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Sunday, June 10, 2012

Fish, Antidepressants, Autism and a Problematic Research Premise

From PLoS Blogs - Diverse Perspectives on Science and Medicine

By Dorothy Bishop
June 8, 2012

This week saw publication of a PLOS One paper on a potential environmental cause of autism that caught the attention of the media. The Daily Mail, a newspaper that has a track record of sensationalist health scares announced “Autism ‘could be triggered by very low doses of anti-depressants or other chemicals found in water supply’”.

On the same day, three excellent critiques of the study appeared on the blogosphere, by Tom Chivers, writing in the Daily Telegraph, by Dianthus Medical, and by Neuroskeptic.

As it happened, I had blogged about autism earlier this week, reconsidering the enduring question of whether there really is an autism epidemic in need of explanation. I was therefore interested to see that the PLOS One paper confidently asserted: “Idiopathic ASD, caused by genetic susceptibility factors interacting with unknown environmental triggers has increased dramatically in the past 25 years.”

Well, everyone agrees there has been a remarkable increase in autism diagnosis across the world in the past 25 years, but in my blogpost, I questioned whether this meant an increase in autism. So here are the arguments that I put forward that might give one pause.

Three very different kinds of explanation exist for the growth in diagnoses:
  • Explanation #1 maintains that something in our modern environment has come along to increase the risk of autism. There are numerous candidates, as indicated in this blogpost by Emily Willingham.
  • Explanation #2 sees the risks as largely biological or genetic, with changing patterns of reproduction altering prevalence rates, either because of assortative mating (not much evidence, in my view) or because of an increase in older parents (more plausible).
  • Explanation #3 is very different: it says the increase is not a real increase – it’s just a change in what we count as autism. This has been termed ‘diagnostic substitution’ – the basic idea is that children who would previously have received another diagnosis or no diagnosis are now being identified with autism spectrum disorder (ASD). This could be in part because of new conceptualisations of autism, but may also be fuelled by strategic considerations: resources for children with ASD tend to be much better than those for children with other related conditions, such as language impairment or intellectual handicaps, so this diagnosis may be preferred.
In 2008, my research group published a study that documented one kind of diagnostic substitution. We contacted people who had taken part in our studies of children with specific language impairment years ago. We carried out a standard diagnostic observation procedure for autism with the young adults themselves and, where possible, interviewed parents about their early history.

We found a number of individuals who had been regarded as cases of specific language impairment ten or twenty years ago but who would nowadays be diagnosed with ASD. Although it’s possible that some people develop autistic symptomatology as they get older, in our cases the autistic symptoms appeared to have been present from early childhood – as indicated by the parental interviews.

Around half of the sample had been identified as having ‘semantic-pragmatic disorder’ in childhood, but autism had been excluded because at that time, prior to publication of DSM-IV diagnostic guidelines, it was regarded as a very rare condition in which there were severe social and behavioural impairments. How many children would have qualified for ASD diagnoses had they been seen today?

Well, it depends. I suspect few people appreciate just how flexible the diagnostic criteria are for autism, even when lengthy standardized diagnostic instruments are used. Although we used the gold standard diagnostic procedures (ADOS-G and ADI-R) we found they seldom gave the same answer. If we diagnosed ASD only when both diagnostic instruments agreed, 21% of cases met criteria. If we included anyone who met criteria for autism or PDDNOS on either ADI-R or ADOS, the rate shot up to 66%.

Recently, we conducted a study with another group: children with an additional sex chromosome (i.e. trisomy). We had not intended to study diagnostic substitution: the goal was rather to understand more about the language difficulties that had previously been described in children with sex chromosome trisomies. The effect of an extra sex chromosome is relatively mild: most of these children attend mainstream schools and they do not have any obvious physical abnormalities. Indeed, they can be hard to study because many individuals with trisomies will be unaware of their condition.

We gathered information by parental report, and did not do any direct evaluation of the child, but we did ask about whether the child had had any kind of diagnosis by a medical or psychological expert. We confirmed that there was a strong association with language problems in all three kinds of trisomy (girls with XXX, and boys with XYY or XXY), many of whom had had speech-language therapy. But we also found that 2/19 (11%) of boys with XXY and 11/58 (19%) of those with XYY had received an ASD diagnosis.

It is important to emphasise that most children with a sex chromosome trisomy did not have an ASD diagnosis, and many were not giving any cause for concern. Nevertheless, although they are only a minority of cases, the proportion with ASD is much higher than in the general population. We were really surprised at this because before publishing our study we had done a systematic review of the literature on children with sex chromosome trisomies, focusing on studies that avoided ascertainment bias.

