Premature mortality in intellectual disability in Australia (and England)

"Adults with ID [intellectual disability] experience premature mortality and over-representation of potentially avoidable deaths."

The paper by Julian Trollor and colleagues [1] (open-access available here) provides some sombre reading today, as once again the topic of early mortality is raised on this blog. Looking at several measures - the "Age Standardised Mortality Rate (ASMR), Comparative Mortality Figure (CMF), years of productive life lost (YPLL) and proportion of deaths with potentially avoidable causes" - authors paint a depressing picture of a 'mortality gap' between those diagnosed with a learning (intellectual) disability and the wider, general population.

I don't want to trawl through the Trollor paper in great detail given that it is open-access for all to see, but a few points are worthwhile raising. So, based on data from some 20,000 adults (aged 20 or over) registered with an intellectual disability (ID) in New South Wales (NSW) in Oz, there were 732 deaths reported (4%) "equivalent to a crude death rate of 5.9 deaths per 1000 people per year." The median age at death was 54 years and about 60% of deaths were in men. A control cohort consisting of adults from NSW was used as a comparator where "a crude death rate of 9.1 deaths per 1000 person years" was calculated. The median age at death however, for the control group, was 81 years. When looking at death rates between the groups according to age banding (20-44 years, 45-64 years, 65+ years) authors noted that: "People with ID in the 20–44 years age category had four times the death rate of the comparison group."

Looking at the causes of death between the ID and control groups, authors noted some potentially important trends. So: "Cause of death in [the] ID cohort was dominated by respiratory, circulatory, neoplasm and nervous system." This bearing in mind that cause of death was not available for everyone diagnosed with an ID (only 87%). Such causes were not wildly different from those noted in the control population but when it came to 'potentially avoidable deaths' the ID group were placed at some quite notable disadvantage, with 31% of deaths falling into this category (revised up to 38% depending on the 'death classification' used) compared with 17% in the general population. Readers should also note that: "Potentially avoidable deaths are deaths from conditions that are preventable through individualised care and/or treatable through existing primary or hospital care for persons aged under 75 years and which are avoidable in the context of the present health system."

As you can see, there are some quite shocking details noted in the Trollor paper. The emerging picture that some of the most vulnerable people in society (certainly in Australia) are (a) at risk of dying earlier than the general population and (b) at greater risk of suffering a 'potentially avoidable death' is one that no-one should be proud of. And just in case you though the results might not be generalisable to other parts of the world... you're wrong [2] (open-access here) as data from England reveals that: "Mortality rates for people with ID were significantly higher than for those without. Their all-cause standardised mortality ratio was 3.18. Their life expectancy at birth was 19.7 years lower than for people without ID." Truly shocking.

What can society do about such a state of affairs? Well, potentially lots (and it doesn't take monumental shifts to achieve better outcomes either). "Particularly stark is the large proportion of
potentially avoidable deaths due to infections. Such deaths suggest that people with ID experience delays, difficulties or differences in accessing specific and effective interventions for infections. Medical assistance must be sought assertively in individuals who manifest symptoms, but this is made difficult as patients with ID may not readily report symptoms, and some providing direct care
lack skills in early identification of relevant physical signs. Primary care providers should consider careful assessment, proactive treatment and close monitoring of progress if there are infections in this population." Sorry for the large chunk of replication text there but several important themes are laid out by Trollor, some of which overlap with other work in relation to autism for example (see here). Not least is the need for 'proactivity' on the part of clinicians and other professionals, potentially dealing with a group who may not be able to readily communicate their physical state for example and so shifting the responsibility on medical care being inspective and proactive. This means regular health screening and, at the basic level, understanding that a diagnosis of ID (or autism or schizophrenia [3]) does not seemingly provide any protection against the development of life-threatening illness or other conditions becoming evident.

I close with an article discussing another part of the reason why people with ID are being placed at an unacceptably high risk of early death: when those who are supposed to provide care, fail.

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[1] Trollor J. et al. Cause of death and potentially avoidable deaths in Australian adults with intellectual disability using retrospective linked data. BMJ Open. 2017. Feb 7.

