"In the milder forms I think it's just a personality variant." Temple Grandin on autism

I draw your attention today to the transcript of an interview (see here) between a Scottish broadcaster, Rona Dougall, and Dr/Prof.Temple Grandin, following Prof. Grandin's recent appearance (Spring 2019) at a conference in Scotland.

The transcript provides readers with quite a lot of insight into Prof. Grandin's views about autism; both from a personal perspective of being diagnosed with autism (and perhaps being one of the most well-known autistic people) and also with reference to some wider discussions about autism.

Alongside the important message that Grandin wants to "see people that learn differently, people that might be labelled with autism getting good jobs" one particular part of the interview stuck out for me: "Rona: How do you define and diagnose autism? Temple: In the milder forms I think it's just a personality variant. In the more severe forms, where the individual remains nonverbal, that is definitely a disability."

I was interested in the notion that 'milder forms' of autism were seen as akin to "a personality variant" by Grandin, whilst more 'severe forms' were labelled "definitely a disability." Interested because, there are some on-going debates in various circles about (a) how one should 'classify' autism from the point of view of how much of an impact symptoms have on daily living, and (b) how the presentation of autistic traits are not solely confined to a diagnosis of autism or autism spectrum disorder (ASD).

On the first point about 'classifying' autism, there is, as I say, debate about how symptoms can variably present and how best to describe the 'differences' between someone diagnosed as being on the autism spectrum who for example, is verbal, is able to navigate the social world to some degree, hold down a job and perhaps raise a family, compared with someone who has no (verbal) language, requires a high level of daily living support and who is likely to need lifelong assistance and support for sometimes simple tasks. Such heterogeneity has been present for many years under the diagnostic label of autism; further compounded by the recent-ish disappearance of Asperger syndrome in current and planned diagnostic texts (see here and see here).

The commonly used terms 'high-functioning' and 'low-functioning' don't seemingly provide the necessary words to differentiate 'levels of autism'; also being perhaps a little demeaning to those they are meant to represent. Outside of the negative connotations of 'low-functioning', one can perhaps see how 'high-functioning' as a term for 'can function' does not always convey the real-life message when it comes to the presentation of autism. I'm thinking specifically about the issue of suicidality and autism for example (see here) and the shocking statistics that continue to emerge. Likewise, to talk about autism in the context of 'severity' comes up against similar obstacles. 'Severe autism' could potentially describe anyone on the autism spectrum during moments of 'meltdown' for example. Indeed, the 'high-functioning' non-severe autistic child who just got handed a school exclusion for having an aggressive meltdown (yes, I said aggression) in class may very well be described as having severe autism in the same way that a 'low-functioning' child screaming and banging their head whilst covering their ears may thus be described. The endpoint in both cases being that autism is significantly and severely affecting both their lives at that point. I firmly believe a lot more thought needs to go into such 'classification' issues (see here) including more mention of the concept of 'profoundness' and perhaps further utilisation of the DSM-5 'support gradings' (see here) which have been installed.

Insofar as the second point covering 'mild' autism as a 'personality variant' and the issue that the label autism does not have exclusive rights to the presentation of autistic traits, another area of interest opens up. I've talked quite a bit on this blog about how autistic features / traits / symptoms are readily seen across a whole variety of different labels (see here and see here) and what this means for the concept of 'self-diagnosis' for example, that is sometimes seen / discussed on social media in particular (see here). Drawing specifically on the presentation of autistic traits in something like borderline personality disorder (BPD) [1] one could very well express an opinion that yes, autism in some cases may well be akin to a personality variant. Such a line of reasoning fits well with the (still emerging) concept of neurodiversity as applied to autism (see here) where autism is viewed as a "natural variation" [2].

But then the questions arise: at what point does autism cease to be a 'personality variant' to then becoming 'definitely a disability'? Is it just based on the acquisition of spoken language? Grandin does mention a few times in the interview about autism "in the milder forms, where the person is fully verbal" so perhaps showing an inclination towards a view that spoken language use is an important measure to differentiate differences vs. disability. But does reliance on spoken language use offer enough to make such a differentiation? Are their other facets of autism (or combinations of facets) which could better reflect any difference vs. disability arguments?

Personally, I'm not inclined to believe that there is a personality variant vs. definite disability debate to be had when it comes to autism. Formal receipt of a diagnosis is based not only on the presentation of autistic features or traits but also that such traits "cause clinically significant impairment in social, occupational, or other important areas of current functioning." If one was to say that some autism is just a personality variation, it could for example, dissipate the meaning of autism and the supports that are required. The risk of 'diluting' an important message about the need for those services and resources to ensure that people across the autism spectrum and their loved ones get the help and support they need to have a good quality of life is not a risk, in my view, worth taking.

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[1] Dell'Osso L. et al. Correlates of autistic traits among patients with borderline personality disorder. Comprehensive Psychiatry. 2018; 83: 7-11.

[2] den Houting J. Neurodiversity: An insider's perspective. Autism. 2019 Feb;23(2):271-273.

