More metabolomics, amino acids, gut bacteria and autism

"Here he goes again" I hear you say as today's micro-post focuses on a rather interesting paper from Xue Ming and colleagues* which, and I quote, "detected abnormal amino acid metabolism, increased oxidative stress, and altered gut microbiomes in ASD".

Ur-inal or mine? @ Wikipedia  

The name of the game was a favourite -omics of mine, metabolomics (see this recent post for a brief overview) and in particular how the appliance of some really quite powerful science to urine specimens provided by children with autism and aysmptomatic controls, revealed some interesting differences.

A brief overview of the paper and results bearing in mind that I'm still pursuing the full-text paper:

• Using a combination of both liquid- and gas chromatography based mass spectrometry, urine specimens were analysed for 48 children diagnosed with as autism spectrum disorder (ASD) and 53 age-matched not-autism controls.
• Results: after some nifty statistical analysis, urinary amino acid output was one of the most important factors and in particular several amino acids presenting in lower, concentration controlled levels in the ASD group over controls. 
• With shadows of the findings from Prof. Jeremy Nicholson a few years back (see this post), the authors conclude that "several gut bacterial metabolites were significantly altered in ASD children who had gastrointestinal dysfunction".

As indicated, this post is a preliminary one and I hope to fill in a few gaps when I get the full-text paper. Nevertheless, such work as this from Ming and colleagues is indeed important fodder for this blog. We've been here before both with autism and indeed conditions like schizophrenia too albeit not necessarily presenting with the same patterns of findings. Indeed, very much like the rising prominence of disciplines like metabolomics to conditions like schizophrenia - five serum and one urine metabolite for example - there is perhaps some important data to be derived from such studies, at least on the functional differences between autism and not-autism. That outside of the known metabolic disorders with a focus on amino acid chemistry that can present with autism or autism-like characteristics.

The gut bacteria-autism connection? Don't get me started again, as once more another study suggests some potential involvement from those trillions of bacterial masters. I haven't forgotten the old correlation does not equal causation mantra by the way, just pointing out that something seems a little bit unusual with gut bacteria in some cases of autism.

More to follow...

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* Ming X. et al. Metabolic perturbance in autism spectrum disorders: a metabolomics study. J Proteome Res. October 2012.

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Ming X, Stein TP, Barnes V, Rhodes N, & Guo L (2012). Metabolic Perturbance in Autism Spectrum Disorders: A Metabolomics Study. Journal of proteome research PMID: 23106572

Parent-led early intervention and autism: what's going on?

I do love my quotes on this blog. So another quote to begin this post: "Parent-implemented intervention studies for early ASD thus far have not demonstrated the large effects seen in intensive-treatment studies".

It comes from quite a recent study by Sally Rogers and colleagues* examining "the efficacy of a 12-week, low-intensity (1-hour/wk of therapist contact), parent-delivered intervention for toddlers at risk for autism spectrum disorders (ASD) aged 14 to 24 months and their families". The reported results it seems were less than spectacular in comparison to community treatment as usual bearing in mind the relatively short study duration.

All this comes a few years after the results of PACT (Preschool Autism Communication Trial)** where the authors concluded (sorry more quotes) "we cannot recommend the addition of this PACT intervention to treatment as usual for the purpose of reduction in autism symptoms". PACT by the way is a strategy based predominantly on shared attention, where parents are encouraged to alter their communicative skills more towards their child's level of understanding (see here for a description). I'm not the first to talk about PACT by the way as per this blog entry.

Whilst based on slightly different programmes - Rogers et al looked at a parent-based version of the Early Start Denver Model (ESDM) - a primary focus of both ESDM and PACT are language and shared attention; in both these studies, delivered by parents to young children with autism. Similar to other programs such as the Hanen More Than Words® initiative (itself the subject of some study with autism in mind***) and others****, the suggestion is that subtle alterations to parent - child interactions may ameliorate the presentation of some of the core and peripheral signs and symptoms associated with early infancy autism.

Although not specifically my area of competence, I'm interested in these various studies and results for lots of different reasons, not least some increasing interest in something called VIG (video interaction guidance) albeit not necessarily with parent-child interactions in mind. Seeing parents as partners when offspring autism is present obviously plays a big role in these kinds of initiatives and their associated study. Given the way autism comes about in early infancy, together with the whole brain plasticity and under-connectivity findings***** (full-text), there is sound logic in ensuring the potential gains already noted from early intensive professional intervention****** can also be extended outside of school hours. That and the fact that parents obviously want to do the best they can to help their children's development and symptom presentation (sorry to use such cold terminology by the way).

I don't however think many people would be surprised to hear that when universally applied to all cases of autism, these programs were not entirely effective for all children as per this commentary on the Hanen results. Indeed the same goes for just about any intervention used for autism, even early intensive behavioural intervention (EIBI) if you accept the results from the latest Cochrane review******* on the subject.

That being said, we're potentially back to the old endophenotypes and responder / non-responder suggestions and the growing need for much more research on autisms rather than autism. The fact that response to intervention might be a more suitable 'indicator' for discerning those homogeneous subgroups over the more traditional shotgun approach to multiple targets based on the autism diagnosis alone is another consideration worthy of future discussion.

I digress.

The question of why the highlighted parent-led interventions don't quite seem to be cutting the statistical mustard is an interesting one. I should at this point demonstrate that other results have indicated some success with home-based programs so we're not talking about a universal failure here bearing in mind some important methodological differences and indeed the targets of such interventions. Other than the reasons already mentioned, there are potentially quite a few other factors at play not least some expected variability in the delivery of the interventions and questions about the outcomes and length of time being studied. It could well be that there is a ceiling effect from such education and behavioural interventions already reached where intensive intervention is already running in the background at school for example.

Outside of the bloomers (or even including the bloomers), we know that there are potentially some great gains to be made from behavioural intervention******* for some children on the autism spectrum and beyond - perhaps also even translating into physiological measures******** - allowing for the fact that much more detailed scientific investigations are required on efficacy and best-responder characteristics. The position of such parent-based programs at a scientific level measured by the current data however, cannot be easily ignored in these evidence-based medicine days. Indeed reliant on the evidence currently available, does this not make a good case for specialist-delivered early intervention to be made more widely available above and beyond the more cost-effective (to the state) parent-led intervention strategies?

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* Rogers SJ. et al. Effects of a brief Early Start Denver Model (ESDM)-based parent intervention on toddlers at risk for autism spectrum disorders: a randomized controlled trial. J Am Acad Child Adolesc Psychiatry. 2012; 51: 1052-1056.

