no need for any grand discussions from me on the topic. I will however extract a choice quote or two from the paper with some comment. So: "There is some evidence that NCGS may exist, but probably only in a small number of people." I would second that statement particularly in light of recent discussions (see here). I might also direct you to some of the discussions from Brusca [2] too, and the idea that: "About half of NCGS patients are DQ2 positive and have IgG AGA [Anti-gliadin antibodies]."

Also: "Currently, there is no evidence for efficacy of gluten exclusion in mental disorders... therefore care must be given when discussing these early results and awareness given to understanding that a major effect of gluten in NCGS patients may be in the perception of their general well-being." Accepting that the term 'mental disorders' is not one that I would necessarily use and certainly not when using it in the context of referencing the paper from Millward and colleagues [3] and the Cochrane Review of gluten- and casein-free diets for [some] autism, I'd be minded to disagree with such a final statement. As has been mentioned previously on this blog, there is evidence for issues with gluten in some cases of conditions like schizophrenia (see here) and autism (see here). Insofar as 'no evidence of efficacy of gluten exclusion', well, again I'd be minded to suggest there have been hints that there may be more to see in this area (see here for example) albeit with the requirement for further, more experimentally strong research to be conducted. This also includes the notion that there may be best and non-responders to this type of intervention (see here) and that core autism symptoms might not be the primary 'target' of such dietary interventions.

And if you really want yet more reviews of NCGS, then look no further [4] or further [5] or further [6]...

Music: OutKast - Ms. Jackson. Oh, and how would art look without the gluten?

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[1] Biesiekierski JR. Non-coeliac gluten sensitivity: piecing the puzzle together. United European Gastroenterology Journal. 2015; 3: 160-165.

[2] Brusca I. Overview of biomarkers for diagnosis and monitoring of celiac disease. Adv Clin Chem. 2015;68:1-55.

[3] Millward C. et al. Gluten- and casein-free diets for autistic spectrum disorder. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD003498.

[4] Czaja-Bulsa G. Non coeliac gluten sensitivity – A new disease with gluten intolerance. Clinical Nutrition. 2015; 34: 189-194.

[5] Molina-Infante J. et al. Systematic review: noncoeliac gluten sensitivity. Aliment Pharmacol Ther. 2015 May;41(9):807-20.

[6] Fasano A. et al. Nonceliac Gluten Sensitivity. Gastroenterology. 2015 Jan 9. pii: S0016-5085(15)00029-3.

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Biesiekierski, J., & Iven, J. (2015). Non-coeliac gluten sensitivity: piecing the puzzle together United European Gastroenterology Journal, 3 (2), 160-165 DOI: 10.1177/2050640615578388

Tics are common in adults with autism

The title of this post comes from a quote included in the paper by Ursula Kahl and colleagues [1] based on their study of the "phenomenology and characteristics" of tics in adults diagnosed with an autism spectrum disorder (ASD) compared with a small control group of adults with Gilles de la Tourette syndrome (GTS). A tic by the way, is a "sudden, fast, repeated movement or sound."

This is not the first time that tics have been examined with the autism spectrum in mind. The paper from Canitano & Vivanti [2] for example, looking at tics and GTS in cases of autism (N=105) concluded that nearly a quarter of children/young adults with autism presented with a tic disorder and about 1 in 10 with GTS. This followed previous research that came to similar conclusions [3].

The hows and whys of an association between tics and [some] autism is still a little up in the air. The presentation of tics has quite a strong genetic influence insofar as the data on familial linkage [4] and their frequency alongside other symptoms such as attention-deficit hyperactivity disorder (ADHD) and/or obsessive compulsive disorder (OCD). With the figures on ADHD comorbidity with autism in mind (see here), one shouldn't perhaps be surprised that tics might be present in some cases of autism. Indeed, my musings on the paper from Chen and colleagues [5] (see here) pretty much said as much.

"Tic awareness is limited in ASD" was the conclusion from Kahl et al.  I'd agree that tics aren't the first thing to come to mind when one talks about autism. That being said, with the increasing moves towards autism or autistic traits co-existing with a variety of other symptoms/diagnoses we shouldn't really be so surprised that tics might be part and parcel of presentation for some on the autism spectrum. As to the issue of management, well, I'd be minded to suggest that a case-by-case approach be taken [6] with something of an open mind to possible correlates bearing in mind no medical advice is given or intended...

