Asking about "growing up with a sibling with autism"

The findings reported by Philippa Moss and colleagues [1] provide the blogging fodder today, and another important research venture into asking siblings about their experiences of growing up with a brother / sister diagnosed with autism. Such work continues an important theme whereby a diagnosis of autism doesn't just impact on the person concerned, but also on significant others around them too (see here). It also reiterates that the 'nothing about us without us' phrase should really be extended to include siblings as well as parents/primary caregivers and of course, those diagnosed with autism (see here)...

Researchers talked to over 50 adult siblings with a brother and/or sister with autism. They asked them questions about growing up with their sibling and importantly "about their worries for the future." The results provided an important snapshot into the experiences of siblings. It was a mixed bag in terms of positive and negative experiences; where themes like tolerance and caring were discussed in relation to how their autistic sibling had positively impacted on their lives. The not-so-positive themes included things like "coping with behavioural difficulties (39%) and disruption to family relationships (32%) or social life (23%)."

There was another important observation to come from the Moss study too: "The main concerns for the future, expressed by the majority of participants, focussed on problems of finding appropriate care (77%) and the potential emotional impact on the autism siblings of loss of parents." Such sentiments take us into some difficulty territory as the issue of long-term care comes into the discussion, alongside other issues voiced by parents such as 'why I can never die' (see here).

Given that siblings will probably emerge as the primary caregiver or at least responsible person when it comes to their brother(s) / sister(s) with autism as parents age, one can see the logic in the suggestion from Moss to "involve siblings in care planning and decision-making." Support for siblings is also required to prepare them for the future and ensure that the sentiments of 'caring for the carers' extends to them too.

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[1] Moss P. et al. Growing older with autism – The experiences of adult siblings of individuals with autism. Research in Autism Spectrum Disorders. 2019; 63: 42-51.

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"parental asthma was associated with slightly elevated risk of ASD in offspring"

The paper by Tong Gong and colleagues [1] provides the blogging fodder today and the finding that "parental asthma was associated with slightly elevated risk of ASD [autism spectrum disorder] in offspring."

As unusual as it might sound to some people that a condition primarily affecting the lungs *might* show a connection to a developmental diagnosis in offspring, this is not the first time that asthma and autism has been talked about on this blog (see here and see here). Granted, much of that previous peer-reviewed research has been looking at the possible *connection* between asthma and autism diagnosed in the same person (albeit not necessarily always describing a link). But there is some research history connecting the two labels. Indeed, one of the primary comorbidities that can follow a diagnosis of autism - attention-deficit hyperactivity disorder (ADHD) - seems to have an even stronger *association* with asthma (see here).

Gong et al set out to investigate a few important issues: "the association between (a) maternal/paternal asthma and offspring ASD, and (b) prenatal exposures to β2-agonists, other asthma medications and offspring ASD." It would be difficult to describe the Gong study as 'underpowered' given that their use of those fabulous Scandinavian population registries - this time in Sweden - covering "all children (N=1,579,263) born in Sweden 1992-2007." From the total population, researchers identified some 22,000 children diagnosed with an ASD. They looked at their exposure to "parental asthma or prenatal asthma medications" and compared the data with other populations (not diagnosed with autism) including various degrees of siblings and extended family members.

As per the title of this post, a possible *association* was revealed between parental medical history of asthma and offspring risk of a diagnosis of ASD. Asthma in either parent seemed to show a connection, but maternal asthma showed the stronger connection. Also: "The risk of offspring ASD in mothers with asthma showed similar estimates when adjusting for shared familial factors among paternal half-siblings... full-cousins... and half-cousins." This suggests that familial factors were not 'confounding' factors. Another detail is important to mention: "Prenatal exposure to asthma medications among subjects whose mothers had asthma was not associated with subsequent ASD." This is an important detail. It mirrors the findings reported in the paper by Su and colleagues [2] looking at another Scandinavian cohort, and their conclusion: "children born to women who used β2AA [β2-adrenoreceptor agonist] during pregnancy have an increased risk of ASDs in later life" with the caveat that risk of offspring autism was "more likely due to underlying maternal diseases rather than the exposure to β2AA itself."

Implications? Well, several. Not least that more study is required looking at the biological and genetic links between autism and asthma. Y'know, something along the lines of the fact that 'autism genes are probably not just genes for autism' (see here) and how autism has been previously studied in the context of lung architecture too (see here).

What else? How about examining the possibility of some shared biological mechanisms also at work? Perhaps start with inflammation for example [3] and work through other potential immune-related issues as well (see here). And how about also thinking about the possibility of shared 'exposure' events being potentially important? Asthma is a condition affecting the lungs. Something like air pollution is therefore a prime suspect when it comes to the development and continuation of the condition. Likewise, air pollution is no stranger to the autism peer-reviewed research landscape (see here for example). Is it possible that air pollution might be implicated in asthma and autism?

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[1] Gong T. et al. Parental asthma and risk of autism spectrum disorder in offspring: a population and family based case-control study. Clin Exp Allergy. 2019 Feb 11.

[2] Su X. et al. Prenatal exposure to β2-adrenoreceptor agonists and the risk of autism spectrum disorders in offspring. Pharmacoepidemiol Drug Saf. 2017 Jul;26(7):812-818.

[3] Murdoch JR. & Lloyd CM. Chronic inflammation and asthma. Mutat Res. 2010;690(1-2):24-39.

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Vaccination rates and patterns among kids with autism and their siblings (again)

The publication of the paper by Ousseny Zerbo and colleagues [1] garnered some media headlines insofar as their conclusion that: "Children with ASD [autism spectrum disorder] and their younger siblings were undervaccinated compared with the general population."

Drawing on data from "6 integrated health care delivery systems across the United States within the Vaccine Safety Datalink" researchers looked at immunisation status for over 3700 children diagnosed with ASD and over half a million kids not diagnosed with autism alongside their respective younger siblings. They were specifically looking at the proportion of children who "received all of their vaccine doses according to ACIP [Advisory Committee on Immunization Practices] recommendations."

Results: "For vaccines recommended between ages 4 and 6 years, children with ASD were significantly less likely to be fully vaccinated compared with children without ASD." Vaccination rates were also significantly lower for younger siblings of those with autism too. Further discussion of the details of the Zerbo results can be seen here.

