Autism, gastrointestinal disorders and comorbidity clusters

I start this post with a few important observations. Please feel free to disagree with me (as long as you can provide peer-reviewed evidence for your alternate viewpoint).

Bunting @ Wikipedia 

(1) Comorbidity can, and quite frequently does, surround a diagnosis of autism.

(2) Gastrointestinal (GI) issues form an important part of that comorbidity spectrum.

(3) The relationship between autism and comorbidity is, at present, poorly understood insofar as which influences the appearance of which and how the two are related.

So, with those statements in mind, I offer some discussion today on two potentially very important papers which variably reference the above points.

The first paper is from Brittany Peters and colleagues* (with many, many thanks to Natasa for the paper) which suggests that there indeed may be an important relationship between GI issues and rigid-compulsive behaviours noted in cases of autism. The second paper is from Finale Doshi-Velez and colleagues** (again, with thanks to Natasa) who looked at 'comorbidity clusters' when it comes to the autism spectrum.

Both these papers come from groups who have some 'research form' in their respective areas. For the Peters paper it comes in the guise of the valuable research contribution from Gorrindo and colleagues*** which basically said that yes, parents might know when their children with autism present with bowel issues: "parents were sensitive to the existence, although not necessarily the nature, of GID [gastrointestinal dysfunction]". For the Doshi-Velez paper I'll link back to the paper by Kohane and colleagues**** (covered in this post) and their notion of 'significantly over-represented' when it comes to the comorbidity burden with autism in mind.

The more recent papers make for interesting reading. Starting with the Peters paper:

• The authors start with a hypothesis: "a possible association between rigid-compulsive behaviors and GI symptoms" based on their clinical experience of the autism spectrum conditions.
• They tested their hypothesis on data from participants (N=5076) in the Autism Treatment Network (ATN) and various measures collected from the ATN database. Alongside including diagnostic data, the database also contains data from a GI symptom questionnaire; both of which were used to collect information for their study analysis.
• Results: Nearly half of the total cohort (43.5%) "had at least one GI symptom". In light of other quite recent reports (see here and here) this finding is not totally unexpected.
• Based on data from children (aged 2-17 years) - nearly 3000 of which were in the 'no GI symptoms' group (n=2957) and 806 in the 'constipation plus diarrhea or underwear staining' - several other details emerged from the data. The latter GI symptoms group were "more likely to have a parental report of repetitive behavior.... or compulsive behavior... and OCD [obsessive compulsive disorder] diagnosis". Ritualistic behaviours were also picked up more frequently in the GI group by clinician report (ADOS) over the no GI symptoms group.
• A few other research nuggets: children in GI symptoms group were "more likely to have a family history of anxiety or OCD" and also more likely to have received "treatment with an atypical antipsychotic".
• The authors conclude that, allowing for potential issues with the use of the ATN database and missing values, "all five primary measures of rigid-compulsive behavior were significantly associated with constipation and diarrhea or underwear staining". 

And then we have the Doshi-Velez paper:

• This was a study looking at "patterns of co-occurence of medical comorbidities in ASDs".
• Electronic medical records or rather electronic health records (EHR) were the source material for the paper and in particular, the ICD-9 codes relevant to particular conditions derived from the i2b2 National Center for Biomedical Computing (N=13,740). This sounds to me like a similar job to that of SHRINE (used in the previous Kohane paper).
• "Key patterns" identified from this rather large participant group were then tested on a smaller, independent cohort comprising 496 participants from Wake Forest University Health Sciences.
• With the application of some technical and statistical wizardry, various subgroups were identified within the cases examined based on the clustering of comorbidity alongside the diagnosis of autism.
• Results: "Four subgroups were identified" based on medical comorbidity and the paper offers quite a bit of detail about the hows and whens certain comorbidity tend to present.
• Group 1. That old comorbidity nemesis seizures (I assume to indicate some kind of epilepsy) was the focus for the first group with a prevalence of 77% within this group. 
• Group 2. Then came in "multisystem disorders" to form group 2 which included GI disorders (distinct from just functional GI issues). That being said "early ear infections" seemed to stand head and shoulders above other comorbidities for this group particularly with preschool presentation. 
• Group 3. Next for comorbidity was group 3 "characterised by psychiatric disorders" (33%). This group "had the highest rate of individuals with Asperger syndrome and the lowest rate of intellectual disability" and included some familiar conditions including anxiety (see here). That being said (again!), "Hyperkinetic syndrome of childhood" also prominently featured in the group 3 comorbidity profile. 
• Group 4. Finally, there was a 'not' resolved group. Not much more to say there really.
• Buried in the text is the quite alarming suggestion that: "All of these subgroups had higher levels of cardiac disorders" which, similar to the example of schizophrenia (see here), implies that health screening should be high on any physician's list when someone presents with autism save any charges of health inequality being levelled.
• The authors conclude that the identification of these comorbidity subgroups centred on the autism spectrum may very well indicate "distinct etiologies with different genetic and environmental contributions". I'm minded to say that we have another possible piece of evidence pertinent to the plural concept of 'the autisms'.

Combined, both these papers offer some really quite important information about the autisms and their very complicated presentation including comorbidity. I would hasten to point out that there is still quite a bit of 'fuzziness' about these results as for example, seen in a quote from the Doshi-Velelz paper: "The 3 subgroups from our original clustering analysis consisted of <10% [less than 10%] of the overall sample". In short, it's complicated. But don't let that take anything away from these results...

Oh and since we're on the topic of 'the autisms' and comorbidity, I note from the recent-ish findings from Giardino and colleagues***** that GI comorbidity has been reported in cases of 22q11.2 deletion syndrome (22q11DS). Autism or autistic behaviours if you like, show more than a passing connection****** to 22q11DS... perhaps research fodder for another blogging day? (Er, yes, watch this space).

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* Peters B. et al. Rigid-Compulsive Behaviors are Associated with Mixed Bowel Symptoms in Autism Spectrum Disorder. J Autism Dev Disord. 2013 Nov 29. [Epub ahead of print]

** Doshi-Velelz F. et al. Comorbidity Clusters in Autism Spectrum Disorders: An Electronic Health Record Time-Series Analysis. Pediatrics. 2013. Dec 9.

*** Gorrindo P. et al. Gastrointestinal dysfunction in autism: parental report, clinical evaluation, and associated factors. Autism Res. 2012 Apr;5(2):101-8. doi: 10.1002/aur.237.

**** Kohane IS. et al. The co-morbidity burden of children and young adults with autism spectrum disorders. PLoS One. 2012;7(4):e33224.

***** Giardino G. et al. Gastrointestinal involvement in patients affected with 22q11.2 deletion syndrome. Scand J Gastroenterol. 2013 Dec 18.

****** Vorstman JA. et al. The 22q11.2 deletion in children: high rate of autistic disorders and early onset of psychotic symptoms. J Am Acad Child Adolesc Psychiatry. 2006 Sep;45(9):1104-13.

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Peters B, Williams KC, Gorrindo P, Rosenberg D, Lee EB, Levitt P, & Veenstra-Vanderweele J (2013). Rigid-Compulsive Behaviors are Associated with Mixed Bowel Symptoms in Autism Spectrum Disorder. Journal of autism and developmental disorders PMID: 24293040

Finale Doshi-Velez, Yaorong Ge, & Isaac Kohane (2013). Comorbidity Clusters in Autism Spectrum Disorders: An Electronic Health Record Time-Series Analysis Pediatrics DOI: 10.1542/peds.2013-0819d