Music: Spiritualized - Electricity.

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[1] Kahl U. et al. Tic Phenomenology and Tic Awareness in Adults With Autism. Movement Disorders Clinical Practice. 2015. March 30.

[2] Canitano R. & Vivanti G. Tics and Tourette syndrome in autism spectrum disorders. Autism. 2007 Jan;11(1):19-28.

[3] Ringman JM. & Jankovic J. Occurrence of tics in Asperger's syndrome and autistic disorder. J Child Neurol. 2000 Jun;15(6):394-400.

[4] O'Rourke JA. et al. The Genetics of Tourette Syndrome: A review. J Psychosom Res. 2009 Dec; 67(6): 533–545.

[5] Chen M-H. et al. Autistic spectrum disorder, attention deficit hyperactivity disorder, and psychiatric comorbidities: A nationwide study. Research in Autism Spectrum Disorders. 2015; 10: 1-6.

[6] Shprecher D. & Kurlan R. The management of tics. Mov Disord. 2009 Jan 15;24(1):15-24.

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Kahl, U., Schunke, O., Schöttle, D., David, N., Brandt, V., Bäumer, T., Roessner, V., Münchau, A., & Ganos, C. (2015). Tic Phenomenology and Tic Awareness in Adults With Autism Movement Disorders Clinical Practice DOI: 10.1002/mdc3.12154

Autistic traits in adult-onset psychiatric disorders?

"To conclude, the presentation of ALTs [autistic-like traits/symptoms] at the sub-threshold or threshold level may be closely associated with BPD [bipolar disorder] and SZ [schizophrenia]."

That was the conclusion reached in the paper by Junko Matsuo and colleagues [1] (open-access here) based on their analysis of nearly 300 adults aged between 25-59 years including those diagnosed with "MDD [major depressive disorder], n=125; bipolar disorder, n=56; schizophrenia, [and] n=44; healthy controls, n=65." The 'healthy controls' definition is that of the authors not mine.

"Autistic-like traits/symptoms were measured using the Social Responsiveness Scale for Adults [SRS-A]" we are told. Bearing in mind quite a bit of variation in the SRS-A scores across various diagnoses (including remitted and unremitted subgroupings too) there was a tendency towards "significantly higher total and social communication and autistic mannerisms subscale scores on the SRS-A compared to the HC [healthy controls] group."

Further: "Almost half of the clinical subjects, except those with remitted MDD, fell into the mild-to-severe range for ALTs, which is typical for sub-threshold or threshold ASD [autism spectrum disorder]." This effect seemed to be independent of symptom severity in those with BPD or SZ. However: "ALTs in subjects with MDD were associated with the depressive symptom severity in our study; in other words, although subjects with severe depressive symptoms tended to exhibit high ALTs, subjects with less severe depressive symptoms did not differ from healthy controls with regard to the proportion or degree of high ALTs."

Acknowledging the requirement for further investigation and the fact that authors "did not conduct a thorough and comprehensive evaluation of ASD" in their participant cohort, these are interesting findings. Regular readers might already have noted that I'm coming around to the idea that there may be some important links between the presentation of [some] autism and a variety of psychiatric diagnoses. I know this might take some people into some uncomfortable territory and muddy the waters when it comes to what exactly is being examined when it comes to autism research (see here for example) but to me this is really quite important science. Not least when it comes to the idea that a diagnosis of autism might elevate the risk of certain other labels being diagnosed (see here) and what that means for diagnostic vigilance and screening save any further health inequalities becoming apparent.

The detail about autistic-like traits/symptoms being 'associated' with depressive symptoms is something particularly interesting. As per some recent discussions on this blog on depression and autism potentially being interlinked (see here) and some flesh being put on the scientific bones when it comes to what facets of depression might be linked to autism (see here), I think there is quite a lot more to see in this area. We're not yet in a position to talk about what [definite] mechanisms might be influencing any correlation between autistic traits and depressive symptoms although I'm minded to suggest that there may be some possible research avenues based on the peer-reviewed literature as it stands. Take for example the idea that vitamin D might be implicated in both cases of autism and depression (see here and see here respectively). Even more 'out there', I'd like to pose another question: could studies of gluten also provide some research leads (see here and see here)? Either way, the application of the spectrum of autistic traits is growing and getting ever more complicated [2].

