Restless leg syndrome in parents of children with autism

The findings reported by Maureen Russell and colleagues [1] provide some blogging fodder today and the observation that: "Biological caregivers of children with ASD [autism spectrum disorder] demonstrated a high prevalence of RLS [Restless Legs Syndrome] symptoms and poorer mental health."

OK, I know some people might be asking 'just what is Restless Legs Syndrome'? It is a recognised condition complete with 'disease' title (Willis-Ekbom disease). Symptoms, as the name suggests, centre on 'an overwhelming, irresistible urge to move the legs'. But things might not just stop at 'jittery legs' when it comes to this condition, as various other parts of the body can also be involved and indeed, affect important functions such as sleep.

Russell et al surveyed 50 biological caregivers (parents) of children diagnosed with an autism spectrum disorder (ASD) with regards to sleep habits "that included RLS as determined by four questions." They also "compared the sleep quality and daytime behaviors of children with ASD in caregivers with and without symptoms of RLS."

They observed that just over a fifth of their caregiver cohort "fit the criteria for RLS symptomatology." They also reported that those 'biological caregivers' who reported RLS symptoms also reported "poorer mental health" based on responses to the "Medical Outcomes Survey (MOS) 12-Item Short Form (SF-12)." When it came to offspring parameters, authors reported that: "Caregivers with RLS described more night waking and greater internalized behavior problems in their children with ASD than the caregivers without RLS." They interpret this 'association' in the context that there is a degree of heritability attached to RLS and some of those sleeping issues noted in offspring could mean that the symptoms of RLS are also present in children diagnosed with ASD too.

Noting the relatively small scale of the Russell study in participant number terms, the very preliminary method of reporting on mental health and the fact that there isn't a single test for RLS, these are interesting findings. I note the lead author has her PhD online (see here) showing how this research fits into a larger scheme of work on sleep and quality of life in caregivers of children with autism.

Looking at the Russell findings in the context of 'hows and whys' there are some potentially important correlations that might be noteworthy. RLS has been linked with the presentation of attention-deficit hyperactivity disorder (ADHD), a not insignificant comorbidity noted in quite a bit of autism (see here). I don't want to make any connections where none might exist but it is reasonable to assume that an over-represented occurrence of ADHD in autism could be important. Insofar as the heritability of ADHD specifically across families, there is more to do in this area but it's not unheard of for ADHD symptoms to be present in other family members including parents. This could impact on the results reported by Russell et al.

Although certain medicines have been associated with the symptoms of RLS, there is also a body of peer-reviewed science suggesting that a deficiency in iron might also be important [2]. There is still a degree of debate specifically as to how iron deficiency might 'cause' RLS but one of the primary lines of thinking revolves around how iron is an important co-factor for the biological reactions that turn the amino acid tyrosine [eventually] into the neurotransmitter dopamine. Again, minus any 'I know all the answers' sentiments, iron levels in relation to autism have been a source of some investigation down the years (see here). Some researchers have also talked about maternal iron intake potentially affecting the 'risk' of offspring autism too (see here) (with appropriate caveats).

Whatever the reason(s) to account for the Russell findings, there is a requirement for further research in this area, for a start to assess just how prevalent RLS might be in both people diagnosed on the autism spectrum and their significant others. Knowing how much comorbidity seems to follow a diagnosis of autism (see here) I wouldn't be surprised to see yet another connection; this one however, might provide some rather important clues as to overlapping genetics and biology...

Music, and Gotye still has an amazing song...

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[1] Russell M. et al. Symptoms of Restless Legs Syndrome in Biological Caregivers of Children with Autism Spectrum Disorders. J Clin Sleep Med. 2016 Oct 28. pii: jc-00043-16.

[2] Li X. et al. Brain iron deficiency in idiopathic restless legs syndrome measured by quantitative magnetic susceptibility at 7 tesla. Sleep Med. 2016 Jun;22:75-82.

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Russell M, Baldwin C, McClain D, Matthews N, Smith C, & Quan SF (2016). Symptoms of Restless Legs Syndrome in Biological Caregivers of Children with Autism Spectrum Disorders. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine PMID: 27855729

Publication bias and autism research

The title of the paper by Konstantin Mechler and colleagues - "Defining the hidden evidence in autism research. Forty per cent of rigorously designed clinical trials remain unpublished - a cross-sectional analysis" [1] - provides some discussion today. Drawing on the ideas that publication bias and/or the so-called 'file-drawer problem' - terms that refer to the non-publication of study results potentially skewing the collected scientific opinion in a particular area - might also extend into autism research too, Mechler et al detail results according to their analysis of a particular trial registration database called: ClinicalTrials.gov.

ClinicalTrials.gov is one of the premier 'tell everyone about your trial' databases designed to provide a bit of transparency to science. The idea is that you register (pre-register hopefully) your research study, register what you are going to do and how, and importantly, provide some details about what your are going to be assessing (outcomes). Some of the research that I've been involved with has a mention in this database (see here) with more to come in future times. Once your entry is in ClinicalTrials.gov it kinda stops you from making any major 'alterations' to your study potentially based on the results you get, whilst at the same time also getting quite a few prods to post things like your raw study results for everyone to see and analyse as they wish. And believe me, they are quite a persistent bunch over at ClinicalTrials.gov!

So Mechler and colleagues "searched for all completed randomized controlled clinical trials investigating interventions in ASD [autism spectrum disorder] and their results made public." They looked at how many trials had been submitted and how many reported results. Where no results were available on ClinicalTrials.gov or on other 'scientific databases' or after "enquiries of the responsible parties or sponsors listed", the authors listed the trial as 'not published'.

The good news: 60% of trials (n=30) were published in the peer-reviewed domain. The not-so-good news was that reported in the opening sentence of this post as some 40% of trials (n=20) fell into that not published category. Authors also mention that some 1600 participants were included in those not published trials, inferring that data on quite a few people diagnosed with an ASD and agreeing (themselves or by proxy) to participate in research remain 'missing' in a research sense.

"The results emphasize the serious issue of publication bias. The large proportion of unpublished results precludes valuable information and has the potential to distort evidence for treatment approaches in ASD." This an important point in any area of science but perhaps more so when you have a label like autism and a whole host of 'unknowns' about the aetiology, nature and course of presentation. I would like to think that there were some rational reasons why so many trials were missing results (studies having to be halted/stopped, collaborations breaking down, resources being exhausted, etc) but there is always going to suspicion around the non-publication of such results particularly the idea that 'researchers or funders did not get the results they hoped for'. Other discussions on this topic outside of autism (see here) point to the failure to publish being tantamount to an ethical breach. Strong words indeed.