** Green J. et al. Parent-mediated communication-focused treatment in children with autism (PACT): a randomised controlled trial. Lancet. 2010; 375: 2152-2160.

*** Carter AS. et al. A randomized controlled trial of Hanen's 'More Than Words' in toddlers with early autism symptoms. J Child Psychol Psychiatry. 2011; 52: 741-752.

**** Soloman R. et al. Pilot study of a parent training program for young children with autism. The PLAY Project Home Consultation program. Autism. 2007; 11: 205-224.

***** Müller RA. et al. Underconnected, but how? A survey of functional connectivity MRI studies in autism spectrum disorders. Cereb Cortex. 2011; 21: 2233-2243.

****** Grindle CF. et al. Outcomes of a behavioral education model for children with autism in a mainstream school setting. Behav Modif. 2012; 36: 298-319.

******* Reichow B. et al. Early intensive behavioral intervention (EIBI) for young children with autism spectrum disorders (ASD). Cochrane Database Syst Rev. 2012; 10: CD009260.

******** Gutstein SE. Empowering families through Relationship Development Intervention: an important part of the biopsychosocial management of autism spectrum disorders. Ann Clin Psychiatry. 2009; 21: 174-182.

********* Dawson G. et al. Early behavioral intervention is associated with normalized brain activity in young children With autism. J Am Acad Child Adolesc Psychiatr. 2012; 51: 1150-1159.

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Rogers SJ, Estes A, Lord C, Vismara L, Winter J, Fitzpatrick A, Guo M, & Dawson G (2012). Effects of a Brief Early Start Denver Model (ESDM)-Based Parent Intervention on Toddlers at Risk for Autism Spectrum Disorders: A Randomized Controlled Trial. Journal of the American Academy of Child and Adolescent Psychiatry, 51 (10), 1052-65 PMID: 23021480

Cerebral palsy and autism

I seem to keep saying this but one of the many important things about autism is that the diagnosis of autism has not yet been found to be protective against other conditions occurring alongside. This is probably not new news to many as per the comorbities which have been, and continue to be found in cases of autism; recognised even by official guidance on autism (see here).

Importantly however in recent times, more attention is being directed to the overlap of autism with other conditions and how those other conditions might potentially further inform sub-groups (endophenotypes) within the autism spectrum in terms of aetiology and pathology. I'm specifically thinking of the 'significantly over-represented' paper published earlier this year (2012) as a prime example.

Enter then another paper by Pål Surén and colleagues* looking at the overlap between autism spectrum conditions, ADHD, epilepsy and cerebral palsy and reportedly finding a "significant burden of disease associated with neurologic and neurodevelopmental disorders in children".

I'm not specifically going to discuss Surén's paper in excruciating detail because the results really don't need me complicating them. What however I am interested in is the body of work in the peer-reviewed arena suggesting a link between the presence of autism and one comorbidity detailed in their paper, cerebral palsy, and what, if anything, we can draw from such an association.

Perhaps best to first describe what cerebral palsy (CP) is (and isn't). The UK charity Scope have quite a good description of CP (here) alongside more detailed information being available. Basically, CP is a catch-all term for a group of conditions primarily affecting movement and resulting in physical disability. The brain is a central organ to CP (hence the name cerebral palsy) and in particular how certain adverse factors whether inborn or during pregnancy and/or the neonatal period may affect brain development. That being said, the mechanisms of brain disturbances linked to CP is still a work in progress and new-ish ideas are still emerging about things like inflammation for example, being potentially linked to CP (see this study by Marlow and colleagues**) and indeed some familiar themes on food and gut hyperpermeability*** when extended to other parts of the body.

Whilst issues with movement is a core symptom of CP, there are a variety of other presentations that also seem to be evident in children with CP. So learning disability, epilepsy and sensory issues have all been noted, as well as more physical issues such as functional bowel problems like constipation. Without wishing to make bridges where none might be required, I was struck by how much overlap in peripheral features there is between CP and cases of autism.

So then to some of the links (or not) between CP and autism:

• Estimated prevalence rates of CP are slightly difficult to interpret bearing in mind that factors such as twin/multiple births are seen as risk factors. Figures from the US report an estimated prevalence of CP of about 0.3%. This paper by Glinianaia and colleagues**** suggested an estimated prevalence rate of 0.2% for singletons and 1.1% in multiple UK births, with birth weight also being a potential modifying risk factor. That multiple birth link with CP also seems to hold where an autism link perhaps doesn't (see here).
• In terms of the overlap between autism and CP, Mouridsen and colleagues***** confirmed that there seems to be an over-representation of CP in cases of autism compared to non-autism controls as per the findings of other datasets (here, here, here, here and here - phew!). Of the limited studies done on the presentation of autism and CP, preliminary results suggest that the severity of core autistic symptoms may also be adversely influenced by the two conditions appearing alongside each other (here).
• Although the brain is undoubtedly implicated in CP, there is still some debate about the precise areas of the brain involved in the different presentations of the condition. Current thought is that different areas of the brain may be involved in individual cases of CP according to how symptoms present. The link between brain and autism is an equally complex relationship made even more complicated by the wide range of abilities/disabilities noted across different cases. I could tentatively suggest a link to brain areas involved with motor control given the overlap (yes, motor issues have been mentioned in cases of autism) between the conditions. Indeed, ataxic CP has been linked to issues with the cerebellum; the cerebellum being a favourite target for some autism research also as per the recent consensus paper by Fatemi and colleagues******. I hasten to add that I am by no means reducing both conditions down to just one area of the brain however. 
• Interestingly, infections such as cytomegalovirus (CMV), previously linked to the onset of autism (here) have also been overlapped with CP (here). Maternal infection and fever during pregnancy has also been associated with an increased risk of offspring CP as per the results of this study****** and some familiar names to autism research. Again without making too many unwarranted connections, the recent CHARGE results spring to mind as a possible comparator.
• The immune system and CP... how long have you got? To take one example, those dastardly IL-6 cytokines rear their head in cases of CP both from a genetics point of view (here) and possibly tied into increasing amounts of circulating IL-6 (here). Other patterns of cytokine presentation have also been reported alongside coagulation anomalies (here). Need I say anymore about IL-6 (and other cytokines) and autism?