Although headline grabbing, this research topic - vaccination rates among children with autism and their siblings - is by no means a new one (see here and see here for examples). The Gena Glickman findings [2] published last year (2017) for example, did not attract the same degree of media attention but highlighted how (a) parents of children diagnosed with autism were extremely vaccine compliant when it came to their earlier born children, and (b) "Families with children who had autism spectrum disorder were less likely to vaccinate subsequent children." To quote from some of the media on the latest Zerbo paper: ""We did not look at vaccination rates before the children were diagnosed with autism," Zerbo noted"; a pretty important omission by all accounts.

What's then also missing from the current data in this area? Well, the question of why - why are children with autism and their siblings less likely to be vaccinated - is a rather glaring omission, and one that stretches into other age ranges [3] too. Yes, it's easy to say that 'fear of the autism-vaccine link' is a primary reason for the undervaccination statistics, particularly with the data on age being a factor in the Zerbo findings and despite the 'too many too soon' argument having some strong evidence against it (see here). But... as per the Glickman and other data, many parents are/were extremely vaccine compliant when it came to earlier born children. If they were going to have long-standing fears about vaccination and indeed, act upon those fears, I would have thought that they would have influenced vaccination behaviour across all their children and not just as and when autism was diagnosed in a family member. Neither do I give much [research-based] credence to the idea that parents of children with autism are somehow over-represented among the so-called 'anti-vaxxer' groups (see here); not that is, as being a long-standing issue.

Glickman et al do provide another possible explanation in their study results that: "changes in vaccination behavior may relate to adverse reactions to vaccine" in their cohort. A sort of once bitten, twice shy sentiment if you like *might* potentially be in action, which kinda makes more sense. I know this takes us down a rather uncomfortable path in that, whilst acknowledging that vaccines represent an important cornerstone of modern healthcare (yes, they do), they are not somehow magically without side-effects for some. Hackles are bound to be raised by such utterances; despite some potentially important clues already appearing in the peer-reviewed research literature [4] relevant to this topic. But without even attempting to try and answer such 'why' questions, we are left with a fairly large number of children who "are at increased risk of vaccine-preventable diseases" with no real solutions in sight for protecting their health and/or the health of the wider population.

Answers are therefore required and required quickly. The simplest and perhaps most logical solution I can see would be to go and ask parents/primary caregivers, under scientifically controlled study, why their children are undervaccinated; perhaps building on important work such as that by Hilton and colleagues [5]. There is the issue of recall to overcome (see here) and I'm sure the range of answers is going to be long and complicated in relation to undervaccination. Armed however, with such answers or at least clues from the parents/caregivers themselves and not just 'speculation', science and policy can perhaps then start to move things forward to further protect the health of all concerned. Hopefully also, such knowledge can be used to chip away at yet another important health inequality that seems to follow a diagnosis of autism throughout the lifespan (see here)...

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[1] Zerbo O. et al. Vaccination Patterns in Children After Autism Spectrum Disorder Diagnosis and in Their Younger Siblings. JAMA Pediatrics. 2018. Mar 26.

[2] Glickman G. et al. Vaccination Rates among Younger Siblings of Children with Autism. N Engl J Med. 2017 Sep 14;377(11):1099-1101.

[3] Filliter JH. et al. The next vaccine-autism question: Are school-aged youth with autism spectrum disorder undervaccinated and, if so, why? Paediatr Child Health. 2017 Aug;22(5):285-287.

[4] Poling JS. et al. Developmental regression and mitochondrial dysfunction in a child with autism. J Child Neurol. 2006 Feb;21(2):170-2.

[5] Hilton S. et al. MMR: marginalised, misrepresented and rejected? Autism: a focus group study. Archives of Disease in Childhood. 2007;92(4):322-327.

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Bullying and autism: not always originating from where you might expect...

There is something rather uncomfortable about the findings reported by Imar Toseeb and colleagues [1] but, at the same time, they do raise an important issue that needs to be openly discussed. Specifically their findings on: "sibling bullying, and the associated psychopathological adversities, in children with and without ASD [autism spectrum disorder]" deserve some airtime.

Bullying and autism is quite a regular talking point in the peer-reviewed research literature (see here) and beyond. Although a diagnosis of autism is by no means protective of someone becoming a bully or being involved in what could be considered bullying behaviour, it is far more typical that those with autism are going to be a victim of bullying rather than perpetrator (see here). Indeed, I reluctantly use the word 'vulnerable' yet again on this occasion but...

When one thinks about bullying in any context including that with autism in mind I would imagine that the school bully who name calls or becomes physical aggressive towards someone - usually smaller and quieter than them - probably first springs to mind. Siblings by contrast, conjure up an image of being caring, supportive and again, with autism in mind, often very protective of their brother(s) and/or sister(s) given their important role, present and probably future. And indeed, many, many siblings are just that (see here).

But real life is rarely so clear-cut or 'homogeneous' as many parents, whether with children diagnosed with autism or not, will attest. Siblings argue, fight and probably because of how well they 'know each other', often know all the right buttons to press to get their required reaction. And yes, behaviour sometimes can spill over to what would be considered bullying under any other circumstance...

Toseeb et al started with the hypothesis that: "children with ASD (child has ASD but their sibling does not) would experience higher levels of sibling bullying compared to those without ASD (child and sibling do not have ASD)." They arrived at this hypothesis on the basis of various factors such as a role for the social-communicative issues that follow autism, the possible effect of the 'broader autism phenotype' (BAP) on siblings, and issues such as a greater frequency of aggression - "reactive aggression" - accompanying particularly boys with autism.

They relied on data from the Millennium Cohort Study (MCS) (a resource that has been mentioned before on this blog) and eventually included data from nearly 500 children with autism alongside over 13,000 not-autism controls. The question(s) on sibling bullying were asked at 11 years of age and went: "he/she was asked to respond to two questions on a six-point scale (never, less often, every few months, approximately once a month, approximately once a week, most days): “how often do your brothers or sisters hurt you or pick on you on purpose?” (victimization) and “how often do you hurt or pick on your brothers or sisters on purpose?” (perpetration)." Responses were coded according to who did what and how often. Various other measures were also examined as part of the MCS and used in the Toseeb paper: socio-demographic data (single parent status, birth order, number of siblings, household incomes), parenting style, psychopathology and cognition.