Music: The Strokes - Reptilia.

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[1] Matsuo J. et al. Autistic-Like Traits in Adult Patients with Mood Disorders and Schizophrenia. PLoS One. 2015 Apr 2;10(4):e0122711.

[2] Koolschijn PC. et al. Are Autistic Traits in the General Population Related to Global and Regional Brain Differences? J Autism Dev Disorders. 2015. April 7.

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Matsuo J, Kamio Y, Takahashi H, Ota M, Teraishi T, Hori H, Nagashima A, Takei R, Higuchi T, Motohashi N, & Kunugi H (2015). Autistic-Like Traits in Adult Patients with Mood Disorders and Schizophrenia. PloS one, 10 (4) PMID: 25838109

Higher cancer mortality rates associated with mental illness

The findings reported by Steve Kisely and colleagues [1] were of some interest recently and their assertion that despite cancer incidence being "the same as the general population for most psychiatric disorders" or even slightly reduced when a diagnosis of schizophrenia was for example received, mortality due to cancer was "increased in psychiatric patients."

Such findings were based on their examination of: "Mental health records [that] were linked with cancer registrations and death records from 2002 to 2007." It follows other work from these authors in this area including that looking at the gap in life expectancy 'from preventable physical illness in psychiatric patients' [2].

Head-scratching (no, not for that reason) aside as to why cancer should be more deadly for those diagnosed with a psychiatric condition, the authors suggest that lifestyle factors such as alcohol or tobacco use probably wouldn't account for the quandary presented. One suggestion however - "inequity in access to specialist procedures" - does invite further investigation on the back of what has been previously reported in the area of psychiatric diagnosis and health inequality (see here for example).

Indeed, 'disparities in cancer-related healthcare provision' was also one of the explanations put forward by one researcher who replied to my tweet about the Kisely paper (and he should know) complete with reference to research backing up this claim [3]. The Mitchell paper found that: "Rates of mammography screening are lower in women with mental illness, particularly women with SMI [severe mental illness]." Whilst this only covers one type of cancer and one type of screening method, the idea that cancer screening and treatment resources may be 'failing' those with a psychiatric diagnosis is an important one also covered by other researchers [4]. Indeed, Martens et al suggested that "good continuity of care by primary care physicians" may mitigate the issues like screening uptake and the idea of a more 'joined-up' service delivery between psychiatry and other branches of clinical care.

Of the various messages to come from the Kisely findings, I'd like to think that a primary one is that of psychiatric diagnoses not appearing in some sort of clinical vacuum with regards to other symptoms and conditions being present and what effect they can have on quality of life. As per my ramblings about autism and the wide spectrum of comorbidities that can and do impact on health and quality of life, we need to be mindful of how presentation of behavioural / psychiatric symptoms can impact on the presentation and treatment of other conditions, many of which are perfectly treatable / manageable in modern medicine.

But the question is not completely answered [5]... and one wonders whether the findings from Minna Torniainen and colleagues [6] on a potential 'protective effect' from antipsychotics on early mortality in cases of schizophrenia might also bring some potential explanation(s) to the table?

To close: The Force Awakens trailer number 2.

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[1] Kisely S. et al. Why do psychiatric patients have higher cancer mortality rates when cancer incidence is the same or lower? Aust N Z J Psychiatry. 2015 Mar 31. pii: 0004867415577979.

[2] Lawrence D. et al. The gap in life expectancy from preventable physical illness in psychiatric patients in Western Australia: retrospective analysis of population based registers. BMJ. 2013 May 21;346:f2539.

[3] Mitchell AJ. et al. Breast cancer screening in women with mental illness: comparative meta-analysis of mammography uptake. Br J Psychiatry. 2014 Dec;205(6):428-35.

[4] Martens PJ. et al. Are cervical cancer screening rates different for women with schizophrenia? A Manitoba population-based study. Schizophr Res. 2009 Aug;113(1):101-6.

[5] Chang CK. et al. A cohort study on mental disorders, stage of cancer at diagnosis and subsequent survival. BMJ Open. 2014 Jan 29;4(1):e004295.

[6] Torniainen M. et al. Antipsychotic Treatment and Mortality in Schizophrenia. Schizophr Bull. 2015; 41: 656-663.