There are other instances of 'overlap' between autism and CP but I am wary of listing all of them because of the risk of falling into the trap of just reciting research and actively looking for connections. Taking the model of autoimmunity and the presence of one autoimmune condition potentially raising the risk of other autoimmune conditions appearing/being diagnosed, I think we might be looking at a similar process here with regards to the various connections being made between autism and CP - be they structural brain issues, infections, immune function or others.

What this and other investigations reiterate is that the links noted between autism and a wide variety of other conditions form an important part of the research landscape and potential clues as to the underlying nature of the condition. Accepting the current stance that both CP and autism are categorised as 'lifelong conditions' the very preliminary shared links between intervention strategies such as HBOT for CP and HBOT for autism (no endorsement given or intended) makes me wonder about the need for some more detailed investigation.

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* Surén P. et al. Autism spectrum disorder, ADHD, epilepsy, and cerebral palsy in Norwegian children. Pediatrics. June 2012.
DOI: 10.1542/peds.2011-3217

** Marlow N. et al. Characteristics of children with cerebral palsy in the ORACLE children study. Developmental Medicine & Child Neurology. 2012; 54: 640-646.

*** Stenberg R. et al. Increased prevalence of antibodies against dietary proteins in children and young adults With cerebral palsy. Journal of Pediatric Gastroenterology & Nutrition. September 2012.

**** Glinianaia SC. et al. Cerebral palsy rates by birth weight, gestation and severity in North of England, 1991-2000 singleton births. Archives of Disease in Childhood. 2011; 96: 180-185.

***** Mouridsen SE. et al. A longitudinal study of epilepsy and other central nervous system diseases in individuals with and without a history of infantile autism. Brain & Development. 2011; 33: 361-366.

****** Fatemi SH. et al. Consensus paper: pathological role of the cerebellum in autism. Cerebellum. 2012; 11: 777-807.

******* Grether JK. & Nelson KB. Maternal infection and cerebral palsy in infants of normal birth weight. JAMA. 1997; 278: 207-211.

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Surén P, Bakken IJ, Aase H, Chin R, Gunnes N, Lie KK, Magnus P, Reichborn-Kjennerud T, Schjølberg S, Øyen AS, & Stoltenberg C (2012). Autism spectrum disorder, ADHD, epilepsy, and cerebral palsy in Norwegian children. Pediatrics, 130 (1) PMID: 22711729

Allergic and autoimmune diseases and autism

Comorbidity is quite a big topic of interest to me. Specifically comorbidity when talking about autism or schizophrenia or quite a few other behaviourally-defined conditions.

Venn-ting @ Wikipedia 

The reason for my interest? Well let's just say that although many a textbook so report, autism for example is not just the sum of its triad (soon to be dyad) of symptoms but much, much more.

That and the fact that based on the current data as it stands, a diagnosis of autism is seemingly protective of nothing and indeed, often significantly increases the risk that one or more of quite a few other conditions can appear alongside.

I've talked about comorbidity quite a few times on this blog (significantly over-represented... and all that) but am drawn back into this area again following the paper from Mu-Hong Chen and colleagues* describing the allergic and autoimmune comorbidity present in autism based on quite a large participant group.

OK you can perhaps see why I might be interested in this paper given the words 'allergy' and 'autoimmunity' in the title and some link back to previous posts (see here and here). Autoimmunity in particular, is something which I personally think is severely under-rated when it comes to conditions manifesting behavioural and developmental aspects, given the more traditional somatic associations that have been made. But that's just my thoughts...

Anyhow, a few details about the Chen paper:

• Quite a big study based on finding cases of autism (N=1596) among a National Health Insurance Database in Taiwan between 1996 and 2010. 
• Autism cases were compared (1:4 ratio) with age and gender-matched asymptomatic controls for the presence of various allergic and autoimmune-defined conditions.
• Results: various allergy and atopic diseases were more readily associated with autism cases than controls including allergic rhinitis, atopic dermatitis and asthma (odds ratios between 1.7-1.5). That added to quite a bit more frequency in autoimmune conditions such as type 1 diabetes (OR=4) and Crohn's disease (OR=1.46). Please note I've not included confidence intervals (CIs) (look them up in the paper if you're interested).
• The authors conclude that there might be some important associations and potentially shared underlying mechanisms between these very somatically defined comorbidities and autism.

I've talked previously about autism in Taiwan on this blog. That post was with reference to some data on the numbers of cases of autism being detailed in Taiwan and how even outside of Europe and North America, autism rates seem only to be going in one direction: up. I'm not wishing to get into any deep conversations about why they might be going up - see the post on the CDC figures - but rather that they are and what implications this might have for lots and lots of people and services right across the globe.

This new data whilst retrospective and reliant on formal recorded diagnoses pretty much confirms what is already out there in the autism research literature. Type 1 diabetes has again been something I've discussed before with autism in mind and cumulatively suggest that this is something that should be considered for testing when a diagnosis of autism is given. I'm not by the way suggesting everyone with autism has diabetes, merely that the possibility of a greater risk should be considered.

Same thing goes for the Crohn's disease overlap, accepting that chatter about inflammatory bowel diseases and autism is a little bit more of a controversial area (should I mention gastrointestinal symptoms...) and perhaps links into a few more recent findings on things like gut permeability and gut bacteria (speculatively). The allergy/atopy side of things is also something which needs to be looked at with greater assiduity bearing in mind where conditions like asthma may eventually lead.

I can't really say too much more about this study and its implications. Harking back to the opening sentence of this post, comorbidity is quite a big area of interest for me. Judging by these and other results, perhaps we need to really start looking at just how important it might be to at least some cases of autism.

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* Chen MH. et al. Comorbidity of allergic and autoimmune diseases in patients with autism spectrum disorder: A nationwide population-based study. Research in Autism Spectrum Disorders. 2013; 7: 205-212.

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Chen, M., Su, T., Chen, Y., Hsu, J., Huang, K., Chang, W., Chen, T., & Bai, Y. (2013). Comorbidity of allergic and autoimmune diseases in patients with autism spectrum disorder: A nationwide population-based study Research in Autism Spectrum Disorders, 7 (2), 205-212 DOI: 10.1016/j.rasd.2012.08.008

More autism developmental trajectory research

Bloomers. No not the clothing variety, but the group described by Christine Fountain and colleagues* (open-access) in their paper on developmental trajectories in autism covered in this post. The bloomers grouping describing a specific group of children with autism who "experienced rapid gains, moving from severely affected to high functioning".