Results: children diagnosed with autism or ASD were more likely to be bullied by their non-autistic sibling compared with those who did not have autism. This finding held "even after controlling for socio-demographic and family level variables" and "was associated with adverse psychopathologies." Further: "having ASD, being a girl, of White ethnicity, having more siblings, and experiencing harsher parenting were all associated with increased odds of being bullied by a sibling." Whilst we're on the topic of 'adverse psychopathologies, it's perhaps pertinent to mention the findings reported by Dantchev and colleagues [2] observing a possible connection between sibling bullying receipt and psychotic disorder. Yes, it is quite an extreme example, but nonetheless demonstrates the effects bullying can have long-term. I might also refer you back to some discussion arising from the ICF core sets development with autism in mind too (see here).

I digress. I note also that authors discuss sibling bullying as a two-way street: "Our findings indicate that children with ASD are specifically at increased risk of sibling victimization as a bully-victim."

As I said at the beginning of this post, this all makes for uncomfortable reading. If it's not bad enough that a child may be being bullied at school to also then potentially learn that there is little respite from such behaviour at home, makes for an uncomfortable (intolerable?) situation all-round. The question then arises minus any sweeping generalisations: what can be done about sibling bullying for the good of all concerned? And please, don't just solely suggest 'coping strategies' for the bullying victim either.

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[1] Toseeb U. et al. The Prevalence and Psychopathological Correlates of Sibling Bullying in Children with and without Autism Spectrum Disorder. J Autism Dev Disord. 2018 Feb 8.

[2] Dantchev S. et al. Sibling bullying in middle childhood and psychotic disorder at 18 years: a prospective cohort study. Psychological Medicine. 2018. Feb 12.

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Weighing up genetics and environment in autism - reanalysed

Consider this post a sort of add-on to a previous entry (see here) published on this blog talking about the relative contributions of genetics and environment when it comes to autism. On that previous blogging occasion, the findings reported by Sven Sandin and colleagues [1] were the source material and the observation: "Heritability of ASD [autism spectrum disorder] and autistic disorder were estimated to be approximately 50%." The press release accompanying those results was titled: "Environment as important as genes in autism, study finds."

Now the same data has been though a bit of a re-analysis [2] and a slightly different conclusion and media headline - "Autism is mostly genetic, suggests study" - has been created. The reason for the quite different conclusions reached: "Instead of looking at just one time point when both members of a sibling pair had been diagnosed, they incorporated the fact that not all siblings would be diagnosed at the same time. They may start as being undiagnosed, then one would get diagnosed and, later, another might be determined to have autism" according to another media take on the findings (see here). I can't argue with the logic.

The data - 37 570 twin pairs, 2 642 064 full sibling pairs, 432 281 maternal and 445 531 paternal half sibling pairs - were now analysed in the context that diagnoses of autism/ASD among siblings are, for many reasons, not always uniform in timing. The influence of genetics or more specifically, heritability was subsequently boosted up to 83% (previously suggested to be 50%) and with it, 'nonshared environmental influence' relegated to an estimates 17%.

I've perhaps been a little unfair by using the word 'relegated' in the context of non shared environmental influence in relation to autism. There are plenty of examples out there whereby such influences might impact on autism risk: prenatal valproate exposure, congenital rubella syndrome, various types of encephalitis being linked to autistic symptoms onset (see here and see here for examples), etc and these are not to be downplayed. Environmental factors can be pretty important.

But it's critical to also mention that genetics do seem to play quite a significant role in many instances of autism too. Yes, the idea of an 'autism gene' is already a distant memory replaced by something altogether a lot more complicated, but when taking into account notions such as the broader autism phenotype (BAP) for example, one cannot discount that particularly in multiplex families, heritability is probably [mostly] driven by genetics and science still needs to continue looking at the specific hows-and-whys (see here for one example). I might add that looking at gene expression over just structural genetics is probably going to be useful in these days of epigenetics and the like.

And whilst the research of Sven Sandin is being discussed today, another recent paper where the name has appeared [3] has suggested that "little or no maternal genetics contribution" is the order of things when it comes to heritability and autism...

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[1] Sandin S. et al. The Familial Risk of Autism. JAMA 2014; 311: 1770-1777.

[2] Sandin S. et al. The Heritability of Autism Spectrum Disorder. JAMA. 2017; 318(12): 1182-1184.

[3] Yip BHK. et al. Heritable variation, with little or no maternal genetics contribution, accounts for recurrence risk to autism spectrum disorder in Sweden. Biological Psychiatry. 2017. Sept 21.

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"What are the sex-specific recurrence rates of autism spectrum disorder among siblings?"

The paper by Nathan Palmer and colleagues [1] attempted to shed some light on the question posed in the title of this post: "What are the sex-specific recurrence rates of autism spectrum disorder among siblings?" The topic of sibling recurrence rates with regards to autism has been discussed for quite a few years (see here for example).

Already covered by Spectrum (see here), the Palmer data was derived from the records of a US health insurance organisation covering the period between 2008 and 2016 and some 3 million+ children. Researchers specifically looked at those in receipt of an autism diagnosis and onward to "estimate high-confidence sex-specific recurrence rates of ASD [autism spectrum disorder] among siblings." In other words, how many boy and girl younger siblings of children with autism were also diagnosed with autism or an ASD and whether the gender/sex of the older diagnosed sibling was an important variable in recurrence risk.

The answers: well, first it's worth noting that that prevalence of ASD came out at ~2%. This was based on administrative health insurance records remember, so is probably quite accurate given that such schemes have to 'pay out' for certain services/provisions as and when autism is diagnosed. Such a figure also adds to other data highlighting this upward trend in cases diagnosed (see here and see here).

Then: "When a male was associated with risk in the family, ASD was diagnosed in 4.2%... of female siblings and 12.9%... of male siblings. When a female was associated with risk in the family, ASD was diagnosed in 7.6%... of female siblings and 16.7%... of male siblings."

You can perhaps see that there were some subtle differences in the autism/ASD recurrence rate according to the sex/gender of the child first diagnosed with autism in a family. The Spectrum review of this paper quotes the lead author saying: "For a girl to emerge with [autism] in the first place indicates that that is a high-risk family" indicating that the appearance of females with autism might mean a greater genetic load is already present in relation to autism risk for example, which then affects subsequent recurrence risk for autism in later born siblings. That is, if one assumes that genes are the be-all-and-end-all of autism risk (see here)...