In these studies, not a single case of autism had been mentioned when discussing outcomes. So was our study a fluke? We are confident this is not the case, because this year two further studies from the USA have been reported (Ross et al and Lee et al, in press), both of which got results very similar to ours, though using different methods.

This research provides further evidence that diagnostic substitution has occurred, suggesting that children who in the past would have been diagnosed with language impairment are now being diagnosed with ASD. The only other way to explain the increased diagnosis rate in children with a known chromosomal abnormality would be if the trisomy acted as a risk factor, making children more sensitive to environmental factors that could cause autism.

That’s a possibility, but it seems more likely that cases of ASD were missed in the past because more stringent diagnostic criteria were used, just as was found in our follow-up of children with SLI.

"It is becoming clear that changing diagnostic criteria, increased awareness of ASD, and strategic use of diagnosis to gain access to services, have had a massive effect on the numbers of children with ASD."

It is becoming clear that changing diagnostic criteria, increased awareness of ASD, and strategic use of diagnosis to gain access to services, have had a massive effect on the numbers of children with ASD. So there clearly is diagnostic substitution, but is it sufficient to explain the increase in diagnoses?

King and Bearman, whose data are shown in the Figure above, have done some elegant analyses looking at correlates of diagnostic changes in an attempt to pin down reasons for variable autism rates, both over time and across geographical regions. They are, however, reliant on data from medical/educational records, which can be influenced by a single diagnostician with more liberal or stringent diagnostic standards.

As I wrote last year in the Guardian, after years of developing ever-more complex diagnostic procedures, we still come down to “expert clinical opinion” as the basis for diagnosis. Last year, a fascinating study by Brugha and colleagues did a study that was not open to such bias. They did an epidemiological survey of a representative sample of adults from the English population, using the ADOS-G, and found that the rates of ASD were similar to those recently reported in children. Furthermore, within the adult population, rates of ASD did not change with age.

Thus, provided we stick to the same diagnostic criteria, then the prevalence of autism is the same for those born several decades ago, as it is for the current generation of children. Importantly, none of these adults with ASD had received a formal diagnosis.

The study by Brugha and colleagues points a way forward: rather than trying to estimate the extent of diagnostic substitution retrospectively from existing data, we need more epidemiological studies that adopt consistent and objective criteria to evaluate rates of autism in cohorts of people born in different time windows. If the findings of Brugha and colleagues are confirmed, then we do not need to look for recent changes in the environment to explain the causes of autism.

About Dr. Dorothy Bishop

Dorothy Bishop, Ph.D. is Professor of Developmental Neuropsychology at University of Oxford, Department of Experimental Psychology, U.K. She blogs HERE. See also Raising Awareness of Language Learning Impairments! on YouTube HERE.


Bishop, D., Jacobs, P., Lachlan, K., Wellesley, D., Barnicoat, A., Boyd, P., Fryer, A., Middlemiss, P., Smithson, S., Metcalfe, K., Shears, D., Leggett, V., Nation, K., & Scerif, G. (2010). Autism, language and communication in children with sex chromosome trisomies. Archives of Disease in Childhood, 96 (10), 954-959 DOI: 10.1136/adc.2009.179747

Bishop, D., Whitehouse, A., Watt, H., & Line, E. (2008). Autism and diagnostic substitution: evidence from a study of adults with a history of developmental language disorder. Developmental Medicine & Child Neurology, 50 (5), 341-345 DOI: 10.1111/j.1469-8749.2008.02057.x

Brugha, T. (2011). Epidemiology of Autism Spectrum Disorders in Adults in the Community in England. Archives of General Psychiatry, 68 (5) DOI:10.1001/archgenpsychiatry.2011.38

King, M. D., & Bearman, P. S. (2011). Socioeconomic status and the increased prevalence of autism in California. American Sociological Review, 76(2), 320-346. doi: 10.1177/0003122411399389

Lee, N. R., Wallace, G. L., Adeyemi, E. I., Lopez, K. C., Blumenthal, J. D., Clasen, L. S., & Giedd, J. N. (2012, in press). Dosage effects of X and Y chromosomes on language and social functioning in children with supernumerary sex chromosome aneuploidies: Implications for idiopathic language impairment and autism spectrum disorders. Journal of Child Psychology and Psychiatry.

Ross, J. L.,et al (2012). Behavioral and social phenotypes in boys with 47, XYY syndrome or 47, XXY Klinefelter syndrome. Pediatrics, 129(4), 769-778. doi: 10.1542/peds.2011-0719

Thomas, M. A., & Klaper, R. D. (2012).  Psychoactive pharmaceuticals induce fish gene expression profiles associated with human idiopathic autism. PLoS ONE, 7(6), e32917. doi: 10.1371/journal.pone.0032917

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