"There is broad parent interest in a genetic/epigenetic test for ASD"

The quote heading this post - "There is broad parent interest in a genetic/epigenetic test for ASD [autism spectrum disorder]" - comes from the findings reported by Kayla Wagner and colleagues [1]. As per the observation that most parents of those diagnosed with an ASD, or developmental delay (DD) or asymptomatic controls "had positive perceptions toward genetic/epigenetic research in ASD", far from being the 'danger' that it is sometimes portrayed as, the science of genetics seems to have an important standing among many parents.

The Wagner results came about as a result of this research group publishing studies "that demonstrate the utility of RNA sequencing technology (non-coding RNA) to identify children with ASD." They did what few genetic studies have done: asked parents participating in their studies whether what they were doing/finding was of interest to them. This was achieved via the use of a questionnaire which included six themes: "(1) reasons for participating in the epigenetic study; (2) prior knowledge of genetics/epigenetics, and the source of this information; (3) overall interest in genetic/epigenetic testing for ASD; (4) concerns about genetic/epigenetic testing for ASD; (5) preferences about the approach for genetic/epigenetic testing (including age of administration and biofluid of choice); and (6) extent of results to be returned." You'll probably have noted that alongside their use of the term 'genetics' they also talk about a still up-and-coming branch of genetics called epigenetics. I've talked about epigenetics and autism before on this blog (see here and see here) but the description Wager et al use just about says it all: "changes in gene expression, where the changes are not due to modification of the actual DNA sequence, but instead result from modifications that regulate DNA structure and expression." Gene expression seems to be particularly important to the science of epigenetics as per the notion that we don't all walk around with all our genes permanently switched to the 'on' or 'off' position.

Results: quite a few important points emerged from the obtained data. Most parents understood at least a little bit about genetics and some of the processes involved. Epigenetics wasn't as well known about or understood (something which is probably not so surprising). Other points also emerged: "There were no parents (0%, 0/244) concerned about a lack of scientific evidence supporting genetic and epigenetics." But that's not to say that some parents weren't concerned about the implications of genetics and epigenetics, as mention about issues like privacy and insurance status were raised during the Wagner study.

Also: "Nearly all parents (96%, 235/244) indicated that if there were genetic testing for ASD, they were interested in learning results about their child’s risk for ASD." And when it came to results, over three-quarters of all parents expressed a preference for "all epigenetic/genetic results, regardless of whether they were implicated in health and disease" and not just an overview or interpretation of any results. People want data not overviews.

And then to some important but potentially controversial findings: "The majority of parents (71%, 164/231) desired results of a genetic/epigenetic test for ASD when their child was 12 months of age or younger. Over half of parents were interested in receiving results at conception (34%, 78/231) or at birth (37%, 86/231), while fewer requested results at 12 months (17%, 40/231) or at 2 years of age (12%, 27/231)." You can perhaps see where this might be going - particularly 'receiving results at conception' - even if the authors seem to have chosen not to pursue it any further in their discussions.

I'm no bioethicist and so am nowhere near qualified to talk about the ins-and-outs of genetic testing in the context of autism and what implications this could have. I note other commentators have approached this subject previously based on some of the peer-reviewed science in this area (see here) and various points have been raised. One of the important things to bear in mind is that, as it currently stands, there is no single genetic test for all autism. Indeed, allied to the idea that the concept of 'a universal autism gene' is fast becoming a distant memory, genetic studies are serving to further highlight how complex autism actually is.

But there is always the possibility that some day someone will potentially deliver a genetic/epigenetic 'test for some autism'. The question then is how will it be used? What checks and balances will be in place to ensure that it is not misused?

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[1] Wagner KE. et al. Parent Perspectives Towards Genetic and Epigenetic Testing for Autism Spectrum Disorder. Journal of Autism & Developmental Disorders. 2019. March 22.

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"his sudden interest in changing gender may have been another of his autistic obsessions"

A recent (online) newspaper report from here in Blighty included the quote used in the title of this post: "his sudden interest in changing gender may have been another of his autistic obsessions" (see here).

The report describes how a male - born biologically male - teenager diagnosed with autism expressed an opinion that "he believed he was female" and how his opinion was received by his parents and other professionals. Differences in the reception and perception of that opinion eventually led to some 'frustration' and, worryingly, the eventual intervention of social (child) services.

I decided to blog about this report primarily because (a) it ties in with some important peer-reviewed science discussions about gender identity and autism (see here and see here), and (b) there is a distinct possibility that the headline accompanying the report - "Social services threaten to take autistic boy into care after his parents refuse to let doctors give him powerful sex-change drugs" - is likely to be replicated again. Such a headline also taps into some wider debates about an increasing number of children talking about their gender and the decision-making rights and abilities of children both on and off the autism spectrum.