What else would I like to see in future investigations? Noting the name Isaac Kohane as part of the authorship group of this paper and acknowledging his past contributions to the autism research landscape with a focus on comorbidity and autism (see here) I do wonder if more could be done on that topic with autism recurrence in mind. Y'know, accepting that various psychiatric and somatic comorbidity are 'over-represented' following a diagnosis of autism (see here), a little more information on what else might be recurring alongside autism could provide some important clues about hows-and-whys, particularly bearing in mind that 'autism genes' aren't necessarily just genes for autism (see here)...

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[1] Palmer N. et al. Association of Sex With Recurrence of Autism Spectrum Disorder Among Siblings. JAMA Pediatrics. 2017. Sept 25.

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Treading carefully: vaccination rates among younger siblings of kids with autism

'Treading carefully' is a requirement for any discussion about a research study that mentions 'vaccination' and 'autism' in the same breath. I say this on the basis that vaccine coverage is an important cornerstone of public health and now appears to be making significant in-roads with regards to public health, at least here in Blighty.

But much like [scientific] discussions covering other areas of the important public health topic of immunisation, one shouldn't be afraid to look, examine and yes, talk about this subject (see here) particularly where there may be a need for further study minus any hype, sweeping generalisations or logical fallacies...

The paper by Gena Glickman and colleagues [1] discussed an important topic in relation to vaccination behaviour - "whether or not and when parents choose to vaccinate a child" - in the context that parents who already have a child with autism may perhaps be slightly more hesitant to vaccinate their other children in light of "the perceived link between vaccines and autism spectrum disorder." This is a topic that has cropped up on this blog previously (see here). Far be it from me to question any parent about their own child, but I will refer you to some of the peer-reviewed science already done on this topic (see here and see here).

Based on a sample of over 200 families, Glickman et al looked at "vaccination behaviors" as a function of having a child with autism or not. From what I surmise from their report, the focus was specifically on "vaccination against measles–mumps–rubella (MMR)." They reported: "no significant difference between rates of vaccination among children with and those without autism" which is rather comforting. Minus too much politics or anything related, this data suggests that anti-vaccination sentiments are not naturally rife among parents/caregivers of children with autism, at least before a diagnosis of autism is given. Indeed with vaccination rates of 100% among children with autism vs. 98% in the slightly larger control group, one might argue that parents of children with autism are/were extremely vaccine compliant when it came to their first born child.

But then also: "Families with children who had autism spectrum disorder were less likely to vaccinate subsequent children." Authors observed that: "the rate of vaccination among full biologic infant siblings of children with autism spectrum disorder was 83.1%, as compared with 97.0% among low-risk infants."

One can speculate (and speculate) about the reason(s) why younger siblings of children with autism were seemingly less likely to be vaccinated but I'm sure the answers are going to be complex. The authors suggest that: "parents who had an older child with autism spectrum disorder retrospectively reported a higher rate of adverse reactions to vaccination among the older child than did those who did not have an older child with autism" and that this may have impacted on subsequent vaccination behaviour. The rates of adverse reactions reported - 22% in the autism group vs. ~4% in the control group - are not to be sniffed at and indeed, seemingly filtered down to observations of adverse reactions in younger siblings too (6.9% vs. 0.8%). Authors also noted that: "Reported reactions included fever, diarrhea, unusual crying or screaming, and general malaise."

This is a nice piece of research. It doesn't go overboard in it's interpretations of the findings and calmly suggests that "a better understanding of the relationship between perceived adverse reactions to vaccine and autism spectrum disorder is necessary in order to more effectively address concerns about vaccination." It is important to note that the authors don't mention 'onset of autism' or anything like that in their discussion of 'reported reactions' following vaccination, despite the seemingly 'once bitten, twice shy' sentiments portrayed in the findings.

Personally, I would have like to have seen more details about the hows-and-whys of this study insofar as what "available data on vaccination behaviors" were used and whether important information on the timescale(s) of adverse reactions were also available keeping in mind certain issues [2]. Some idea of the rate of autism recurrence among younger siblings might also have been useful too (something that at least one of the authors on the Glickman paper seems to be interested in [3]). Given also the quite apparent differences noted in the rates of reported adverse reactions among those with autism vs. controls, there is also a requirement for further careful investigation in this area. Specifically, whether aspects of the biology (or genetics [4]) of at least 'some' autism (or it's possible comorbidity [5]) might be something to consider when it comes to studies of adverse reactions [6] or indeed whether for example, other medications used at the same time of vaccination might have had an effect [7] onward to finding ways and means to minimise such issues.

To close, although some ten years old, the paper by Shona Hilton and colleagues [8] still stands the test of time in this often fractious area...

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[1] Glickman G. et al. Vaccination Rates among Younger Siblings of Children with Autism. N Engl J Med. 2017 Sep 14;377(11):1099-1101.

[2] Ozonoff S. et al. Reliability of parent recall of symptom onset and timing in autism spectrum disorder. Autism. 2017. Sept 13.

[3] Ozonoff S. et al. Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium study. Pediatrics. 2011 Sep;128(3):e488-95.

[4] Verbeek NE. et al. Effect of vaccinations on seizure risk and disease course in Dravet syndrome. Neurology. 2015 Aug 18;85(7):596-603.

[5] Poling JS. et al. Developmental regression and mitochondrial dysfunction in a child with autism. J Child Neurol. 2006 Feb;21(2):170-2.

[6] McClenathan BM. et al. Metabolites as biomarkers of adverse reactions following vaccination: A pilot study using nuclear magnetic resonance metabolomics. Vaccine. 2017 Mar 1;35(9):1238-1245.

[7] Schultz ST. et al. Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: the results of a parent survey. Autism. 2008 May;12(3):293-307.

[8] Hilton S. et al. MMR: marginalised, misrepresented and rejected? Autism: a focus group study. Archives of Disease in Childhood. 2007;92(4):322-327.

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The links between autism and ADHD: sibling study adds a new layer

'A diagnosis of autism or autism spectrum disorder (ASD) does not typically appear in a diagnostic vacuum'. I've said that sentence several times on this blog (see here for example) in line with how science has shown that many different labels (both behavioural and somatic) are over-represented when it comes to a diagnosis of autism. All very ESSENCE like (see here)...