Although Mechler et al focused on data from the ClinicalTrials.gov initiative I'd perhaps suggest that the issues they discuss probably go a lot deeper as a function of there being quite a few other databases where such trial information is held and listed. Perhaps also just as concerning is the fact that many other pieces of research are not listed anywhere when it comes to trial registration and therefore have even less 'motivation' to publish results or are perhaps more likely to be subject to 'alteration' in terms of methodology or outcome(s). All of which contributes to the possible tarnishing of science and the reporting of said science and paves the way for criticism.

Music, it's not Mother's Day or anything like that but do give her a call from time-to-time and treat your mother right...

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[1] Mechler K. et al. Defining the hidden evidence in autism research. Forty per cent of rigorously designed clinical trials remain unpublished - a cross-sectional analysis. International Journal of Methods in Psychiatric Research. 2016. Nov 9.

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Mechler K, Hoffmann GF, Dittmann RW, & Ries M (2016). Defining the hidden evidence in autism research. Forty per cent of rigorously designed clinical trials remain unpublished - a cross-sectional analysis. International journal of methods in psychiatric research PMID: 27862603

On moving off the autism spectrum

The paper by Nahit Motavalli Mukaddes and colleagues [1] provides some important, if small-scale, information when it comes to that still controversial term - optimal outcome - with the diagnosis of autism in mind. Optimal outcome basically refers to a particular 'type' of autism whereby following a definite diagnosis of autism or autism spectrum disorder (ASD), a later re-evaluation of signs and symptoms reveals that diagnostic thresholds are subsequently not reached and/or exceeded and hence, the criteria for autism are not fulfilled.

I say this is a controversial term because it is. Still after quite a bit of peer-reviewed published research saying 'yes, it exists' (and alongside quite a few manifestations of autism) coupled with quite a bit of research talking about different developmental trajectories accompanying different 'types' of autism (see here) the old 'they weren't really autistic' phrase still comes out time and time again. And with it, children/adults who were diagnosed with autism are doubted to have been actually autistic. The skills of the professionals who made the diagnosis are doubted. The parents and significant others who most likely initiated the screening and diagnosis of autism are doubted. All of this seemingly to uphold the 'lifelong' tag that accompanies quite a bit of discussion about autism. Not a great state of affairs eh?

Work by Mukaddes et al has previously made an appearance on this blog (see here) talking about possible predictors of optimal outcome. This time around they aimed to "assess the autism symptoms and other psychiatric disorders in a group of children with a past history of autism." Their group, comprised of 26 who "lost the diagnosis of autism two to eight years previously", were assessed for autism - DSM-5 autism no less - together with various other psychometric/behavioural schedules.

Results: "None of the participants met criteria for an autism diagnosis." What this means is that for their cohort, 'loss' of a diagnosis of autism was not some short-term thing. But be careful here, as I remind you that DSM-5 criteria "were used for [a] diagnosis of ASD" for autism and the emerging data suggesting that DSM-5 is already likely to move quite a few people off the autism spectrum compared with previous diagnostic schedules (see here). Indeed, I wonder how many of their cohort might be labelled with SCD instead?

When it came however to looking at other psychiatric/behavioural labels, being an optimal outcomer with autism in mind did not necessarily mean symptom-free: "81% had a present psychiatric disorder based on the K-SADS. ADHD [attention-deficit hyperactivity disorder], specific phobia and Obsessive Compulsive Disorder (OCD) were the most common disorders." This finding is interesting. Interesting because it does not necessarily tally with other work on this topic (see here) but at the same time, reiterates that a diagnosis of autism rarely exists in a diagnostic vacuum (see here) (and that includes past diagnoses of autism). That ADHD in particular, is a label of growing importance to quite a few cases of autism should also be mentioned (see here) as should be the 'effects' that such a label has been linked with (see here).

"It is crucial to maintain psychiatric follow up of children who move-off ASD." Wise words from Mukaddes and colleagues but given the state of things here in Blighty, with continued austerity and long, long wait lists for assessments (see here), I don't really have a great deal of confidence that removal from the autism spectrum is going to prompt much in the way of follow-up. Indeed, going back to the question of whether optimal outcomers might nevertheless hit SCD - 'autism lite' -  diagnostic thresholds, I'm not even sure that those fitting into the SCD description are going to receive anything like the services and support they will still no doubt require. I do hope that I am wrong but...

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[1] Mukaddes NH. et al. What Happens to Children Who Move off the Autism Spectrum? A Clinical Follow-Up Study. Pediatrics Int. 2016. Nov 12.

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Motavalli Mukaddes, N., Mutluer, T., Ayik, B., & Umut, A. (2016). What Happens to Children Who Move off the Autism Spectrum? A Clinical Follow-Up Study Pediatrics International DOI: 10.1111/ped.13202

Acetylation focus over methylation in autism epigenetics?

The paper by Wenjie Sun and colleagues [1] (open-access) provides the blogging fodder for today's post and although based on the science of epigenetics, the usual suspect - DNA methylation - gives way to another concept: histone acetylation with autism in mind. Before heading into the paper myself, I'll draw your attention to some other write-ups of the study including a hat-tip to Jeff Craig and his piece on the topic (see here).

So histone acetylation... I've covered the subject before on this blog (see here) but basically DNA, the stuff that carries the genetic blueprint, complexes with histones to form something called nucleosomes. It's a combination likened to thread wrapped around a spool. Continuing that thread wrapped around a spool analogy, protruding threads called histone tails can be modified in a chemical sense (via processes such as acetylation where an acetyl group is added or deacetylation where one is removed) which can subsequently affect genetic transcription.

Still with me? Good. Sun and colleagues set out to look at histone acetylation in the context of autism; specifically in post-mortem brain samples donated from those deceased who were diagnosed with autism and whether they might show some important changes based on the use of "a histone acetylome-wide association study (HAWAS)."