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Baby teeth, metals and autism part 2

Consider this post on the findings reported by Paul Curtin and colleagues [1] which concluded that "altered zinc-copper rhythmicity precedes the emergence of ASD [autism spectrum disorder]" an extension of other previous discussions on this blog (see here). The research starting material was, once again, baby teeth, including teeth derived from an interesting initiative called "the Autism Tooth Fairy Project" based in Texas, USA.

On the last blogging occasion, the paper by Manish Arora and colleagues [2] was central to my discussions, and the use of some really interesting analytical technology to look at levels of various metals in tooth layers: Laser ablation-inductively coupled plasma mass spectrometry. Fast forward a year or so, and authors (including Arora) moved on to bigger and better things, this time focusing specifically on the metals zinc and copper "from the second trimester to approximately 1 year postnatally." Such a feat was achieved because baby teeth, much like the rings of a tree, provide a sort of 'album' of levels of such metals over a child's earliest years. Both these metals and their ratio also have some previous research 'form' when it comes to autism (see here).

"Our participants were recruited from four different studies being undertaken in three countries." Yep, so alongside teeth from the RATSS study initiative (aptly named the 'roots' of autism/ADHD study) forming a discovery dataset, authors also examined teeth gathered as part of other research initiatives including a favourite here in Blighty: the Avon Longitudinal Study of Parents and Children (ALSPAC). These non-RATSS teeth formed a replication set (to try and replicate the data found in the discovery set). Add in some nifty statistical analysis and set lasers to stun or should that be ablate...

Results: authors reported finding "strong evidence for abnormalities in zinc-copper cycles in ASD characterized by shorter duration, lower complexity, and less determinism." A quick translation: well, I'll be honest and tell you that I'm not exactly sure what that actually meant. I think it had something to do with the way the data were analysed, being "analogous to a spectrogram." Suffice to say that levels of copper and zinc were seemingly different in those diagnosed with autism compared with not-autism controls at different tooth time periods. When all this metal data was analysed using some statistics designed to try and 'classify' those with autism from those not-autistic, authors also noted zinc-copper cycles in teeth "allowed for a robust classification of ASD cases and controls." So: "Using optimal threshold criteria, this model was 90% accurate in predicting ASD cases, with 100% sensitivity for ASD diagnosis and 85% specificity to controls." Those stats aren't bad when one considers the importance of sensitivity and specificity to any classifying 'test'.

Although interesting, one has to bear in mind that this research was based on the use of baby teeth and their possible 'retrospective' association with autism. Nobody is advocating pulling out baby teeth as some sort of autism test! The focus on metals however, and specifically "measures of metal rhythmicity" provides some welcome information about how such 'rhythms' *might* show differences in relation to autism. This could reflect things like differing 'exposure' patterns or, more likely, some innate differences in the biological 'processing' of such metals. On that last point, this work potentially fits in with what is emerging in other independent data: metal (various metals) metabolism in the context of some autism seems to be 'unusual' (see here).

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[1] Curtin P. et al. Dynamical features in fetal and postnatal zinc-copper metabolic cycles predict the emergence of autism spectrum disorder. Science Advances. 2018. 30 May.

[2] Arora M. et al. Fetal and postnatal metal dysregulation in autism. Nat Commun. 2017 Jun 1;8:15493.

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Behind the headline: "Autism: Scientists take 'first steps' towards biological test"

Monday 19th February 2018. I opened my computer up early in the morning and lo and behold, headlines about autism appeared, as exemplified by the BBC article titling this post: "Autism: Scientists take 'first steps' towards biological test." A cold shudder ran down my body as memories of previous 'Super-parenting' improves children's autism and similar headlines sprung to mind and with it, the question of whether big claims were being made...

The paper behind the headlines this time around was from Attia Anwar and colleagues [1] (open-access) and I have to say at first sight I was really rather interested in the specific topic under investigation. Namely: "to explore the diagnostic utility of proteotoxic biomarkers in plasma and urine, plasma protein glycation, oxidation, and nitration adducts, and related glycated, oxidized, and nitrated amino acids (free adducts), for the clinical diagnosis of ASD [autism spectrum disorder]." Interested because the words 'amino acids' (an area of interest to this blog) were mentioned and also that their description of using "stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry" plays to the analytical chemistry nerd that I've seemingly become down the years.

So, bearing in mind the Anwar paper is open-access, what were the hows-and-whys of this 'first steps' research? Well, the initial premise was a sensible one as words like '3-nitrotyrosine (3-NT)' are mentioned following other research noting this compound with some autism in mind (see here). It all ties into the process of oxidative stress and neuroinflammation that are becoming more readily accepted to be part-and-parcel of at least some autism (see here and see here). Researchers set out to see if they could detect some important compounds involved in the process of protein homeostasis (amino acids are the building blocks of protein) and whether, by using the process of machine learning on the derived data (see here for another example of this being applied to autism), the possibility of a diagnostic test for autism might be forthcoming from such work. Yes, this was another example of metabolomics being applied to autism research (see here and see here) and seems to continue a research journey from members of this authorship group [2].