Of the various over-represented comorbidity, attention-deficit hyperactivity disorder (ADHD) - either in symptoms or in diagnosis - is one of the more common ones (see here); something that has implications for screening (see here) and also management. The findings reported by Yi-Ling Chien and colleagues [1] (open-access) add something to the research looking at the possible hows-and-whys of ADHD appearing alongside autism with their focus on "unaffected siblings of probands with autism and Asperger syndrome (AS)." Such work ties into that observing 'unaffected by autism' does not necessarily mean 'symptom or trait-free' in the context of ideas such as the broader autism phenotype (BAP) (see here).

With the aim to "investigate the ADHD-related traits and attention performance in unaffected siblings of probands with autism and Asperger syndrome (AS), as well as the clinical correlates of ADHD-related traits" researchers concluded that generally, unaffected siblings (unaffected by autism) of those diagnosed with an ASD "were more hyperactive/impulsive and oppositional" than those so-called typically developing controls. The finding was based on the use of various questionnaires/schedules pertinent to both the "the core symptoms of DSM-IV ADHD" and also tests to "assess attention performance."

Of particular note was the observation of "more ADHD and oppositional traits in unaffected siblings of AS probands" when looking at subgroups on the autism spectrum. With caution, the authors suggest that such a finding may be evidence "that these traits might be a broader phenotype for AS." They also posit that "more severe ADHD-related symptoms in AS probands rather than autism probands suggest that these two subtypes may not be the same in their clinical expression regarding ADHD symptoms." In these days of plural autisms (see here), things seemingly get even more complicated when diagnostic subgroup x comorbidity is also thrown into the mix.

Although quite a bit more investigation is required in this area, there is at least one important point to take from the Chien work: unaffected siblings of those diagnosed with autism - particularly Asperger syndrome - may benefit from preferential clinical assessment for something like ADHD. I say that with the understanding that a diagnosis of ADHD has been linked to a heightened risk of various 'adverse' outcomes in the longer term (see here and see here) and again, minus any sweeping generalisations, specific interventions for ADHD can seemingly mitigate quite a bit of that excess risk (see here) and onward improve quality of life and more.

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[1] Chien Y-L. et al. ADHD-related symptoms and attention profiles in the unaffected siblings of probands with autism spectrum disorder: focus on the subtypes of autism and Asperger’s disorder. Molecular Autism. 2017; 8: 3.

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Caring for the carers continued

Consider this post a brief extension to a previous one talking about how greater efforts need to be put into supporting those raising and caring for a person diagnosed as being on the autism spectrum (see here).

The science accompanying this post is that published by Cécile Rattaz and colleagues [1] who drew on data derived from the EpiTED cohort (see here), an initiative designed to "understand the heterogeneity of developmental trajectories among children with a diagnosis of PDD [pervasive developmental disorder] and the role of clinical, biological and environmental factors in their adaptive outcome." Researchers concluded that certain aspects associated with a diagnosis of autism in offspring - "young adults' level of adaptive skills... symptom severity and the presence of challenging behaviors" - can very much impact on parental quality of life (QoL). They argue for "the importance to propose specific interventions to target associated challenging behaviors in ASD [autism spectrum disorder]."

Quality of life when it comes to parents or primary caregivers of those young people on the autism spectrum is an often overlooked area when it comes to research and practice. Yes, the focus should quite rightly be on the person who lives with and experiences autism (in it's many different forms) but QoL for children/offspring is often inter-connected with QoL of parents and other family members. I appreciate that some might construe this work as autism presenting a 'burden' to the family and that is not something that anyone really wants to perpetuate. It is however important to realise that issues like challenging behaviours for example (bearing in mind what this covers) can affect many aspects of parenting behaviours, including those related to fatigue (see here) and perhaps further over the longer term [2]. When added to the dwindling resources available to parents (see here for example) there can be real strains placed on parents; more so bearing in mind other factors such as one-parent families and the demands placed on parents also potentially caring for siblings or even other family members.

There are no easy answers to the question of what to do to improve parental (and child) QoL in the context of autism. As mentioned, the sentiments of 'doing more with less' in these days of continued austerity for example, do not readily lend themselves to improving the situation in terms of the availability of something like respite care for example. The onus therefore continues to fall on parents and primary caregivers...

Music to close: The Saw Doctors - I Useta Lover.

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[1] Rattaz C. et al. Quality of Life in Parents of Young Adults with ASD: EpiTED Cohort. J Autism Dev Disord. 2017 Jun 17.

[2] Benson PR. The impact of child and family stressors on the self-rated health of mothers of children with autism spectrum disorder: Associations with depressed mood over a 12-year period. Autism. 2017 Jun 1:1362361317697656.

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Non-febrile seizures in children with autism vs unaffected siblings

"Children with idiopathic ASD [autism spectrum disorder] are significantly more likely to have non-febrile seizures than their unaffected siblings, suggesting that non-febrile seizures may be ASD-specific."

So said the findings from Lena McCue and colleagues [1] (open-access) continuing a research theme looking at one of the important 'comorbidities' that seems to be over-represented when it comes to a diagnosis of autism (see here). Idiopathic autism or ASD refers to autism as the primary diagnosis and not something tied to an existing condition where autism can also present. Non-febrile seizures are seizures without fever (where fever can very much result in seizures).

McCue et al "conducted a secondary analysis of data from a registry-based retrospective cohort study of 731 children with ASD and their 192 children unaffected siblings from the AGRE project for whom phenotypic data were collected." Data from around 320 families with at least one child diagnosed with an ASD (n=610) were compared with sibling data (n=160) in relation to the presence of non-febrile seizures. Siblings (not autism) were chosen as the control group because "siblings share, on average, fifty percent of genes as well as the same environment" so perhaps providing an alternative to just general population control groups.

Results: "The prevalence of non-febrile seizures in the ASD group was 8.2% (50/610) and 2.5% in the unaffected siblings (4/160)." What this tells us, aside from the increased frequency of non-febrile seizures in those children diagnosed with autism, is that so-called 'unaffected' siblings are not completely immune to seizures or seizure-linked conditions minus fever. Further: "the odds of having non-febrile seizures increased with age..., presence of GI [gastrointestinal] dysfunction..., and those with a history of febrile seizures had five times the odds of reporting non-febrile seizures."