Specific areas of the brain were assessed using the HAWAS approach - "prefrontal cortex (PFC), temporal cortex (TC), and cerebellum (CB)" - and researchers were looking for a specific type of acetylation mark called H3K27ac linked to gene activation. Based on brain samples from 94 participants ("45 ASD [autism spectrum disorder], 49 control"), a few details emerged:

• Despite the expected heterogeneity across the presentation of autism in terms of whether the diagnosis of autism was syndromic (secondary to an existing condition) or non-syndromic (idiopathic), the authors reported that approaching 70% of the autism cases "shared a common acetylome signature at >5,000 cis-regulatory elements in prefrontal and temporal cortex." In other words, a not uncommon molecular signature in relation to histone acetylation seemed to be present in quite a few of the participant samples included for study.
• Although one needs to be a little cautious about making grand, sweeping claims about how such an 'acetylome signature' comes about, the authors reported "that ASD-specific differential acetylation is driven mostly by.. factors such as environmental influences, SNPs in trans (at a different locus), indels, and larger chromosomal variants." Note the term 'environmental influences' (something I'll come back to shortly).
• When it came to what types of genes were potentially being 'affected' by acetylation, the authors report on quite a diverse spread "involved in synaptic transmission, ion transport, epilepsy, behavioral abnormality, chemokinesis, histone deacetylation, and immunity." Epilepsy and autism is a recurrent theme in the research and clinical literature (see here for example) so there are no great surprise there. 'Immunity' and autism is something else that keeps cropping time and time and time again (see here).
• I appreciate that the authors also acknowledge that whilst autism was the focus on the current work, they do also mention: "By correlating histone acetylation with genotype, we discovered >2,000 histone acetylation quantitative trait loci (haQTLs) in human brain regions, including four candidate causal variants for psychiatric diseases." This opens up the idea that various different psychiatric/behavioural labels might show 'overlap' when it comes to the histone acetylome too.

Interesting stuff by all accounts. I do like the idea that autism research is continuing to look at other areas of gene expression outside of just structural issues to the genome being linked to the condition (or should that be plural). Aside from the fact that people don't walk around with their genes permanently stuck in the 'on or off position' in every tissue all the time, the whole epigenetics field is a welcome complement to more traditional genomics. The focus on gene expression being potentially 'modifiable' might also reunite genetics and environment too (see here).

Criticisms of the Sun study? Well, brain samples from the deceased are a precious resource but not without complications when it comes their use for science (see here). I appreciate that we don't have the technology to look at histone acetylation in real-time or real-life yet with the brain in mind but one has to be cautious about the results from the brains of the deceased who may have passed away for many different reasons. There is also the temptation to move the whole epigenetics 'thing' towards acetylation on the basis of such research, but the methylome still remains potentially important (see here) and probably for more than one reason (see here). Perhaps soon we'll see a study looking at more than one epigenetic factor with autism in mind?

Going back to the concept of 'environmental influences' mentioned in the Sun paper, there are some potentially important repercussions from study results such as these. As with the concept of DNA methylation, one of the important concepts linked to the science of epigenetics is that such chemical alterations affecting the expression of DNA are potentially modifiable. This could mean that particular environmental factors working at critical periods might affect acetylation and methylation patterns and onward the expression of certain genes pertinent to the presentation of something like autism or at least facets of autism. The other scenario is that certain 'conditions' or 'interventions' might 'reverse such changes. On that last point, I might bring in some previous discussions on this blog in relation to something called HDAC (histone deacetylase) inhibitors (see here) that, as their name suggests, have the ability to inhibit the action of histone deacetylases (they remove acetyl groups). Various classes of medicines are classed at HDAC inhibitors including something called valproic acid which has some autism research history (see here for example). It's not therefore beyond the realms of possibility that the actions of certain medicines or other non-genetic factors with an influence on acetylation could be a source for further research in this area.

Independent replication is the next stage in the research process here. Alongside marrying acetylation trends with methylation trends, I do also wonder whether more functional analysis of other tissue(s) outside of just the brain might also be revealing too. I might add that traditional structural genomic issues (all those SNPs and CNVs that are talked about) can still play a role and indeed, might show some association with epigenetic issues too (see here).

And with all this talk of epigenetics and the like, due credit needs to be given to those who've been talking about this for quite a while in the peer-reviewed domain [2]...

To close, we have one final look at Rogue One before touchdown...

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[1] Sun W. et al. Histone Acetylome-wide Association Study of Autism Spectrum Disorder. Cell. 2016. Nov 17.

[2] Lasalle JM. Autism genes keep turning up chromatin. OA Autism. 2013 Jun 19;1(2):14.

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Sun, W., Poschmann, J., Cruz-Herrera del Rosario, R., Parikshak, N., Hajan, H., Kumar, V., Ramasamy, R., Belgard, T., Elanggovan, B., Wong, C., Mill, J., Geschwind, D., & Prabhakar, S. (2016). Histone Acetylome-wide Association Study of Autism Spectrum Disorder Cell, 167 (5), 1385-2147483647 DOI: 10.1016/j.cell.2016.10.031

Screening for coeliac disease in autism

"The overall CD [coeliac disease or celiac disease depending on where you live] prevalence was 2.62%, which is statistically significant higher to that reported in the Italian paediatric population... If replicated, these data suggest the importance of regular screening for CD in young patients with ASD [autism spectrum disorder]."

Those were some of the findings/conclusions reported in the paper by Sara Calderoni and colleagues [1] (open-access) and with them, some important data quite pertinent to some of the primary interests of this blog and indeed, my research career.

Coeliac disease is an autoimmune condition (NOT AN ALLERGY!) whereby genetics, biology and environment converge on how dietary gluten - the stuff in foods like bread, pasta and cereals - is not necessarily a great idea for everyone. The ideas that: (a) a diagnosis of autism or ASD is seemingly protective of nothing and (b) all that chatter about gluten potentially affecting 'some' autism [2] plays heavily into the quite longstanding research history probing any connection between CD and autism. The question of whether CD is over-represented in autism has had many twists and turns including famously being studied by a certain H Asperger charcter.

Calderoni and colleagues, drawing on data from a country with more than it's fair share of interest in CD, retrospectively examined data for over 380 children diagnosed with an ASD who had also been screened (serologically) for possible CD. Such screening included "determination of the titres of Anti-Gliadin (AGA) immunoglobuline (Ig)A and IgG, Anti-Transglutaminase (anti-tTG) IgA, and Anti-Endomysium (EMA) IgA antibodies." Further examinations of medical records for those screening positive to some of these parameters was undertaken to see "whether the CD diagnosis had been subsequently confirmed by paediatric gastroenterologists."