Urine and plasma samples were the chosen analytical media, as authors report on the recruitment of 38 children diagnosed with an ASD and 31 not-autism controls. Yet again, the words 'healthy controls' are used to denote not-autism; something that we really shouldn't be seeing in this day and age. I'd also, by the way, say the same things about the term 'neurotypical' too (see here). The autism group did seem to have quite an extensive diagnostic work-up as both ADOS and CARS scores are presented. Spot blood and urine samples were provided by all and metabolomic analysis was begun...

Results: bearing in mind the significant complexity of both urine and plasma samples when it comes to the presence of small molecules and metabolites, the use of that mass spec method made short work of detecting the glycation markers indicated for study. I note also authors also provide some results on various amino acids in both urine and plasma that is, I think, rather important.

The first thing that struck me was the authors use of a compound called creatinine to correct for sample strength and dilution. I'd like to think I know a thing or two about creatinine (urinary) in relation to some autism on the back of a bit of published research a decade or so back [3]. Our conclusion then and also in some other independent work since (see here) is that caution is required when using creatinine as a corrector with autism in mind...

Having said that, a few findings are noteworthy: "we identified changes in plasma protein AGE [advanced glycation endproducts] and oxidation adducts, increased CML [Nε-carboxymethyl-lysine], CMA [Nω-carboxymethylarginine], and DT [dityrosine] and decreased 3DG-H [3-deoxyglucosone] in ASD." I'm not all too familiar with all of those compounds listed but going back to my observation on oxidative stress being something pertinent to some autism [4], I think there are some important connections to be seen. I note also that at least one of the findings - increased DT residue content of plasma proteins - might also provide a role for those trillions of wee beasties that call us home, the gut microbiota. Mention of the gastrointestinal (GI) tract in the context of autism is likely not to sit well with some people, despite multiple evidence of involvement for some in both a functional sense (see here) and also at a more biological level (see here).

Then to the headline maker: "Algorithms to discriminate between ASD and healthy controls gave strong diagnostic performance with features: plasma protein AGEs—CML, CMA—and 3-deoxyglucosone-derived hydroimidazolone, and oxidative damage marker, DT. The sensitivity, specificity, and receiver operating characteristic area-under-the-curve were 92%, 84%, and 0.94, respectively." Those sensitivity and specificity stats aren't bad at all. They are certainly on a par with other 'classification' attempts with autism in mind, such as when cortisol and a suite of cytokines got the same analytical treatment for example (see here). The trouble is that such stats are based on a relatively small sample size and indeed, children aged between 5-12 years old. Given that many children (but not all) are diagnosed quite a bit earlier than 5 years of age, one has to wonder how relevant any biological test might be at such a later age. One is left feeling that perhaps the discrimination analysis part of the Anwar paper should have perhaps been left until replication on an independent cohort with a larger sample size was carried out, and perhaps relying on more than one testing occasion.

I was also a little bit 'put out' that I couldn't find any 'limitation' discussions in the paper by Anwar et al. There was lots of chatter about how this, that and t'other might relate to biological processes pertinent to some autism but in the discussion section there was very little about what could be wrong with the results as they stand (e.g, small sample sizes). In the current age also when autism is more and more being talked about as NOT being a stand-alone diagnosis (see here) and indeed, probably is a more plural diagnosis ("the autisms"), it is always worthwhile mentioning how any obtained results might have to be framed in those contexts. Yes, authors did have exclusion criteria for study entrance: "Subjects with ascertained medical and neurological comorbidity were excluded, through a medical work up including electroencephalography (recorded during awake and sleep), cerebral magnetic resonance imaging, standard clinical and neurological examination, neurometabolic, and genetic investigations (including comparative genomic hybridization array, molecular assay for Fragile X and MECP2)" but autism pure might not be so typical in the real world [5].

Although some people have reacted quite strongly to the Anwar results, I do think this is quite a good study. No, as it stands, I don't think it can say that autism might be diagnosed on the basis of a urine and/or blood sample. Indeed, we've been here before (see here for example). But it does provide some welcome insight into some of the potential biology associated with at least some autism, and once again, champions the use of some really, really advanced metabolomic technology to provide potential systems biology insights into at least some autism...

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[1] Anwar A. et al. Advanced glycation endproducts, dityrosine and arginine transporter dysfunction in autism - a source of biomarkers for clinical diagnosis. Molecular Autism. 2018; 9: 3.

[2] Anwar A. et al. Quantitation of plasma thiamine, related metabolites and plasma protein oxidative damage markers in children with autism spectrum disorder and healthy controls. Free Radic Res. 2016 Nov;50(sup1):S85-S90.

[3] Whiteley P. et al. Spot urinary creatinine excretion in pervasive developmental disorders. Pediatr Int. 2006 Jun;48(3):292-7.

[4] Rossignol DA. & Frye RE. Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism. Front Physiol. 2014 Apr 22;5:150.

[5] Gillberg C. & Fernell E. Autism plus versus autism pure. J Autism Dev Disord. 2014 Dec;44(12):3274-6.

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