I was particularly interested in the observations that: (a) gastrointestinal (GI) dysfunction, denoting functional bowel issues such as constipation or diarrhoea, were pretty well over-represented among the children with autism in this cohort, similar to other research (see here) and (b) said GI issues might itself/themselves 'up' the risk of non-febrile seizures in relation to autism. In these days of the 'gut-brain axis' where the grey/pinkish matter floating in the skull might not be totally separate and independent from the more mucus-y matter situated in the torso (see here for example), it strikes me as important that further investigations be carried out on how epilepsy might not just be a 'brain-thing'. We have for example, evidence pertinent to an autoimmune connection to some epilepsy (see here) that has implications for other autoimmune conditions affecting the gut too as per the notion that 'birds of an autoimmune feather may flock together'. That also one of the primary 'treatments' for epilepsy not responsive to the usual anti-epileptic medicines is the ketogenic diet (see here) is something else to consider when talking about gut and brain potentially being quite close neighbours.

"Our study found a five-fold higher lifetime prevalence of non-febrile seizures in children with idiopathic ASD from largely multiplex families compared to their unaffected siblings. These findings suggest that the reported non-febrile seizures may be ASD-specific and cannot be explained by genetic predisposition alone." With that conclusion from the study authors, one might similarly also suggest that the presence of autism in affected children vs. siblings also cannot be explained by genetic predisposition alone...

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[1] McCue LM. et al. Prevalence of non-febrile seizures in children with idiopathic autism spectrum disorder and their unaffected siblings: a retrospective cohort study. BMC Neurology. 2016; 16:245.

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McCue, L., Flick, L., Twyman, K., Xian, H., & Conturo, T. (2016). Prevalence of non-febrile seizures in children with idiopathic autism spectrum disorder and their unaffected siblings: a retrospective cohort study BMC Neurology, 16 (1) DOI: 10.1186/s12883-016-0764-3

'Big data' Taiwan and schizophrenia risk

Today I bring the findings reported by Chou and colleagues [1] (open-access available here) to the blogging table and how the research might of the Taiwan National Health Insurance Database (NHIRD) brought it's 'big data' ("n = 23 422 955") to bear on the question: what is the risk of developing schizophrenia where one or more first-degree or other relatives are affected?

The answer: "Having an affected co-twin, first-degree relative, second-degree relative, or spouse was associated with an adjusted RR [relative risk] (95% CI) of 37.86 (30.55-46.92), 6.30 (6.09-6.53), 2.44 (1.91-3.12), and 1.88 (1.64-2.15), respectively. Compared with the general population, individuals with one affected first-degree relative had a RR (95% CI) of 6.00 (5.79-6.22) and those with 2 or more had a RR (95% CI) of 14.66 (13.00-16.53) for schizophrenia."

To translate the science-talk: if one twin is diagnosed with schizophrenia, there is a hugely increased risk of the other twin also being affected. If a mother or father, sister or brother, or your child(ren) are diagnosed with schizophrenia, there is an enhanced risk but nothing like the risk to twins. As you move outwards to other outlying family members (uncles, aunts, grandparents, etc) affected, your risk continues to diminish albeit still noticeable. Interestingly, when it comes to spouses (husband or wife), there is a small but increased risk that if they are diagnosed with schizophrenia so the other partner is at some small, enhanced risk. This tallies with the concept of assortative mating [2] but does not necessarily rule out other shared non-genetic factors either.

The final sentence in that quote provides some evidence for a cumulative effect too. So if one of your close family members is diagnosed with schizophrenia, so the risk to yourself might be heightened. If two or more close family members are diagnosed, the relative risk to yourself jumps quite a bit more.

"A family history of schizophrenia is therefore associated with a higher risk of developing schizophrenia, mood disorders, and delusional disorders. Heritability and environmental factors each account for half of the phenotypic variance of schizophrenia."

To close, Yoda don't like seagulls...

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[1] Chou IJ. et al. Familial Aggregation and Heritability of Schizophrenia and Co-aggregation of Psychiatric Illnesses in Affected Families. Schizophr Bull. 2016 Nov 21. pii: sbw159.

[2] Parnas J. Assortative mating in schizophrenia: results from the Copenhagen High-Risk Study. Psychiatry. 1988 Feb;51(1):58-64.

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Chou IJ, Kuo CF, Huang YS, Grainge MJ, Valdes AM, See LC, Yu KH, Luo SF, Huang LS, Tseng WY, Zhang W, & Doherty M (2016). Familial Aggregation and Heritability of Schizophrenia and Co-aggregation of Psychiatric Illnesses in Affected Families. Schizophrenia bulletin PMID: 27872260

Polycystic ovary syndrome (PCOS) and risk of psychiatric disorder

"Polycystic ovary syndrome (PCOS) is an endocrine disorder affecting 5-15% of reproductive-aged women and characterized by high levels of circulating androgens."

OK, go on.

"Women with PCOS had higher risks for a range of psychiatric disorders not shown before. Elevated risk in their siblings suggests shared familial factors between PCOS and psychiatric disorders."

So said the findings reported by Carolyn Cesta and colleagues [1] who using Swedish national register data concluded that there may be something more to see when it comes to the presentation of PCOS and risk of receipt of a comorbid psychiatric label. Included under the banner of psychiatric conditions were a variety of different labels: "schizophrenia, bipolar disorder, depressive and anxiety disorders, eating disorders, personality and gender identity disorder, autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), tics, attempted and completed suicide." Personally, I'm not so sure these days that ASD should necessarily be termed a psychiatric condition but that was a decision made by the authors and I'm sure others might disagree with me.

Participant numbers for the Cesta study were in the tens of thousands as one might expect when it comes to research using the various Scandinavian registries ("all women diagnosed with PCOS between 1990 and 2013 (n = 24,385), their full-siblings (n = 25,921), plus matched individuals (1:10/100) from the general population and their full-siblings") and results were presented as odds ratios and adjusted odds ratios (AORs).

One particular part of the Cesta results stood out for me bearing in mind the primary focus of this blog: "Significantly higher AORs were found for ASD in both brothers and sisters of women with PCOS." Added to other research by Sunday Kosidou and colleagues [2] discussed on this blog (see here), these results potentially tap into some history in autism research talking about androgens and autism (minus any sweeping generalisations).