Results: ten participants were identified "with CD or with positive CD serology." The authors provide some details about these 10 children - "six males and four females, with mean age of 41 months." They make an important point about their 'prevalence of CD' figures: "the prevalence of “CD patients plus screening detected individuals with both anti-tTG and EMA positivity” was 2.62% (10/382 subjects)." This based on the fact that not everyone of these 10 children had formally received a diagnosis of CD from a gastroenterologist for various reasons. Interestingly too, when it came to the data about whether CD was symptomatic i.e. outside of just being serologically present whether the corresponding symptoms of CD were present, the authors conclude that quite a few "had no symptoms or risk factors correlated with CD at the time of the serological screening." Finally, compared with other population data on CD prevalence, researchers suggested that CD may be yet another over-represented comorbidity following a diagnosis of ASD.

Interestingly, the authors suggest that their figures on CD in ASD might be an underestimate. They say this based on the idea that for example, generally low IgA levels is an issue when it comes to CD screening and onwards the possibility of false-negative results [3]. Although not necessarily widespread, low levels of IgA or IgA deficiency is not an unstrange finding in relation to some 'types' of autism [4].

I can't argue with the Calderoni findings and the potential importance of preferential screening for CD when a diagnosis of autism is received [5] . What I might add however, is that more and more science and clinical practice is understanding that there are grey areas between coeliac disease and not coeliac disease (see here) and such notions on 'non-coeliac gluten/wheat sensitivity' might open up issues with gluten for quite a few more people diagnosed on the autism spectrum (see here). Indeed, as I always seem to do when talking about such issues, I would refer you to my 'Gluten and autism: probably not coeliac disease but...' post (see here) as representing an important step in our understanding of this topic. That and the idea that birds of an autoimmune feather tend to flock together, and other potential associations are opened up as a result of any links between coeliac disease and autism (see here)...

But whatever you do, don't mention leaky gut as potentially also being involved (see here) (whisper it instead).

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[1] Calderoni S. et al. Serological screening for Celiac Disease in 382 pre-schoolers with Autism Spectrum Disorder. Italian Journal of Pediatrics. 2016; 42: 98.

[2] Whiteley P. Nutritional management of (some) autism: a case for gluten- and casein-free diets? Proc Nutr Soc. 2015 Aug;74(3):202-7.

[3] Prince HE. et al. Immunoglobulin A (IgA) Deficiency and Alternative Celiac Disease-Associated Antibodies in Sera Submitted to a Reference Laboratory for Endomysial IgA Testing. Clinical and Diagnostic Laboratory Immunology. 2000;7(2):192-196.

[4] Wasilewska J. et al. Low serum IgA and increased expression of CD23 on B lymphocytes in peripheral blood in children with regressive autism aged 3-6 years old. Archives of Medical Science : AMS. 2012;8(2):324-331.

[5] Genuis SJ. & Bouchard TP. Celiac disease presenting as autism. J Child Neurol. 2010 Jan;25(1):114-9.

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Calderoni, S., Santocchi, E., Del Bianco, T., Brunori, E., Caponi, L., Paolicchi, A., Fulceri, F., Prosperi, M., Narzisi, A., Cosenza, A., Tancredi, R., & Muratori, F. (2016). Serological screening for Celiac Disease in 382 pre-schoolers with Autism Spectrum Disorder Italian Journal of Pediatrics, 42 (1) DOI: 10.1186/s13052-016-0308-x

Breastfeeding and autism (or autistic traits) continued?

"After adjustment for several confounders, longer duration of breastfeeding was independently associated with better cognitive development and with fewer autistic traits."

So said the paper by Olivier Boucher and colleagues [1] communicating findings based on the examination of data from "the INMA Project, a Spanish multicenter birth-cohort study" (an initiative that has cropped up on this blog before).

Including over 1300 children who were subject to a battery of psychometric and behavioural assessments, researchers set about examining how various scores might be 'associated' with breastfeeding patterns: "Duration of any, predominant, and exclusive breastfeeding." The results as I've mentioned, seemed to show something of a connection between breastfeeding and particularly when it came to 'autistic traits' as assessed by the Childhood Autism Spectrum Test (CAST). I'll leave readers to draw their own conclusions about the relevance of this finding. Insofar as the more general conclusion on breastfeeding potentially aiding offspring cognitive development, well, let's just say that this has previously been mentioned before in the research literature (see here).

Having talked about breastfeeding in the context of autism before on this blog (see here) I don't really want to head too far into the collected literature in this area alongside the other aspects/discussions that it draws in. All I will say is that the relationship between breastfeeding patterns and offspring autism/autistic traits is not likely to be straight-forward [2] (few things with regards to autism research ever are) and there could even be occasions when breast milk might not be the preferred option* (see here) (*I should reiterate that I am not providing medical or clinical advice on this blog). There are, for example, a multitude of potentially confounding variables that could impact on any association between the two; not least that early manifestations of offspring autism might already be present and impacting on the ease of breastfeeding practices during the very earliest days and weeks of infancy. I'm not gonna say too much more on this topic at this time but will perhaps return to the subject in future posts.

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[1] Boucher O. et al. Association between breastfeeding duration and cognitive development, autistic traits and ADHD symptoms: a multicenter study in Spain. Pediatr Res. 2016 Nov 15.

[2] Penn AH. et al. Breast Milk Protects Against Gastrointestinal Symptoms in Infants at High Risk for Autism During Early Development. J Pediatr Gastroenterol Nutr. 2016 Feb;62(2):317-27.

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Boucher O, Julvez J, Guxens M, Arranz E, Ibarluzea J, Sánchez de Miguel M, Fernández-Somoano A, Tardon A, Rebagliato M, Garcia-Esteban R, O'Connor G, Ballester F, & Sunyer J (2016). Association between breastfeeding duration and cognitive development, autistic traits and ADHD symptoms: a multicenter study in Spain. Pediatric research PMID: 27846197

ADHD symptoms not methylphenidate treatment might prime for psychotic events

"This study does not support the hypothesis that MPH [methylphenidate] increases risk of incident psychotic events. It does indicate an increased risk of psychotic events before the first prescription of MPH, which may be because of an association between psychotic events and the behavioural and attentional symptoms that led to psychiatric assessment and initiation of MPH treatment."