Crateva religiosa @ Wikipedia  

The whole idea of looking at children in the here and now and trying to predict where they will be in X years time seems to be gaining some ground in autism research circles.

The paper by Katherine Gotham and colleagues**, she of the revised algorithm*** for everyone's best loved gold standard autism assessment instrument, the ADOS, joins the crystal-ball reading, based as one might expect on longitudinal ADOS scores.

In brief:

• The aim was to plot developmental trajectory in cases of autism. The hypothesis: "a substantial minority of children will show marked changes in ASD severity over time, with “Improvers” demonstrating the highest mean baseline and rate of growth in verbal IQ (VIQ)". The speculation: a link between autism 'functioning' and verbal intelligence, accepting that functioning means different things to different people.
• Quite a large group of children (N=345) were examined, with at least one 'estimate' of an autism diagnosis at some point between the ages of 2 - 15 years and who received more than one ADOS session.
• Results: move over Christine Fountain and your six developmental trajectories, Gotham et al describe a statistical model made up of 4 classes which best represented the observed data.
• The majority of participant stuck to their allocated class based on severity of symptoms according to ADOS, although participants allocated to two of the classes showed increasing and decreasing severity of symptoms over development. As hypothesised, verbal intelligence was an important factor in predicting class membership increasing "at the greatest rate in the improving class".
• Discussions start to turn to a possible role for trajectories in terms of endophentotypes and further delineation of the autism spectrum.

Once again, I'm really quite interested in this research and indeed this whole area of investigation. I've kinda said it before about how autism is, in some cases, actually quite an unstable diagnosis and how, given this instability combined with the heterogeneity and elevated risk for comorbidity noted across the autism spectrum, we need to find new ways to look at autism research outside of just an autism diagnosis as a starting point. In that respect it's good to see that people are starting to look into this issue (and not just the MIND Institute and their Autism Phenome Project).

Using ADOS to measure symptoms longitudinally is by no means a new phenomenon as per other articles from the authorship team such as this one from Lord and colleagues**** who reported again on four trajectory classes and again highlighted verbal ability as being involved. Elizabeth Pellicano***** likewise reported on developmental trajectory (using ADOS) and also detailed instances of 'diagnostic discontinuity'.

The suggestion that verbal intelligence might be a key part of predicting where a child with autism might be in X years time is also not a new concept. Gillespie-Lynch and colleagues****** (open-access) followed twenty participants with autism from child- to adulthood suggesting that "both early childhood language and RJA [responsiveness to joint attention] predicted adult social functioning". I'm sure that the movers and shakers of the new DSM-V 'social affect' bundling  with autism in mind were very happy to read this. Language and verbal intelligence it appears are pretty crucial to how autism progresses, bearing in mind what is known about verbal intelligence outside of autism.

There's not too much more to add to this post and topic of investigation. I should perhaps mention that when we talk about bloomers and improvers with autism spectrum disorders in mind, there is still a little bit of a gap as to the potential effects from intervention on certain cases. Research which I have been involved with for example, suggested that ADOS scores can also change alongside the adoption of dietary intervention at least in some cases of autism. I hold back from saying that this is 'proof' of any change in clinical presentation, but one does wonder exactly what effects interventions like those based in education or behavioural programs (early intervention?) might have for the current studies in this area.

Oh, and the idea that autism is actually autisms...

To finish, a spot of the fiddles is in order as Bellowhead go Ten Thousand Miles Away. Land ho!

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* Fountain C. et al. Six developmental trajectories characterize children with autism. Pediatrics. 2012; 12: e1112-20.

** Gotham K. et al. Trajectories of autism severity in children using standardized ADOS scores. Pediatrics. October 2012.

*** Gotham K. et al. The Autism Diagnostic Observation Schedule: revised algorithms for improved diagnostic validity. J Autism Dev Disord. 2007; 37: 613-27.

**** Lord C. et al. Patterns of developmental trajectories in toddlers with autism spectrum disorder. J Consult Clin Psychol. 2012; 80: 477-489.

***** Pellicano E. Do autistic symptoms persist across time? Evidence of substantial change in symptomatology over a 3-year period in cognitively able children with autism. Am J Intellect Dev Disabil. 2012; 117: 156-166.

****** Gillespie-Lynch K. et al. Early childhood predictors of the social competence of adults with autism. J Autism Dev Disord.  2012; 42: 161-174.


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Gotham, K., Pickles, A., & Lord, C. (2012). Trajectories of Autism Severity in Children Using Standardized ADOS Scores PEDIATRICS, 130 (5) DOI: 10.1542/peds.2011-3668

Antipsychotics, autism and core symptoms

NICEly does it @NICE

Analysis of the quite recent publication of the NICE guidance on autism in adulthood in the UK (see here for the full-text) has filled quite a lot of my spare time over these past weeks. That and reading the meta-analysis on medications used in cases of autism in young adults* by Dove and colleagues which concluded that there was "a marked lack of data on use of medication treatments for adolescents and young adults with ASD".

There is quite a bit of material to get through on this latest strand produced by NICE but some interesting information does seem to be included, particularly their advice on the use, or rather non-use, of pharmacotherapy for managing the 'core symptoms' of autism.

Turning for example to page 28 of the document, quite a lot of very direct guidance is offered. So statements like 'Do not use anticonvulsants for the management of core symptoms of autism in adults', don't use special diets for 'the management of core symptoms of autism in adults', don't use oxytocin for 'the management of core symptoms in adults'; and the same goes for testosterone regulation, secretin, HBOT, vitamins and minerals, etc, etc.

The fact that NICE ruled out such interventions for 'the management of core symptoms' might be only five little words but does not necessarily mean that such interventions have been 'ruled out' altogether when looking at other potential features; some of which may have the capacity to impact on core symptom presentation.

Epilepsy is the obvious example - where anticonvulsants have been shown to not only be a life-saver but in a roundabout way also potentially impacting on certain core symptoms in some cases (see Hollander et al**). Indeed bearing in mind the current focus on physical health and autism, one has to perhaps be careful not to 'rule out' say iron supplementation when anaemia may be present, just in the same way that a gluten-free diet would not be ruled out when coeliac (celiac) disease is comorbid. Assuming that is, that such conditions are screened for in the first place. If there is one thing repeated on this blog, it is that a diagnosis of autism is seemingly protective of nothing when it comes to comorbidity.

This got me thinking about the evidence for such medication use in cases of autism and how results were spread between core behaviours and those more peripheral presentations. At the same time I'm mindful of the potential health implications 'around' the use of certain medications such as the antipsychotics (see here for the tragic story of Harry Horne-Roberts) despite some gaps in the knowledge about direct effects.