"Health professionals treating women with PCOS should be aware that these patients – as well as their family members – are important targets for mental health care." Yet again the idea that preferential screening for something like autism and other labels appears as further clues potentially emerge as to the risk factors for autism. The familial aspect to the Cesta data also provide some ideas for research directions too and I might, speculatively, suggest at least one course of future investigation (see here).

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[1] Cesta CE. et al. Polycystic ovary syndrome and psychiatric disorders: Co-morbidity and heritability in a nationwide Swedish cohort. Psychoneuroendocrinology. 2016; 73: 196-203.

[2] Kosidou K. et al. Maternal polycystic ovary syndrome and the risk of autism spectrum disorders in the offspring: a population-based nationwide study in Sweden. Mol Psychiatry. 2015 Dec 8.

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Cesta, C., Månsson, M., Palm, C., Lichtenstein, P., Iliadou, A., & Landén, M. (2016). Polycystic ovary syndrome and psychiatric disorders: Co-morbidity and heritability in a nationwide Swedish cohort Psychoneuroendocrinology, 73, 196-203 DOI: 10.1016/j.psyneuen.2016.08.005

Induced labour and autism (again)

"In this nationwide sample of live births we observed no association between induction of labor and offspring ASD [autism spectrum disorder] within sibling comparison. Our findings suggest that concern for ASD should not factor into the clinical decision about whether to induce labor."

So said the findings reported by Anna Sara Oberg and colleagues [1] supposedly providing some reassurance to mums-to-be and other groups around the likelihood of offspring autism when birth or labour has to be induced. Based on the analysis of one of those oh-so important Scandinavian health registries, researchers followed all the live births recorded in Sweden between 1992 and 2005 looking for signs that labour was induced. As per some media discussion of the study: "Methods to induce labor include rupturing of membranes, mechanical or pharmacological ripening of the cervix, and administration of oxytocin, either used alone or in combination." They also followed the cohort, numbering above a million offspring, looking for recorded diagnoses of ASD in children and, taking into account "a wide range of measured confounders" examined whether induced labour might elevate the risk of offspring ASD.

The headlines suggesting 'no link' between induced labour and offspring autism don't however actually tell the full story of these findings. When taking into account the full cohort - "1 362 950 births"- there did seem to be a slight increased risk of offspring autism associated with labour induction. This association persisted "after adjustment for measured potential confounders" albeit to an even lesser degree. The 'no link' headlines seemed to have focused on further analysis where siblings, one who was induced, one who was not, were compared with regards to autism rates: "thus accounting for all environmental and genetic factors shared by siblings, labor induction was no longer associated with offspring ASD."

I've talked about labour induction and autism risk before on this blog (see here) based on findings [2] that Oberg et al were knowledgeable about and that had reported something of an increased risk based on the analysis of over half a million births in a part of the United States. Personally, I do think there is a little more to see in this area than has hitherto been uncovered. The reasons for induction is something to focus on as per the observations that issues such as pre-eclampsia and gestational diabetes are mentioned and the body of research linking such factors to offspring autism risk (see here and see here for examples). That induction also might mean use of oxytocin (the cuddle hormone!) is something else that perhaps require further investigations too. Without trying to scaremonger, I do wonder whether further thought might be needed based on the findings reported by Leffa and colleagues [3] with oxytocin in mind.

The take-away message: induced labour is pretty unlikely to 'cause' offspring autism but beware of sweeping generalisations and media headlines...

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[1] Oberg AS. et al. Association of Labor Induction With Offspring Risk of Autism Spectrum Disorders. JAMA Pediatr. 2016. 25 July.

[2] Gregory SG. et al. Association of autism with induced or augmented childbirth in North Carolina Birth Record (1990-1998) and Education Research (1997-2007) databases. JAMA Pediatr. 2013 Oct;167(10):959-66.

[3] Leffa DD. et al. DNA damage after chronic oxytocin administration in rats: a safety yellow light? Metab Brain Dis. 2016 Aug 3.

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Oberg, A., D’Onofrio, B., Rickert, M., Hernandez-Diaz, S., Ecker, J., Almqvist, C., Larsson, H., Lichtenstein, P., & Bateman, B. (2016). Association of Labor Induction With Offspring Risk of Autism Spectrum Disorders JAMA Pediatrics DOI: 10.1001/jamapediatrics.2016.0965

Epilepsy begets autism?

"Individuals with epilepsy are at increased risk of ASD [autism spectrum disorder], especially if epilepsy appears in childhood. Further, ASD is more common in the siblings and offspring of individuals with epilepsy, suggesting shared etiology."

That was the research bottom-line from Heléne Sundelin and colleagues [1] reporting results based on examination of the "Swedish Patient Register" with regards to the "risk of autism spectrum disorder (ASD) in individuals with epilepsy and in their first-degree relatives." Including one Jonas F. Ludvigsson, PhD on the authorship list (yes, he of 'gluten and autism: probably not coeliac disease but...' fame), researchers identified some 85,000 individuals diagnosed with epilepsy "as well as all their siblings (n = 80,511) and offspring (n = 98,534)." With some nifty statistical analysis including matching cases 5:1 with control participant data, they were able to conclude that around 1.6% of those with epilepsy were diagnosed with an ASD compared with 0.2% of controls. Those percentages are seemingly quite small both in real terms and also in differences between the groups but given the huge participant numbers included for study came out with a hazard ratio (HR) around 10.49 "confidence interval [CI] 9.55–11.53)." To put that HR of 10.49 in context, other work by Ludvigsson on epilepsy coinciding with coeliac disease for example, with a participant number in the tens of thousands came out with a HR of 1.42.

When also looking at what happened to siblings and offspring of those diagnosed with epilepsy, the authors also observed something of a potentially increased risk of autism being also diagnosed, although quite a bit less than risk to those themselves diagnosed with epilepsy. The results did however suggest that: "The risk in the offspring was particularly high in mothers with epilepsy." And just for good measure, the Sundelin results also noted that risk of epilepsy was "also associated with a prior diagnosis of ASD" confirming what many others have reported over the years (see here).

Although making some headlines I wasn't particularly shocked by the bi-directional associations reported by Sundelin and colleagues. Quite a few times on this blog I've talked about autistic features being potentially over-represented in cases of epilepsy (see here and see here) so to see some of those features crossing diagnostic thresholds into an actual autism diagnosis is perhaps not unsurprising. Continuing that line of thought I do wonder what might happen if the broader autism phenotype (BAP) was also analysed with epilepsy in mind (even the new DSM-5 categorisation of social communication disorder?)