The results published by Man and colleagues [1] (open-access) sit right with me. I say that on the basis that previous research suggesting that attention-deficit hyperactivity disorder (ADHD) may 'prime' someone for an elevated risk of developing psychosis (see here) has potentially received some welcome substantiation. That MPH might not be the bogeyman that some people might think (see here too) is also an important part of the Man findings (minus any charges of me providing medical or clinical advice on this blog... I'm not).

The Man paper is open-access but a few choice details are worthwhile mentioning:

• Based on data from the "Clinical Data Analysis and Reporting System (CDARS)" an initiative based in Hong Kong, researchers set about identifying those "aged 6–19 years who received at least one prescription of MPH with at least one psychotic disorder and/or hallucination diagnostic code (psychotic events) during the study period (January 2001 to December 2014)." Given that only MPH and atomoxetine are seemingly licensed in the Hong Kong for "the treatment of ADHD", the authors were able to focus specifically on MPH quite easily.
• Although over 20,000 patients were in receipt of MPH prescriptions, only data for 103 participants were used in the study as a result of that diagnosis of a psychotic/hallucinatory condition. Most were male and 76 out of the 103 participants had "a clinical ADHD diagnosis."
• Researchers looked at MPH treatment and those psychotic/hallucinatory events taking into the account timing and including "a 90-day pre-exposure period" representing a period before MPH use (see here).
• Results: "The primary analysis indicated no statistically significant association between MPH treatment and occurrence of incident psychotic events." But, when compared with baseline data, there did seem to be something to see during that pre-exposure period (before MPH) and incident psychotic event(s). Ergo, something other than MPH use seemed to be linked to the experience of psychosis and we therefore head back to the idea that ADHD as one reason for MPH use might have some quite profound implications for future mental health.

There is still quite a bit more to do in this area as per more longitudinal research with greater participant numbers. I might also draw your attention to Table 2 of the Man paper (see here) examining other 'psychiatric comorbidities' when it came to those participants experiencing a psychotic episode. The list of potential correlates is interesting in light of other work (see here).

Whilst MPH comes out of such research with more than a whiff of roses, it is perhaps important to understand that medicines, all medicines come with potential side-effects and that includes MPH. Nevertheless, the idea that the benefits of controlled use of MPH might trump the risk of serious psychiatric side-effects such as psychosis is something that needs to be said and with it, a realisation that treating/managing the signs and symptoms of ADHD early, might have more profound repercussions for those diagnosed...

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[1] Man KKC. et al. Methylphenidate and the risk of psychotic disorders and hallucinations in children and adolescents in a large health system. Translational Psychiatry. 2016; 6: e956.

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Man, K., Coghill, D., Chan, E., Lau, W., Hollis, C., Liddle, E., Banaschewski, T., McCarthy, S., Neubert, A., Sayal, K., Ip, P., & Wong, I. (2016). Methylphenidate and the risk of psychotic disorders and hallucinations in children and adolescents in a large health system Translational Psychiatry, 6 (11) DOI: 10.1038/tp.2016.216

Probiotics and 'subclincial' psychological symptoms: meta-analysed

I'm gonna be fairly brief today and draw your attention to yet another systematic review and meta-analysis this time looking at how "probiotic supplementation can have a positive effect on mood and psychological symptoms such as depression and anxiety." [1] Probiotics by the way, include a variety of bacteria and related lifeforms that are thought to confer some health advantage.

The review/re-analysis by Jennifer McKean and colleagues found 7 studies on this topic in the peer-reviewed research literature, that overall "showed that supplementation with probiotics resulted in a statistically significant improvement in psychological symptoms... compared with placebo." Personally, I wasn't surprised at these findings having covered a few bits of science on probiotics and psychology before on this blog (see here for example). Some recent discussions on how probiotics might be a possible 'stress-reliever' (see here) also add to this area.

I know some people are still a little sceptical of the whole 'gut-brain' thing (i.e. what goes on in the gut might have the ability to influence what goes on the grey/pink matter floating in the skull) and all the associated 'hype' that has accompanied the new science around the gut microbiota including the use of probiotics. There is lots more to do in this area; also overlapping with how other interventions may more detrimentally affect the trillions of bacteria that call us home and onwards may have 'psychological consequences' too (see here).

But it is getting rather more difficult not to think that there may be some important processes at work in these times of psychobiotics [2]...

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[1] McKean J. et al. Probiotics and Subclinical Psychological Symptoms in Healthy Participants: A Systematic Review and Meta-Analysis. J Altern Complement Med. 2016 Nov 14.

[2] Dinan TG. et al. Psychobiotics: a novel class of psychotropic. Biol Psychiatry. 2013 Nov 15;74(10):720-6.

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McKean J, Naug H, Nikbakht E, Amiet B, & Colson N (2016). Probiotics and Subclinical Psychological Symptoms in Healthy Participants: A Systematic Review and Meta-Analysis. Journal of alternative and complementary medicine (New York, N.Y.) PMID: 27841940

On C-reactive protein and bipolar disorder

"CRP [C-reactive protein] concentrations are increased in bipolar disorder regardless of mood state, but are higher during mania than in depression and euthymia, suggesting an increased inflammatory burden in mania."

So said the systematic review and meta-analysis published by Brisa Fernandes and colleagues [1] who surveyed the peer-reviewed literature on the topic of "measured serum and plasma CRP concentrations in adult patients with bipolar disorder (as defined by DSM-IV-TR) and healthy controls" and arrived at their conclusions based on an analysis of some 2000 people diagnosed with bipolar disorder (BD). CRP by the way, a member of the pentraxin family, is the molecule of choice when it comes to looking at response to inflammation. BD, previously known as manic depression, is a condition characterised by periods of depression and mania.

Continuing an important theme in psychiatry - that the immune system or expression of the immune system whether in terms of genetics or biology, seems to show some important associations with behaviour (see here for example) - the Fernandes paper represents important work. Of course it's not the first time that CRP levels and bipolar disorder have been mentioned on this blog (see here) but the 'collecting' of results based on the use of systematic review and meta-analysis this time around strengthens the association between these variables.

Where next I hear you ask? Well, the idea that CRP levels might be linked to cases of BD needs further research not least to ensure that certain over-represented medical comorbidity linked to BD are not an interfering variable when it comes to CRP levels (see here). The findings should also perhaps be seen in a larger context where CRP levels have been reported in other psychiatric / behavioural labels (see here). The non-specificity of CRP (i.e. not tied to just one label) also has implications for the idea that many different psychiatric / behavioural labels might show overlapping features (see here) for example.