First things first, I know there are lots of strong opinions about sex and gender and 'what's right for children' these days. I don't offer an opinion either way nor do I claim to be an expert on issues such as gender dysphoria - "where a person experiences discomfort or distress because there's a mismatch between their biological sex and gender identity" - or gender reassignment or related issues. As mentioned, I'm interested in the science behind such discussions because autism has been discussed, on more than one occasion, as being potentially 'over-represented' among those with gender dysphoria [1] and/or wanting to/going through gender reassignment services. I say 'potentially over-represented' but wouldn't want anyone to think that any scientific debates have been settled at the current time: they haven't [2] (see here). I'm also interested in this topic because, aside from any gender reassignment issues, autism not so long ago was faced with something called the 'Lupron protocol'. Then leuprorelin, a drug sometimes used to 'delay puberty', was touted as something important to autism for very, very different reasons. I might add that the story of such a 'protocol' did not end well, as words like 'chemical castration' were banded around (see here).

I selected the quote that heads this post because it strikes me that there are some 'unique' issues that arise in the context of autism being mentioned alongside gender dysphoria and/or reassignment. Issues that don't seem to have been properly considered at the time of writing. Indeed, when I first tweeted about the source article for this post, a couple of response summed up the positions taken. First: "That child is not a boy. She is a girl and she needs the medical transition that will treat her dysphoria and allow her to live her best life." Another response was from someone who is themselves autistic and mentioned an important word: 'impulsivity'. Indeed, the article itself also mentions some similarly important phrases which require consideration. So: "they [his parents] suspected his abrupt decision to change sex was a result of his autism" and "All we were doing was trying to get him to pause and think about his actions" and "The school and social workers took what our child said as gospel. But considering he has autism, his perception of social scenarios is seen through an autism lens." An autism lens?

As you can see, a lot of those quotes/opinions focus on the idea that the traits that stem from or follow autism are potentially important to this debate. Minus any 'pity me' sentiments, they imply for example, that autism confers some specific 'vulnerability' that cannot simply be brushed under the carpet particularly when a person makes, or wants to make, important, potentially life-changing, decisions. I've talked about the issue of vulnerability and autism before on this blog (see here and see here) with some equally life-changing issues in mind. The topics differ but the sentiments remain the same. It's highly likely that the parents discussed in that news report know a little a bit about such vulnerability and autism purely in the context of raising their offspring.

Such vulnerability does however have to be balanced with individual rights; that is the rights of an individual to make important decisions that affect them. Such decisions might not always be 'the correct ones' or the ones that significant others necessarily want them to make but nonetheless, still need to be valued particularly within the context of assumed competence (see here). Indeed I get the impression that it's the possibility that the child has expressed an opinion with future consequences - "My biggest worry as a mum is my child gets pushed down this route, becomes a woman, goes through the surgery, then gets to 25 and says, “I’ve made a mistake.”" - that seems to worry the parents in the news report more than anything else. The use of the word 'surgery', implying the degree of 'invasiveness' needed and potentially also inferring 'irreversibility', is perhaps also an important part of their response.

What else? Well, without heading too far into scientifically unexplored territory I think there are other issues that come into play in such a scenario. Going back to the comment on impulsivity and the 'abrupt decision' talked about in the article, another important (and contentious) issue is potentially introduced: rapid-onset gender dysphoria (ROGD) [3]. ROGD is something that is not well-liked in some quarters (see here) and still remains a topic of some (heated) discussion (see here). It defines a state whereby "teens and young adults who did not have symptoms of gender dysphoria during childhood but who were observed by their parents to rapidly develop gender dysphoria symptoms over days, weeks or months during or after puberty." I don't make any comment on the rights or wrongs of something like ROGD but would encourage further study. Specifically with autism in mind and on the basis of the case being reported, questions like: 'how abrupt was the decision?' (or was the decision taken many moons ago but just communicated recently?) are important. Whether those who are diagnosed with autism or present with significant autistic traits are 'over-represented' among cases of ROGD is another research question that perhaps needs considering. And then there's the possible question of why?

Ultimately there are no easy answers to the issue described in today's post despite some significant strength of feeling. What will help however, is research; good quality research that is not afraid to test difficult hypotheses. And whilst individuals should always be empowered to make decisions for themselves, there should always be an appreciation that decision-making typically does not occur in a vacuum...

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[1] Janssen A. et al. Gender Variance Among Youth with Autism Spectrum Disorders: A Retrospective Chart Review. Transgend Health. 2016 Feb 1;1(1):63-68.

[2] Nobili A. et al. Autistic Traits in Treatment-Seeking Transgender Adults. J Autism Dev Disord. 2018. April 13.

[3] Littman L. Rapid-onset gender dysphoria in adolescents and young adults: A study of parental reports. PLoS One. 2018 Aug 16;13(8):e0202330.

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Mesenchymal stem cell transplantation and a mouse model of autism

I once again tread carefully in this brief post talking about stem cells and autism on the back of what seems to be some growing research interest in this area (see here).

The paper by Hadar Segal-Gavish and colleagues [1] adds to this increasing interest with their efforts detailing what happened to a mouse model of autism (the BTBR mouse) following "intracerebroventricular MSC [mesenchymal stem cells] transplantation."