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Kisely S, Forsyth S, & Lawrence D (2015). Why do psychiatric patients have higher cancer mortality rates when cancer incidence is the same or lower? The Australian and New Zealand journal of psychiatry PMID: 25829481

Paternal sperm epigenetic differences and offspring autism risk

"These data suggest that epigenetic differences in paternal sperm may contribute to autism risk in offspring."

So said the preliminary study results published by Jason Feinberg and colleagues [1]  (open-access) looking at "paternal semen biosamples obtained from an autism spectrum disorder (ASD) enriched-risk pregnancy cohort, the Early Autism Risk Longitudinal Investigation (EARLI) cohort." Researchers analysed 44 semen samples to ascertain whether DNA methylation differences - one type of epigenetic mechanism - might be linked to "prospective ASD development" in offspring. Said potential development of autism in offspring was measured via scores at 12 months on the Autism Observation Scale for Infants (AOSI), a schedule designed to "detect and monitor early signs of autism as they emerge in high-risk infants."

Based on some nifty technology looking at "genome-wide DNA methylation (DNAm)" Feinberg et al reported various differentially methylated regions (DMRs) in semen samples associated with offspring infant scores on the AOSI. In all, 193 sites were located where methylation was upregulated or downregulated, some of them clustering "near genes involved in developmental processes." Just in case you're still a bit baffled by all this talk of DNA methylation and what it means, I might refer you to some chatter in another area of medicine [2] and how for example, hypermethylation of a genetic site normally means gene silencing. DNA methylation might also have important implications for genetic stability too [3].

Further to their methylomic analysis of semen samples, researchers also "examined associated regions in an independent sample of post-mortem human brain ASD and control samples" to complement their study. They reported "consistent differences in the cerebellums of autistic individuals compared with controls" as a function of probes covering those "AOSI-associated DMRs" previously discussed. In summary, epigenetic differences in paternal semen DNA might transmit to offspring at-risk for autism, and that epigenetic profile may also tie into epigenetic differences found in specific brain sites of some of those diagnosed with autism. I might add that we had seen some hint that this work was coming as per some interesting data from this group presented at IMFAR 2014 (see here).

Epigenetics is an emerging area when it comes to autism research (see here). I've tried to cover quite a bit of the research with autism in mind including other studies of the methylome (see here) and some of that previous research on brain epigenetic differences potentially being linked to autism (see here). It is a complicated area and easily over-hyped, but what is perhaps so attractive about epigenetics tied into autism (and in many other conditions/labels) is the focus on gene function over and above just structural changes to the genome (and their effects) as per more traditional genetics looking solely at mutations such as SNPs. The idea is that those chemical changes to the genome described by epigenetics, affecting gene function, might bridge the gap between genetics and environment that has plagued autism research down the years (see here). That such epigenetic changes may be amenable to 'alteration' is also an interesting prospect for many people.

The Feinberg results are pretty exciting and further open up many areas of epigenetic research to autism including whether factors such as age or environmental exposure(s) might affect paternal methylation patterns (see here and see here respectively) and onwards offspring autism risk. I have to caution though that the current results were based on quite a small number of participants and covered only one part of the epigenomic landscape. Those epigenetic changes noted by Feinberg et al also need to be replicated before anyone gets ahead of themselves with the findings, bearing in mind the heterogeneity of the autism spectrum and all that elevated risk of various comorbidity (see here) potentially also coming into play.

Music: Rags To Riches - Tony Bennett.

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[1] Feinberg JI. et al. Paternal sperm DNA methylation associated with early signs of autism risk in an autism-enriched cohort. Int. J. Epidemiol. 2015. 14 April.

[2] Baylin SB. DNA methylation and gene silencing in cancer. Nature Clinical Practice Oncology. 2005; 2: S4-S11.

[3] Li J. et al. Genomic Hypomethylation in the Human Germline Associates with Selective Structural Mutability in the Human Genome. PLoS Genet. 2012; 8: e1002692.

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Jason I Feinberg, Kelly M Bakulski, Andrew E Jaffe, Rakel Tryggvadottir, Shannon C Brown, Lynn R Goldman, Lisa A Croen, Irva Hertz-Picciotto, Craig J Newschaffer, M Daniele Fallin, & Andrew P Feinberg (2015). Paternal sperm DNA methylation associated with early signs of autism risk in an autism-enriched cohort International Journal of Epidemiology : 10.1093/ije/dyv028