With no medical or clinical advice given or intended, there is also the intriguing idea that interventions targeting specific immune function findings may also have behavioural implications (see here for example). This alongside the idea that some medicines intended for the treatment or management of aspects of BD may already have some 'immune-modulating' actions (see here) potentially tied into their potential efficacy (or not). Again, further research is very much implied.

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[1] Fernandes BS. et al. C-reactive protein concentrations across the mood spectrum in bipolar disorder: a systematic review and meta-analysis. Lancet Psychiatry. 2016 Nov 9. pii: S2215-0366(16)30370-4.

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Fernandes BS, Steiner J, Molendijk ML, Dodd S, Nardin P, Gonçalves CA, Jacka F, Köhler CA, Karmakar C, Carvalho AF, & Berk M (2016). C-reactive protein concentrations across the mood spectrum in bipolar disorder: a systematic review and meta-analysis. The lancet. Psychiatry PMID: 27838212

Low gestational age is associated with risk for autism

The results published by Robert Joseph and colleagues [1] provide some blogging fodder today, observing that as part of the ELGAN (Extremely Low Gestational Age Newborns) Research Study, gestational age might matter when it comes to offspring risk of autism spectrum disorder (ASD).

Gestational age is a measure of how far along a pregnancy is but in the context of the Joseph study refers to premature birth or those "born at least 3 months early." Researchers included data for nearly 1000 children born extremely premature using a prospective (rather than retrospective) methodology who, at age 10, were "evaluated for ASD and ID [intellectual disability]." They also took into account various other 'pregnancy information' derived from both medical records and interviews with mums. This included instances of cervical-vaginal ‘infection’ among other things.

The results: over 90% of their cohort were assessed for autism/ASD and ID. Rates of ASD alone (without ID) were 3.2%. Some 3.8% of participants screened positive for autism and ID and 8.5% of participants presented with ID but not autism. Whilst these autism (with or without ID) rates might seem high, I'm not actually convinced that they are 'significantly higher' than that suggested in modern times (see here). The authors also noted that: "The lowest gestational age category (23-24 weeks) was associated with increased risk of ASD+/ID+... and ASD+/ID-."

Also: "Maternal report of presumed cervical-vaginal ‘infection’ during pregnancy was associated with increased risk of ASD+/ID+." The sorts of things included under the heading of cervical-vaginal infection were "bacterial infection (n = 4), bacterial vaginosis (n = 30), yeast infection (n = 62), mixed infection (n = 4) or other/unspecified infection (n=43; e.g., chlamydia, trichomonas or herpes, etc.)."

I agree with the authors that "low gestational age is associated with increased risk for ASD" and this research does seem to tally with other studies on this topic (see here for example). The one caveat I do want to make however is that the absolute numbers of children diagnosed with autism (with or without ID) were quite low (27 and 32 children respectively out of a total of 840) and somewhat dwarfed in comparison to those presenting with ID without autism (71 children out of 840). Still, preferential screening for autism and ID might be implied from these results; assuming that is, that the screening instrument in question is up to the job [2].

As to potential mechanisms of effect... well, it's rather difficult to pin any 'excess autism risk' to any one mechanism in light of the various factors that can accompany prematurity. Aside from the immaturity of various biological system associated with premature birth (including the brain), the obvious effect of a reduced birth weight is something to consider (see here). I am also interested in the idea that infection (using the term quite broadly) during pregnancy might also impact on offspring autism risk in light of other data (see here). Specific pathogens during pregnancy affecting offspring developmental risks have already made a mark on the peer-reviewed research literature (see here for example) and could provide a template for the processes pertinent to infection plus prematurity too.

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[1] Joseph RM. et al. Extremely low gestational age and very low birth weight for gestational age are risk factors for ASD in a large cohort study of 10-year-old children born at 23-27 weeks gestation.  American Journal of Obstetrics and Gynecology. 2016. Aug 13.

[2] Kim SH. et al. Predictive Validity of the Modified Checklist for Autism in Toddlers (M-CHAT) Born Very Preterm. J Pediatr. 2016 Nov;178:101-107.e2.

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Joseph, R., Korzeniewski, S., Allred, E., O’Shea, T., Heeren, T., Frazier, J., Ware, J., Hirtz, D., Leviton, A., & Kuban, K. (2016). Extremely low gestational age and very low birth weight for gestational age are risk factors for ASD in a large cohort study of 10-year-old children born at 23-27 weeks gestation American Journal of Obstetrics and Gynecology DOI: 10.1016/j.ajog.2016.11.1009

Acute psychosis and urinary tract infection (again)

Consider this short blog post an extension of some previous discussions (see here and see here) on a rather peculiar 'association' between urinary tract infections (UTIs) and psychosis. UTIs basically refer to an infection in any part of the urinary system (kidneys, bladder, etc) typically treated with antibiotics. Psychosis is a state that causes a person to perceive or interpret things around them in an atypical way, usually accompanied by delusions or hallucinations. For a while now research has been connecting these two conditions.

The paper by Chelsea Carson and colleagues [1] further adds to the peer-reviewed literature in this area with the observation of: "an association between UTIs and children and adolescents with acute non-affective psychosis." Based on a "retrospective chart review of 227 subjects ages 10–18 who were hospitalized between 2005 and 2014 for an acute episode of DSM-IV non-affective psychosis" compared with those presenting with depression with and without psychotic features, researchers noted that a UTI was not an uncommon diagnosis (20%). Bearing in mind the lack of any asymptomatic control group, authors concluded that screening for [comorbid] UTI in those presenting with acute psychosis might be warranted.

I can't disagree with these findings and conclusions. Combined with other work [2] looking at "an association between an increased prevalence of UTI and acute psychotic relapse" in those diagnosed with schizophrenia, the idea that infection or immunological response to infection might have behavioural as well as physiological outcomes gathers strength from such findings. We still don't know all the hows-and-whys of such an association outside of the idea that inflammatory mechanisms may be at work (see here) but further investigations are most definitely implied.

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[1] Carson CM. et al. Urinary tract infections in children and adolescents with acute psychosis. Schizophrenia Research. 2016. Nov 10.

[2] Miller BJ. et al. A prevalence study of urinary tract infections in acute relapse of schizophrenia. J Clin Psychiatry. 2013 Mar;74(3):271-7.