I've zoomed in on antipsychotics in this post simply because antidepressants, certain classes of antidepressants, have sort of already been covered by past writings (see here). I should at this point reiterate that no medical advice is given or intended from anything in this post. If you need advice, speak to a medical doctor or similarly qualified healthcare professional (preferably not from the Internet 'fountain of information').

Perhaps also at the stage I should re-emphasize the important point made by the NICE guidance on 'managing core symptoms'; that is the triad (dyad!) of behaviours (social, communication, repetitive/restricted repertoire) that make up the diagnostic criteria. This is an important distinction from secondary presentation such as what might be described as 'maladaptive' or 'challenging' behaviours for example tied into the persistence of such behaviours (whether acute or chronic). One has to realise however that secondary behavioural presentations might be able to influence the presentation of core symptoms just as core symptoms may also affect secondary symptoms.

OK after all that, lets see what there is:

• Well, type in 'autism antipsychotics' and autism into PubMed and you get several hundred results returned. I can't possibly cover every paper in this post as some kind of unofficial meta-analysis, so am instead going to be a bit selective. I am going to try and be objective but you are advised to do your own searches and make your own judgements - don't take my word for it.
• Discounting a lot of early studies looking at the use of earlier antipsychotics and autism, alongside those pediatric studies, there is quite a body of work suggesting some effect of various antipsychotics on 'peripheral' signs and symptoms linked to cases of autism. So this review by Elbe and Lalani*** (full-text) focused on the use of drugs like risperidone and aripiprazole for managing irritability in cases of autism. They also noted the approval (FDA approval) of risperidone for the treatment of irritability in cases of autism in children and young adults
• Clozapine, another second-generation antipsychotic (neuroleptic) has also come under scrutiny with regards to peripheral behaviours present in autism. Beherec and colleagues**** discussed the use of clozapine on disruptive / aggressive behaviours; concluding that aside from important side-effects such as weight gain (remembering Harry Horne-Roberts), the drug might offer some benefit to some people. 
• Stachnik & Nunn-Thompson***** conducted quite a good review of the various data on the use of antipsychotics - second generation antipsychotics - and autism. They concluded that there may be some merit in looking at some of these medications for peripheral symptoms associated with autism but "these drugs do not affect the core symptoms of autistic disorder and are associated with potentially significant adverse effects".
• Potenza and colleagues****** might to some degree disagree with that last statement about core symptoms with the result of the their study looking at the use of olanzapine and their description of clinical responders showing "improvements in overall symptoms of autism, motor restlessness or hyperactivity, social relatedness, affectual reactions, sensory responses, language usage, self-injurious behavior, aggression, irritability or anger, anxiety, and depression" balanced again with the weight gain issue.

What conclusions could we take from this collected work?

Well, possibly a few. So for example, that the lines between the effects of medication on core and peripheral symptoms are perhaps less clear-cut than one might first imagine. We've kinda seen it before with other classes of pharmacotherapy such as melatonin and its effects on sleep in cases of autism; another peripheral issue not generally noted under 'core' behaviours but potentially impacting quite significantly on the presentation of some core behaviours. 

There is also the issue of cost vs. benefit when it comes to the use of antipsychotic medication in cases of autism. Similar to just about any intervention for autism, benefits must always outweigh costs and costs shouldn't generally be significant in the longer term such as making a person more prone to developing other health issues. Reading between the lines, I am perhaps beginning to realise why NICE made the recommendations they did; based not purely on the efficacy data (i.e. do antipsychotics work in cases of autism?) but rather cumulatively on the efficacy and safety data and the important impact that side effects such as weight gain can have on a person and their long-term health. Indeed The Mental Elf carries quite a good overview of of the research around side-effects from neuroleptics (in children and adolescents).

Finally, and without giving any advice on the matter, more attention should perhaps be given to the use of antipsychotics in cases of autism as being a last resort option. I think back to the area of dementia and that study on the use of painkillers vs. antipsychotics (see here) to decrease levels of 'agitation' and can't help but make a comparison. I'm not insinutaing that all challenging behaviours observed in autism are due to pain nor that there is no place for antipsychotics with appropriate monitoring, but rather that there may be other antecedents to the presentation of challenging behaviours. The trick is to find out what they might be, both at an individual and group level and if needs be, offering good medicines management.

I realise that I might have been a little pedantic in this post; focusing more on wording than the 'spirit' of the text. But given that this and the other strands of NICE guidance are very likely to have a strong influence on the way that autism is viewed and managed by healthcare professionals in the UK and perhaps beyond, as per lots of other areas, a focus on the text is ultimately going to govern what clinical decision are made, or not, about the lives of people with autism.

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* Dove D. et al. Medications for adolescents and young adults with autism spectrum disorders: a systematic review. Pediatrics. September 2012.

** Hollander E. et al. Divalproex sodium vs. placebo in the treatment of repetitive behaviours in autism spectrum disorder. International Journal of Neurospychopharmacology. 2006; 9: 209-213.

*** Elbe D. & Lalani Z. Review of the pharmacotherapy of irritability of autism. Journal of the Canadian Academy of Child & Adolescent Psychiatry. 2012; 21: 130-146.

**** Beherec L. et al. Retrospective review of clozapine in the treatment of patients with autism spectrum disorder and severe disruptive behaviors. Journal of Clinical Psychopharmacology. 2011; 31: 341-344.

***** Stachnik JM. & Nunn-Thompson C. Use of atypical antipsychotics in the treatment of autistic disorder. The Annals of Pharmacotherapy. 2007; 41: 626-634.

****** Potenza MN. et al. Olanzapine treatment of children, adolescents, and adults with pervasive developmental disorders: an open-label pilot study. Journal of Clinical Psychopharmacology. 1999; 19: 37-44.

The health inequalities of schizophrenia

Heart to heart @ Wikipedia  

Dare I start this post by saying that when it comes to many conditions with a behavioural or cognitive aspect to them, there are some worrying trends emerging from the research literature suggestive of stark differences in both access to healthcare and indeed mortality statistics compared with the general population. Think wandering and elopement with autism in mind as one prime risk factor.

I've touched upon health inequality before with autism spectrum disorders in mind, but on this occasion want to briefly discuss some of the literature with schizophrenia spectrum disorders in mind following yet another revelation of more overlap between the conditions.