Looking at what happened when MSC transplantation was used, the authors highlight various behavioural and biological effects including: "a reduction of stereotypical behaviors, a decrease in cognitive rigidity and an improvement in social behavior." BDNF (brain-derived neurotrophic factor) was also reported to show changes following transplantation: "elevated BDNF protein levels in the hippocampus accompanied by increased hippocampal neurogenesis in the MSC-transplanted mice compared with sham treated mice."

The authors conclude: "Our study suggests a novel therapeutic approach which may be translatable to ASD [autism spectrum disorder] patients in the future."

Acknowledging that stem cells and autism is still a little bit of a hot potato in terms of the limited available research and more ethical questions about its use, these are interesting results. A recent opinion paper from Simberlund and colleagues [2] on the topic of MSC and autism highlighted the 'pitfalls and potential promises' of this line of investigation, and how despite almost universal scientific approval in terms of 'success' of this type of intervention so far, "substantial methodological and theoretical challenges and pitfalls remain before this can be considered a viable therapeutic option."

I'm gonna leave it at that for now.

Music: Aerosmith - Walk This Way.

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[1] Segal-Gavish H. et al. Mesenchymal Stem Cell Transplantation Promotes Neurogenesis and Ameliorates Autism Related Behaviors in BTBR Mice. Autism Res. 2015 Aug 10.

[2] Simberlund J. et al. Mesenchymal stem cells in autism spectrum and neurodevelopmental disorders: pitfalls and potential promises. World J Biol Psychiatry. 2015 Jul 31:1-8.

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Segal-Gavish H, Karvat G, Barak N, Barzilay R, Ganz J, Edry L, Aharony I, Offen D, & Kimchi T (2015). Mesenchymal Stem Cell Transplantation Promotes Neurogenesis and Ameliorates Autism Related Behaviors in BTBR Mice. Autism research : official journal of the International Society for Autism Research PMID: 26257137

Children as research participants: assessing competence

I was brought to writing about this topic after reading an interesting post by Virginia Hughes titled: Personhood Week: Do Kids Count? Among the various points raised in that article was some discussion about minors having medical autonomy and how this might impinge on areas outside of just medical decision-making. It also reminded me about something which was raised on more than one occasion when I undertook a stint on a University Ethics committee...

Most people involved in the medical or social care of children in the UK will probably have heard about Gillick competence or the Fraser guidelines. Coupled together under the heading of assessing competency to consent to treatment, these guidance derived from judgements in law offer details on how and when a child under the age of 16 years old is able to consent to his or her own medical treatment without parental input and/or knowledge. Contraception was the test case upon which such guidance was first introduced, but the guidance has subsequently been more widely applied to cover many areas of childhood competence in medicine.

You wouldn't eat your spinach

Gillick competence has also drifted into the arena of research (as members of any University ethics committee might know), alongside questions about whether child participation in research should be similarly governed by such guidance [1].

The recent paper by Irma Hein and colleagues [2] adds to the discussion in this area, specifically with their analysis of the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR) and the question of when competency to participate in research studies might actually come about in the paediatric population. I will also direct you to some of the preamble about their study by the same authorship group [3] (open-access).

Hein et al based on data derived from some 160 children aged between 6-18 years of age, concluded that the MacCAT-CR is a pretty good instrument when it comes to its use as a tool for assessing children's competence to consent to clinical research involvement. Perhaps more importantly however based on their results: "[in] children younger than 9.6 years, competence was unlikely (sensitivity, 90%); in those older than 11.2 years, competence was probable (specificity, 90%)". Further that: "The optimal cutoff age was 10.4 years (sensitivity, 81%; specificity, 84%)".

Acknowledging that there is quite a bit more to do in this area, including whether there may geographic variations in the age cut-off described (this was a study conducted in The Netherlands), I found these results to be potentially very important. Not only because "consent may be justified when competence can be demonstrated in individual cases by the MacCAT-CR" suggestive that the MacCAT-CR can be administered to paediatric populations, but also because of the implications for whole disciplines involving children under the age of 16 as research participants.

And on the basis of this being a blog about autism research, the question is: what influence the Hein findings might have on top of previous other ethical issues [4]?

Music to close. Mr Pharmacist by The Fall.

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[1] Hunter D. & Pierscionek BK. Children, Gillick competency and consent for involvement in research. J Med Ethics. Nov 2007; 33(11): 659–662.

[2] Hein I. et al. Accuracy of the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR) for Measuring Children’s Competence to Consent to Clinical Research. JAMA Pediatrics. 2014. October 13.

[3] Hein IM. et al. Assessing children's competence to consent in research by a standardized tool: a validity study. BMC Pediatr. 2012 Sep 25;12:156.

[4] Hoop JG. et al. Ethical issues in psychiatric research on children and adolescents. Child Adolesc Psychiatr Clin N Am. 2008 Jan;17(1):127-48, x.

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Hein IM, Troost PW, Lindeboom R, Benninga MA, Zwaan CM, van Goudoever JB, & Lindauer RJ (2014). Accuracy of the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR) for Measuring Children's Competence to Consent to Clinical Research. JAMA pediatrics PMID: 25317644