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Carson, C., Phillip, N., & Miller, B. (2016). Urinary tract infections in children and adolescents with acute psychosis Schizophrenia Research DOI: 10.1016/j.schres.2016.11.004

Caring for the carer: what the science suggests

Papers such as the one published by Nikko Da Paz & Jan Wallander [1] I think represent one of the most important areas of autism research and practice when it comes to the practical translation of science to real-life. Tackling a very important topic - caring for the carers - the authors provide a "narrative review" of the peer-reviewed science literature looking at how "treatments that directly target parents' psychological well-being" in the context of autism are doing so far.

Personally, I don't like the use of the word 'treatment' in this context because it implies that caring for the carers is akin to tackling some sort of disease. It's not. It also 'medicalises' the experience of caring for/raising children on the autism spectrum which I don't think anyone really wants to do. I might suggest that 'intervention' could be a better word to use.

Da Paz and Wallander reported on "a total of 13 studies, seven randomized controlled trials (RCTs) and six pre-post test designs" that looked at various interventions pertinent to improving parent stress and reducing instances of depression and anxiety. They report: "Interventions that appeared promising included: Stress Management and Relaxation Techniques, Expressive Writing, Mindfulness-Based Stress Reduction, and Acceptance and Commitment Therapy" with some important caveats. Not least that if English is not your language of choice and/or you are not aged between 39-42 years old, the evidence base is rather sparse when it comes to what might be useful or not for managing your psychological health. In light of other research [2] there is quite a bit more to do in this area.

Accepting that the publishing journal - Clinical Psychology Review - gives a rather large hint as to why the listed 'psychological' interventions were focused upon, I might also add a few comments about how other science and practice might also aid parents raising children on the autism spectrum. I've for example, covered the topic of respite care and parent stress before on this blog (see here) and how depending on your definition of respite, there is perhaps some value in either the utilisation of short break facilities or the use of domiciliary care/support where available. As per my previous discussion of this area, there is a rather large stumbling block to any talk about respite care insofar as in these austere times in which we live, some of the first social services that seem to suffer when budgets need to be reduced are respite services.

I'm also minded to bring in the idea that outside of psychological techniques potentially impacting on parenting stress and any adverse outcomes, one might also look at more physical interventions too. So, for example, exercise is something that could be a rather useful intervention to look at given the pretty strong research links being forged between body and mind. The thing about exercise is that (a) depending on what regime you choose costs can range from free to expensive, and (b) there are a whole host of other factors potentially tied into a chosen sport, based on the choice of solitary sports vs. group sports for example and other factors. That various health agencies are already shifting when it comes to notions of potentially 'prescribing exercise' for something like depression and anxiety (see here for example) reflects how valuable moving a little more might be to lots of groups.

I would champion the idea that quite a few more resources need to be put into caring for the carers when it specifically comes to parenting and autism. This is not about further 'blaming autism' for parenting stress or adverse outcomes but rather acknowledging that parenting whether in the context of autism or not, is a sometimes difficult task. And nobody benefits if parents/carers are just left to fend for themselves without the appropriate help and support...

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[1] Da Paz NS. & Wallander JL. Interventions that target improvements in mental health for parents of children with autism spectrum disorders: A narrative review. Clin Psychol Rev. 2016 Oct 27;51:1-14.

[2] Zuckerman KE. et al. Pediatrician identification of Latino children at risk for autism spectrum disorder. Pediatrics. 2013 Sep;132(3):445-53.

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Da Paz NS, & Wallander JL (2016). Interventions that target improvements in mental health for parents of children with autism spectrum disorders: A narrative review. Clinical psychology review, 51, 1-14 PMID: 27816800

PACE-gate!

With all rights reserved for Keith Geraghty and his publication in the Journal of Health Psychology [1] (open-access) I want to reproduce his abstract relevant to the PACE trial commenting on the ups-and-downs of this study looking at the use of CBT (cognitive behaviour therapy) and GET (graded exercise therapy) for chronic fatigue syndrome (CFS) (also known as myalgic encephalomyelitis, ME):

"Science is not always plain sailing and sometimes the voyage is across an angry sea. A recent clinical trial of treatments for chronic fatigue syndrome (the PACE trial) has whipped up a storm of controversy. Patients claim the lead authors overstated the effectiveness of cognitive behavioural therapy and graded exercise therapy by lowering the thresholds they used to determine improvement. In this extraordinary case, patients discovered that the treatments tested had much lower efficacy after an information tribunal ordered the release of data from the PACE trial to a patient who had requested access using a freedom of information request."

For those familiar with PACE [2] and the 'angry sea' saga following its publication (see here for some of that saga), this paper represents one of the the first 'peer-reviewed' discussions that makes reference to the reanalysis of 'trial improvers' vs. that included in the original PACE trial publication (see here). Indeed, combined with other (as yet unpublished in the peer-reviewed domain) re-analyses (see here), there seem to be some pretty stark differences noted between the different 'versions' in terms of the effectiveness of different arms of the intervention tested during the PACE trial. Even before these latest re-analyses, some agencies were already adjusting the strength of their recommendations when it came to CBT and/or GET for CFS/ME (see here). Does this mean other organisations might follow suit?

The other issue central to the Geraghty discussions is that of 'enforced data release' and data transparency. This has been a focal point when it comes to PACE (including that with reference to other papers on the trial) and perhaps something that has significantly added to the sometimes bitter discussions about the trial. As Geraghty notes: "The PACE-Trial stands out as a showcase example of why data transparency is needed in contemporary science. Patients suffering from health conditions like CFS, and independent scientists, should have the right to see the evidence behind the claims of any scientific study, especially if this evidence is used to direct health policy or promote certain treatments – as was the case for the PACE-Trial." In light of how PACE has been contributory to public policy, and indeed was part funded by agencies such as "the UK Department for Work and Pensions", I don't think many people would argue against suitable data transparency in this case.

I say nothing more at this point in time but will no doubt be returning to this topic as the peer-reviewed literature allows (which should be quite soon). If there are however, some lessons that can already be learned from PACE-gate (e.g. stick to your "original protocol thresholds", make your data 'open-access' and think about how to do this in the planning/recruitment stages of your trial, be mindful that short-term gains don't necessarily translate into long-term ones, work with the ME/CFS community rather than labelling elements of them 'vexatious' or worse) one would hope that they would be applied to future research projects related to CFS/ME (see here) as well as their anticipated long-term follow-up [3]...