The paper which brought me to this post is this one from Paul Kurdyak and colleagues* who reported that people diagnosed with schizophrenia were more likely to die as a result of an acute myocardial infarction (heart attack to you and me) and indeed were less likely to receive the appropriate care (including access to a specialist physician) after such an event. 

The quite shocking figures: individuals with schizophrenia were 56% more likely to die within 30 days of discharge and 50% less likely to receive the appropriate after-event healthcare. One could argue on this basis that schizophrenia and its effects go well beyond the psychiatric symptoms that characterise the condition.

Of course there is already quite a lot of suggestion that schizophrenia and related conditions might place an individual at higher risk of quite a few different conditions. So for example, diabetes - type 2 diabetes - is something which has been on the research radar for a while now as per the study by Schoepf and colleagues**. So too issues with obesity, being overweight and other parts of the so-called metabolic syndrome as per reports like the one from Subashini et al*** covering some of the more usual suspects with heart health risk in mind.

The hows and whys of such an increased prevalence of such conditions are complicated. Certainly the research literature seems to suggest that just having a schizophrenia spectrum disorder might increase the risk of engaging in known lifestyle choices linked to poorer heart health. So smoking tobacco, including being heavy tobacco smokers, seems to be more frequent in cases of schizophrenia as per this study by Zhang and colleagues**** (open-access). Physical inactivity has also been reported to be more common too***** and perhaps even tied into illness duration. Not to also mention a role for food choices****** albeit not necessarily consistently*******. There is however some difficulty in unpicking individual behaviours and factors when assessing overall risk.

Before anyone suggests that I am somehow apportioning 'blame' in listing these lifestyle choices, I think it is also important to highlight other factors as potentially contributing to a heighten risk including that of pharmacotherapy. By saying this I'm not going down the 'pharma-bashing' route despite some quite worrying issues recently discussed reiterating that medicines tend to have quite a few more actions that those just indicated on the insert. No, but certainly some of the medicines used to manage schizophrenia and other conditions have long been linked to certain cardiometabolic issues as per editorials like this one from Remington********. Indeed I have a post scheduled soon talking about antipsychotics and autism following the recent NICE guidance published on adult autism which will discuss this further. Good medicines management seems to be key to mitigating the effects of such risks.

Social factors might also play an important role in the accessing of appropriate healthcare for conditions like schizophrenia. Here in the UK we have something called the NHS (National Health Service) which provides healthcare to everyone "free at the point of use". Not everywhere in the world has such a generous policy however as studies like this one by Khaykin and colleagues********* which suggested that around 7% of their cohort with schizophrenia were medically uninsured all year round.

Although perhaps mixing apples and oranges, when you take into account the high rates of unemployment associated with a diagnosis of schizophrenia, upto 96% according to this study by Perkins & Rinaldi**********, having the financial means to access healthcare in some parts of the world must surely be considered an important factor in determining outcome.

I don't claim to have covered all the literature on health inequality and schizophrenia in this post. Indeed the reasons for the figures cited by Kurdyak are likely to be complex and multiple across different people and different situations. What perhaps such data do suggest however is that looking beyond the immediate and overt presentation of mental 'ill-health' should be a priority where general healthcare is concerned. Realising for example, that ticking boxes on a clinical diagnostic schedule and managing current symptoms of that condition might do little for the long-term health of that individual. Indeed when faced with a life expectancy potentially reduced by the order of 14 years*********** there is most definitely a real issue to be tackled here.

To finish a song about blackbirds by the Beatles.

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* Kurdyak P. et al. High mortality and low access to care following incident acute myocardial infarction in individuals with schizophrenia. Schizophr Res. September 2012.

** Schoepf D. et al. Type-2 diabetes mellitus in schizophrenia: increased prevalence and major risk factor of excess mortality in a naturalistic 7-year follow-up. Eur Psychiatry. 2012; 27: 33-42.

*** Subashini R. et al. Prevalence of diabetes, obesity, and metabolic syndrome in subjects with and without schizophrenia (CURES-104). J Postgrad Med. 2011; 57: 272-277.

**** Zhang XY. et al. Cigarette smoking in male patients with chronic schizophrenia in a Chinese population: prevalence and relationship to clinical phenotypes. PLoS One. 2012; 7: e30937.

***** Vancampfort D. et al. A systematic review of correlates of physical activity in patients with schizophrenia. Acta Psychiatr Scand. 2012; 125: 352-362.

****** McCreadie RG. et al. Diet, smoking and cardiovascular risk in people with schizophrenia: descriptive study. Br J Psychiatry. 2003; 183: 534-539.

******* Henderson DC. et al. Dietary intake profile of patients with schizophrenia. Ann Clin Psychiatry. 2006; 18: 99-105.

******** Remington G. Schizophrenia, antipsychotics, and the metabolic Syndrome: is there a silver lining? Am J Psychiatry. 2006; 163: 1132-1134.

********* Khaykin E. et al. Health insurance coverage among persons with schizophrenia in the United States. Psychiatr Serv. 2010; 61: 830-834.

********** Perkins R. & Rinaldi M. Unemployment rates among patients with long-term mental health problems. The Psychiatrist. 2002; 26: 295-298.

*********** Chang CK. et al. Life expectancy at birth for people with serious mental illness and other major disorders from a secondary mental health care case register in London. PLoS One. 2011; 6: e19590

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Kurdyak P, Vigod S, Calzavara A, & Wodchis WP (2012). High mortality and low access to care following incident acute myocardial infarction in individuals with schizophrenia. Schizophrenia research PMID: 23021899

Leaky mice guts, bacteria and autism?

I might have said it before but I'll admit that I'm a fan of the work coming out of the laboratory of Prof. Paul Patterson. I've never really been one to take the whole hero-worship or anything like that too far (he says with history of toilet roll lightsaber duelling) but I'm certainly impressed with his work and often quite radical views in respect of conditions like autism and schizophrenia.

In a recent post on his blog, I (and a few others) were left decidedly tantalised by the promise of some future results appearing based on the continuation of his maternal immune activation impacting on offspring mouse studies. The fact that said results, presented at the recent Society for Neuroscience 2012 meeting, also linked into gut bacteria was an added incentive to keep an eye out for them.

Well, recently Virginia Hughes over at the SFARI blog posted an entry on the latest revelations titled: Probiotic curbs autism features in mouse model. I'm not going to re-hash the post here because everything you need to know is in that post, bearing in mind that these are conference proceedings and so are not yet peer-reviewed published results.