Insofar as the hows and whys of the association between epilepsy and autism, well, we're still in guessing mode at the current time. I've talked about some of the various genetic syndromes that tend to include autism and epilepsy together as a diagnostic package (see here) as evidence for the more plural 'autisms'. Such syndromes suggest that mechanisms linking the two conditions are likely to be multiple and not necessarily the same for everyone. The issue of GABA and autism might also show some connection in some cases as per what is starting to be known about this neurotransmitter (see here) and where it might fit with some autism (see here) on top of epilepsy. Assuming also that epilepsy in pregnant mothers for example is being managed by medication, it is also not outside of the realms of possibility that certain preparations could also exert an effect on offspring autism risk (see here). I say this with no scaremongering intended.

I might also (speculatively) advance the idea that another research area might also be a connecting feature for some autism and some epilepsy: diet. Don't just click away yet as I will first bring your attention to the increasing peer-reviewed literature talking about the use of a ketogenic diet and autism (see here); said dietary intervention more typically indicated in 'some' cases of epilepsy. It's still early days but it strikes me that quite a bit more research is required in this area. Allied to the use of a ketogenic diet (see here) and also perhaps linking back to that other important research area frequently examined by Dr Ludvigsson (coeliac disease) I'm also inclined to ask whether some autism and some epilepsy might show a more specific connection to dietary gluten too. No, I'm not saying that a gluten-free diet nor a ketogenic diet is some sort of 'cure-all' for autism and epilepsy (please don't mess with epilepsy) but rather there may be overlapping genetics or biology potentially linked to facets of gluten metabolism that might be important for some on the autism spectrum with epilepsy. Certainly much more research on this and other less-traditional areas is indicated [2].

There are many questions that remain unanswered in this area of research. With regards to the here and now, well, the Sundelin and other data perhaps suggest that as and when epilepsy is diagnosed, preferential screening for autism could and should be offered particularly in infancy; and perhaps even offered family wide.

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[1] Sundelin HEK. et al. Autism and epilepsy: A population-based nationwide cohort study. Neurology. 2016. June 15.

[2] Frye RE. et al. A review of traditional and novel treatments for seizures in autism spectrum disorder: findings from a systematic review and expert panel. Front Public Health. 2013 Sep 13;1:31.

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Sundelin, H., Larsson, H., Lichtenstein, P., Almqvist, C., Hultman, C., Tomson, T., & Ludvigsson, J. (2016). Autism and epilepsy Neurology DOI: 10.1212/WNL.0000000000002836

Siblings of probands with autism: preferential screening suggested?

"Psychiatric and neurodevelopmental disorders cluster among siblings of probands with ASD [autism spectrum disorder]."

That was the research bottom line presented in the paper by Elina Jokiranta-Olkoniemi and colleagues [1] who extracted data from the Finnish Prenatal Study of Autism and Autism Spectrum Disorders (FIPS-A). FIPS-A has been mentioned previously on this blog (see here) but this time around the aim was to look not at the various risk factors potentially associated with receipt of an autism diagnosis, but rather how siblings of those with autism might require some preferential screening for a variety of potential psychiatric and/or neurodevelopmental labels. I know that might not make great reading but burying ones head in the sand is not likely to do anyone any good.

With a starting participant sample in the thousands - "31, 2005, who received a diagnosis of ASD" - researchers matched cases with asymptomatic (not autism) controls to a ratio of 4:1. "This nested case-control study included 3578 cases with ASD with 6022 full siblings and 11 775 controls with 22 127 siblings from Finnish national registers." Various psychiatric and behavioural diagnoses were searched for among siblings of those with autism and compared with rates among control participant siblings. An adjusted risk ratio was generated; authors also taking into account the various ASD sub-diagnoses (many of which have been subsumed under the latest DSM-5 definition of autism).

Results: as per the opening sentence, siblings of those diagnosed with autism were at a significantly increased risk of various psychiatric and neurodevelopmental outcomes. Around 10% of siblings of those with autism were diagnosed with an ASD tallying with what has been previously reported in the peer-reviewed literature on familial recurrence (see here). This compared with the similarly standard 1% of siblings of asymptomatic controls who were diagnosed with an ASD. Actually, 1% might not be the standard any longer...

Other associations were also noted; so learning and coordination disorders were reported in around 15% of siblings of those with autism compared with 6% in control siblings. Similar patterns were noted with regards to attention-deficit hyperactivity disorder (ADHD) and interestingly, tic disorders too (a particular interest to this blog). The bottom line again being that siblings of those with autism might have something of an increased risk of receiving various developmental or behavioural diagnoses.

The authors conclude that when it comes to discussions about aetiology, there may be some common risk factors that predispose to the various labels included for study. Of course this is not necessarily new news as per other research looking at 'overlapping' structural genetics for example (see here) and the realisation that a diagnosis of autism is by no means protective against other conditions occurring (see here). Indeed, other research published in the same journal hints at some important genetic overlap when it comes to autism and other diagnoses [2] which may be particularly relevant (see here). If there is anything that I would add to any future research agenda it would be some way of incorporating the concept of the broader autism phenotype (BAP) into proceedings (see here) and also the inclusion of more somatic diagnoses (see here) as well as neurodevelopmental and psychiatric as a means to search for overlapping variables. As for clinical practice, well to reiterate again, the implication is to potentially offer preferential screening for a variety of neurodevelopmental and/or psychiatric labels when autism appears in the family...

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[1] Jokiranta-Olkoniemi E. et al. Risk of Psychiatric and Neurodevelopmental Disorders Among Siblings of Probands With Autism Spectrum Disorders. JAMA Psychiatry. 2016. May 4.

[2] Goes FS. et al. Exome Sequencing of Familial Bipolar Disorder. JAMA Psychiatry. 2016. April 27.

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Jokiranta-Olkoniemi, E., Cheslack-Postava, K., Sucksdorff, D., Suominen, A., Gyllenberg, D., Chudal, R., Leivonen, S., Gissler, M., Brown, A., & Sourander, A. (2016). Risk of Psychiatric and Neurodevelopmental Disorders Among Siblings of Probands With Autism Spectrum Disorders JAMA Psychiatry DOI: 10.1001/jamapsychiatry.2016.0495