Music: The King and what wise men (might) say (easily recognisable to any Black Cats fan).

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[1] Geraghty KJ. 'PACE-Gate': When clinical trial evidence meets open data access. J Health Psychol. 2016 Nov 1. pii: 1359105316675213.

[2] White PD. et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011 Mar 5;377(9768):823-36.

[3] Nijhof SL. et al. Internet-based therapy for adolescents with chronic fatigue syndrome: long-term follow-up. Pediatrics. 2013 Jun;131(6):e1788-95.

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Geraghty KJ (2016). 'PACE-Gate': When clinical trial evidence meets open data access. Journal of health psychology PMID: 27807258

Autism, ESSENCE and the question of reassessment

I talked about ESSENCE - Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations - only yesterday (see here) and here I am covering the topic again on this blog. There is good reason however that this concept appears once more, as I draw your attention to the paper by Anne-Katrin Kantzer and colleagues [1] and the specific observation that: "Co-existence with other conditions was the rule" when it comes to the diagnosis of autism.

OK, it's nothing new to say that the label of autism rarely appears in some sort of diagnostic vacuum (see here). Indeed, if there is anything that has been learned about autism over the years it is that aside from the incredible heterogeneity present across the spectrum in terms of clinical presentation, many grand theories 'about autism' have been scuppered as a consequence of their assumptions on autism being some sort of stand-alone label. A case in point: theory of mind (ToM); that even some of the major proponents of this theory have come to realise [2] has seen a "a widening of interest to other clinical groups." Indeed it has (see here for example), indeed it has. And other grand theories appear also to be following suit [3]...

The Kantzer paper - including some notable names on the authorship list - set out to examine the diagnostic outcomes of some 96 children "initially assessed for suspected ASD [autism spectrum disorder] at an average age of 2.9 years" who were followed up some two years later. There is an important word included in the Kantzer study: prospectively; as opposed to retrospectively, meaning that participants were assessed and followed in real-time (rather than solely relying on the examination of previous historical records). Various behavioural and psychometric measures were employed by the authors as part of a "broad neurodevelopmental examination... by a multi-professional team" and some rather interesting details emerged.

So: "In a cohort of young children who screened positive for autism spectrum symptoms, 93% of all with an Autism spectrum disorder (ASD) at time1 (T1) had ASD two years later." What this tell us is that in the most part, the diagnosis of autism/ASD over 2 years in young children is fairly stable. Other data has highlighted similar things. But then the question: what about the ~7% where an ASD diagnosis perhaps wasn't as stable? I've covered this topic a few times on this blog (see here and see here), where for whatever reason, the diagnosis of autism is not necessarily a lifelong label for everyone. The still controversial idea that around 9% of those originally diagnosed with autism might 'lose' their diagnosis (see here) and indeed any/many 'broader autism features' (see here) could be pertinent here accepting that in the Kantzer data we are told: "The children who did not meet criteria for ASD at T2 had symptoms of or met criteria for other neurodevelopmental/neuropsychiatric disorders in combination with marked autistic traits." I might also draw your attention to other work from members of the Kantzer group that indicated that even into adulthood, diagnoses along the autism spectrum might similarly not always be 'lifelong' for whatever reason(s) (see here).

Next: "The vast majority of children with ASD also had other neurodevelopmental symptoms or diagnoses." This kinda reiterates the notion of ESSENCE, as details such as: "Hyperactivity was observed in 42% of children with ASD at T2, and Intellectual Developmental Disorder in 30%" provide some diagnostic flesh on the bones of what ESSENCE might look like in clinical terms. Indeed, although the topic of continued debate [4] insofar as how one screens for something like attention-deficit hyperactivity disorder (ADHD) in autism, the overlap between the conditions is likely to be significant (see here).

Finally: "The risk of “over-diagnosis” of ESSENCE/ASD problems by screening for ASD at 2.5 years appears to be minimal." Accepting that important changes to the way that autism is diagnosed by at least one schedule is likely to produce some important differences in who fulfils criteria (see here), the authors seem to be fairly confident that early diagnosis might actually be (a) possible and (b) pretty accurate. The stress is most definitely on 'early diagnosis' save any charges of further health inequalities facing those on the autism spectrum.

I titled this post  'Autism, ESSENCE and the question of reassessment' because I do also want to pass some brief comment about the value of reassessment picked up by the authors: "Reassessments covering the whole range of these conditions are necessary for an optimized intervention—adapted to the individual child’s needs." This is going to take quite a huge shift in thinking and practice insofar as ensuring that a diagnostic assessment for autism does not just include an ADOS or something related but rather includes a wider spread of behavioural and psychometric instruments pertinent to various other labels/features. I can see there being objections to this line of thought; not least that in these austere times we live in when waiting times for an initial assessment can already be quite long (see here) and money and resources are stretched thin on the ground for autism, screening for a range of potential additional issues is likely to further burden limited resources. The idea also that not hitting diagnostic thresholds for autism at one point does not rule out a child hitting them at a later time point is also something likely to impact on screening and assessment services. I suppose it all depends on whether policy-makers and purse-string holders value detail or value cost-saving?

Either way, the Kantzer paper once again highlights that a diagnosis of autism rarely exists in a diagnostic vacuum.

Music to close (it's been a while) and an 80's blast from the past: Billy Ocean - Get Outta My Dreams, Get Into My Car (although please, do not get into a car with someone you don't know, no matter how well they serenade you).

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[1] Kantzer A-K. et al. Young children who screen positive for autism: Stability, change and “comorbidity” over two years. Research in Developmental Disabilities. 2016. Nov 3.

[2] Happé F. & Conway JR. Recent progress in understanding skills and impairments in social cognition. Curr Opin Pediatr. 2016 Dec;28(6):736-742.

[3] Dajani DR. et al. Heterogeneity of executive functions among comorbid neurodevelopmental disorders. Sci Rep. 2016 Nov 9;6:36566.

[4] Yerys BE. et al. Evaluation of the ADHD Rating Scale in Youth with Autism. J Autism Dev Disord. 2016 Oct 13.

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Kantzer, A., Fernell, E., Westerlund, J., Hagberg, B., Gillberg, C., & Miniscalco, C. (2016). Young children who screen positive for autism: Stability, change and “comorbidity” over two years Research in Developmental Disabilities DOI: 10.1016/j.ridd.2016.10.004