I will draw your attention to a few details however:

• Aside from the behavioural presentation of maternally immune activated mouse offspring, there was a suggestion of "unusually permeable intestinal membranes". I know its still a little bit controversial to talk about leaky gut and autism, but suffice to say this is not the first time its been mentioned in the published research literature and not just in autism. Indeed, the whole bacterial translocation (bacteria ending up in places it really shouldn't) is also mentioned in passing albeit I don't think, part and parcel of the results yet.
• "One such metabolite, 4-ethylphenylsulfate, shows a 40-fold increase in the blood of offspring born to infected mice compared with controls". I'm still searching for further data on 4-ethylphenylsulfate; but at the moment it seems this might be a uremic compound of some note.
• Big quote coming up: Most provocatively, feeding young mice Bacteroides fragilis, a bacterial species that’s common in the healthy human gut, makes the intestinal barriers less permeable and normalizes levels of 4-ethylphenylsulfate in the blood. “[It] completely blocks leaky gut,” Patterson says. Wow. Completely blocks leaky gut? Makes me wonder how this might translate to compounds associated with leaky gut such as [General] zonulin. 

I tend to find there is a degree of standoffishness (is that a word?) when one mentions things like probiotics with autism in mind. Antibiotics and autism ... OK there's a history there too. Probiotics have however been mentioned in the peer-reviewed research domain with autism in mind as per the review from Critchfield and colleagues* (open-access) albeit with some way to go in terms of looking at efficacy and safety - and in the long-term too.

I'm not advocating anything on the basis of this conference report, a conference report on mice which certainly requires independent replication. What Prof. Patterson's research does however suggest is that even if in a subgroup of people diagnosed with autism, it is wise not to write off some involvement for gut bacteria just yet and a greater inspection of the immune-bacterial link related to cases of autism might be warranted.

[Update: 18/10/12: Similar findings to these will/were also presented at an in-house conference at CalTech (abstract here, bottom of page 2) scheduled for 20/10/12].

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* Crichfield JW. et al. The potential role of probiotics in the management of childhood autism spectrum disorders. Gastroenterology Research & Practice. 2011. 161358.

"We of the craft are all crazy"

I hope that you don't think I am making light of mental illness with the title of this post which originally comes from Lord Byron but I got from this article by Hankir* on bipolar disorder and poetic genius. The reason for it stems from this paper by Simon Kyaga and colleagues** which, in quite a large population group, asked the eternal question about whether those in the creative professions are more likely to be treated for mental illness compared with the general population.

Nevermore, nevermore @ Wikipedia 

This latest work follows on from a previous study from the same group*** who talked about a "familial cosegregation of both schizophrenia and bipolar disorder with creativity". I had to look it up but cosegregation apparently is a genetics term relating to "the transmission of two or more linked genes on a chromosome to the same daughter cell leading to the inheritance by the offspring of these genes together".

Going back to the most recent work by Kyaga and colleagues, a few important points are worth mentioning:

• A sample size which was positively eye-watering at 1,173,763 participants based on a nested case-control methodology, looked at cases diagnosed with one or more of psychiatric diagnoses and compared them with asymptomatic cases to ascertain the rate of creative (scientific and artistic) occupations. 
• Psychiatric diagnoses included: schizophrenia, bipolar disorder, anxiety disorders, alcohol abuse, drug abuse, autism, ADHD, and completed suicide, to name some.
• The study was not just confined to patient cases but also their non-diagnosed relatives.
• Results: although some of the headlines are a little misleading (see here), outside of bipolar disorder, there was no significant trend towards creative occupations = more psychiatric disorder. Unless that is, you were an author which "was specifically associated with increased likelihood of schizophrenia, bipolar disorder, unipolar depression, anxiety disorders, substance abuse, and suicide".
• A look at the relatives of those diagnosed with a psychiatric disorder however did suggest an association with the creative occupations.

I've perhaps been a little harsh in translating these results which have already received some media attention. The connection between being diagnosed with bipolar disorder and also being in a creative occupation is not to be sniffed at, as per the Hankir paper and some quite high profile cases such as Twitter royalty Stephen Fry. Indeed seemingly everyday now, one or more of the creative geniuses in public life seem to 'come out' and talk about their experiences of bipolar disorder as per the Wikipedia page titled: List of people with bipolar disorder. Obviously I'm going to have to be careful here not to make too much of the link based on comparatively few names set against the hundreds of thousands of people involved in the creative arts who do not seemingly present with the features of bipolar disorder (or at least don't tell the public). Things are never so cut-and-dried. 

Indeed I was also interested in the other links that have been made between diagnoses such as bipolar disorder and cognitive styles. So, this research from Gales and colleagues**** who asked whether bipolar disorder was more commonly present in highly intelligent people. Their conclusion was very possibly but generally seen more in men and without the interference of other comorbidity. Indeed I hope Mr Fry does not mind me using him again as an example, but one would speculate that his IQ score (or should that be QI?) would be 'up there somewhere'. 

Looking at the occupations listed under creative careers, I also noted 'scientific' to be listed. I have to say that I did a bit of double-take at this given that I never really looked at science as sharing the same creativity as say a writer or an artist. Having said that, if we take the literal meaning of creativity to mean invention and originality, I can see how even boring old researchers talking about study design and p-values might have reason for some creative flair at times. One might ask whether the most creative scientists, such as those Nobel Prize winners for example, might also be more prone to mental ill-health like bipolar disorder? The subsequent questions are: which came first (creativity or bipolar disorder) and whether the propensity and/or actuality of bipolar disorder might drive someone to make certain creative career choices.

I cannot leave this post without also making further mention of the author - mental illness link reported by Kyaga et al. Reading between the lines it seems that the notion of a tormented writer - like for example Edgar Allan Poe - might actually have more truth than fiction. Noting for example, that authors were significantly more likely to commit suicide is an important observation and something which could potentially inform strategies to reduce suicide. That being said, suicide is a complicated thing. Based on the wealth of other literature on occupation and suicide, as per the high rates of suicide in medical physicians for example, one has to be cautious at making such correlations set against the bigger picture.

This is an interesting area of research and discussion, not just in terms of cognitive styles and mental health, but also as to how aspects of creativity may very well overlap with the perceptions of mental health and ill-health. I draw back from making too much of such data however (despite the current study sample size) given the multitude of other factors potentially at work and the seemingly increasing tide of labelling the extraordinary with some kind of diagnosis.

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* Hankir A. Review: bipolar disorder and poetic genius. Psychiatr Danub. 2011; 23 Suppl 1: S62-S68.

** Kyaga S. et al. Mental illness, suicide and creativity: 40-Year prospective total population study. J Psychiatr Res. 2012. pii: S0022-3956(12)00280-4.

*** Kyaga S. et al. Creativity and mental disorder: family study of 300,000 people with severe mental disorder. Br J Psychiatry. 2011; 199: 373-379.

**** Gales CR. et al. Is bipolar disorder more common in highly intelligent people? A cohort study of a million men. Mol Psychiatry. April 2012.

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Kyaga S, Landén M, Boman M, Hultman CM, Långström N, & Lichtenstein P (2012). Mental illness, suicide and creativity: 40-Year prospective total population study. Journal of psychiatric research PMID: 23063328

Autism: the sum of its SNPs?

I chanced upon a new piece of research published by Lambertus Klei and colleagues* (open-access) on single nucleotide polymorphisms (SNPs) and autism, and how lots of little mutations might additively contribute to increasing autism risk.

Calculate this @ Wikipedia 

OK, stop.. hammertime.. a few descriptions and details are needed first as well as a caveat about my amateur status when it comes to all things genetics.

SNPs and mutations. A short description is included here but basically think small changes to the letters of the genetic code. Suffice to say that I've covered SNPs and those copy number variations (CNVs) and autism on more than one occasion on this blog as per posts like this one on no single SNP being associated with the universality that is the autism label and this one on just how complex autism seems to be from a genetics perspective.

I hope I've not been too unkind to genetic mutation research (sorry for the cold science term) specifically with autism in mind, but like other developmental conditions such as attention-deficit hyperactivity disorder (ADHD), the whole 'genetics is absolute ruler' argument has not been borne out by the data produced so far. Each and every one of us, whether diagnosed with autism or anything else, are the product of mutation and autism is a mighty diverse condition.

With all this in mind, the Klei paper whilst open-access has a few interesting points worth noting:

• This was a study aiming to look at a few important issues. Not only the question of simplex (one child) vs. multiplex (more than one child) genetic risk of autism and whether they might be different, but whether despite not one SNP being universally applied across all autism, there may be some argument for more [important] SNPs cumulatively = a greater risk of autism.
• Based on genotype data derived from two autism-related datasets representing simplex and multiplex families respectively, the Simons Simplex Collection (SSC) and the Autism Genome Project (AGP), comparisons were made with control data (HealthABC) across several hundred thousands of SNPs for something called narrow-sense heritability - in effect additive genetic variance. There was also a further test group used to assess the robustness of findings (Neurogenetics Research Consortium, N=1986).
• Results: "For simplex families, who have only a single affected individual in multiple generations, approximately 40% of liability traces to additive effects whereas this narrow-sense heritability exceeds 60% for ASD individuals from multiplex families". The actual results were: simplex (39.6%) and multiplex (65.5%); this last figure reflective of the AGP cohort splitting, with some simplex and some multiplex families included; simplex heritability in the AGP group being estimated at 49.8%. These estimates also bearing in mind the "unrealized multiplex potential" of taking snapshots of families.
• Another result: "These results suggest that AGP parents carry a greater load of additive risk variants than SSC parents and thus are, on average, closer to the threshold of being affected". Translation: parents of participants in the AGP cohort, bearing in mind this included both simplex and multiplex families, showed more additive risk SNPs and hence were closer to the diagnosis of autism or the broader phenotype than in the SSC cohort taking into account differences in screening for autism in parents between the two cohorts.
• And another result: "A curious observation from AGP multiplex families was that fathers generate larger heritability than mothers". Translation: lots of potential reasons for it (including the issue of mums, dads and differing proportions of sex hormones) but dads seemed to generate more 'risk' than mums in multiplex autism.
• And a final result: "Our results suggest that common variants affecting liability do not cluster on chromosome X". An interesting observation given the focus on the X chromosome as a result of the reported male domination of autism.
• Mention is also made of assortative mating as being involved in the results but as yet no new data is presented on this possibility.

I like the quote from one of the chief authors on the paper, Prof. Bernie Devlin reported here: "The genetic components alone are far more complex than many imagined a decade ago, including the additive effects we have found, rare inherited mutations, and new mutations arising spontaneously before conception." To me this embodies everything about the current state of knowledge on the genetics of autism in that (a) there is probably no universal 'autism' gene, (b) mutations are likely to be an important part of autism risk and (c) new mutations opens the door up to environment as playing a hand (spontaneous eh?). Indeed the only thing missing from this sentence is discussion about the relative newcomer, epigenetics, and how looking at the function of genes might be able to plug some of that gap in the risk for developing autism.

As per my recent post on systems biology and autism, one also has to ask whether there might be some common biochemical pathways to be derived from these additive genetic effects. Not so long ago, Skafidas and colleagues** were discussing SNPs in relation to gene and biochemical functions, with some interesting observations detailed (see this post). I'd be very interested to see what might come from similar analyses on the Klei data and whether there is overlap or differences based on simplex or multiplex cases.

Whilst an interesting paper, there still remains some significant holes in our knowledge about autism and the risk factors for receiving a diagnosis of autism. Those 40% and 60% risk figures are probably what many people are going to focus on, but my question is what about the remaining 60% or 40% of risk and indeed the question of 'where did the heritability go?' based on previous twin studies lining the autism research trail (see here). Where does that risk come from? and should we perhaps be looking at environmental factors with as much assiduity as we do genetic ones?

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* Klei L. et al. Common genetic variants, acting additively, are a major source of risk for autism. Molecular Autism. 2012; 3: 9. doi:10.1186/2040-2392-3-9

** Skafidas E. et al. Predicting the diagnosis of autism spectrum disorder using gene pathway analysis Molecular Psychiatry. September 2012; DOI: 10.1038/mp.2012.126

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Klei, L., Sanders, S., Murtha, M., Hus, V., Lowe, J., Willsey, A., Moreno-De-Luca, D., Yu, T., Fombonne, E., Geschwind, D., Grice, D., Ledbetter, D., Lord, C., Mane, S., Lese Martin, C., Martin, D., Morrow, E., Walsh, C., Melhem, N., Chaste, P., Sutcliffe, J., State, M., Cook, E., Roeder, K., & Devlin, B. (2012). Common genetic variants, acting additively, are a major source of risk for autism Molecular Autism, 3 (1) DOI: 10.1186/2040-2392-3-9