[2] Glover G. et al. Mortality in people with intellectual disabilities in England. J Intellect Disabil Res. 2017 Jan;61(1):62-74.

[3] Hjorthøj C. et al. Years of potential life lost and life expectancy in schizophrenia: a systematic review and meta-analysis. Lancet Psychiatry. 2017 Feb 22. pii: S2215-0366(17)30078-0.

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Trollor J, Srasuebkul P, Xu H, & Howlett S (2017). Cause of death and potentially avoidable deaths in Australian adults with intellectual disability using retrospective linked data. BMJ open, 7 (2) PMID: 28179413

Low muscle tone and autistic traits

"This large study showed a prospective association of infant muscle tone with autistic traits in childhood."

So said the findings reported by Fadila Serdarevic and colleagues [1] who, looking at nearly 3000 children, were able to assess early motor development and muscle tone "between ages 2 and 5 months" and later parental ratings of autistic traits in children at 6 years of age. Said autistic traits were surveyed using the "the Social Responsiveness Scale (SRS) and the Pervasive Developmental Problems (PDP) subscale of the Child Behavior Checklist." Authors concluded that there was something of a connection between low muscle tone and autistic traits: "Low muscle tone in infancy predicted autistic traits measured by SRS... and PDP" and further: "early detection of low muscle tone might be a gateway to improve early diagnosis of ASD [autism spectrum disorder]."

Just before anyone gets ahead of themselves with this data, it is worth pointing out that despite the large participant group included for study and the prospective nature of the study design, this was a study only really looking at two sets of variables across quite a long time-frame. It's not beyond the realms of possibility that other factors might influence the presentation of [parent-reported] autistic traits outside of just early measures of muscle tone or anything related...

But let's set this research in some context. Muscle tone in a broader sense had been noted to be potentially 'linked' to autism in some of the earliest texts on the topic (see here). More recent discussions on how motor skill in the context of gait for example, might be something important to at least some autism (see here) add to the relevance. One might also look to the some of the typical reasons why low muscle tone (hypotonia) may present to see whether there are areas that could inform autism research too. I note for example, mention of Ehlers-Danlos syndrome (EDS) in some of the texts and this would perhaps appeal to further investigation on any overlap between EDS (or other connective tissues disorders) and autism (see here). Serious infections such as encephalitis and meningitis have also been mentioned in the context of hypotonia, and again, might be indicated in relation to hypotonia and some autism (see here). There is also a possibility that hypotonia could (in some cases) be tied into mitochondrial disease; something else that could be relevant to at least some 'types' of autism (see here). All of these areas are worthy of further research inspection added to the idea that muscle tone might be rather more core to autism than many people might appreciate.

'And the best picture goes to'...

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[1] Serdarevic F. et al. Infant muscle tone and childhood autistic traits: A longitudinal study in the general population. Autism Res. 2017 Feb 9.

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Serdarevic F, Ghassabian A, van Batenburg-Eddes T, White T, Blanken LM, Jaddoe VW, Verhulst FC, & Tiemeier H (2017). Infant muscle tone and childhood autistic traits: A longitudinal study in the general population. Autism research : official journal of the International Society for Autism Research PMID: 28181411

1 in 5 children "met criteria for low language at 7 years"

Although primarily looking at the potential predictors of language outcome, the study results published by Cristina McKean and colleagues [1] revealed the rather important title heading this blog entry: "Almost 19% of children (22/1204;18.9%) met criteria for low language at 7 years."

The source of the finding was a cohort of some 1900 infants "recruited at age 8 to 10 months" who were followed until aged 7 years old and subject to quite a bit of research inspection looking at "early life factors", maternal factors and "child language ability" at various points through the childhood years. I believe this was part of the The Early Language in Victoria Study (ELVS) initiative; something that has previously created a bit of stir in speech and language circles. The authors reported that alongside the quite high percentage of children who met 'low language' criteria (based on standardized receptive or expressive language scores "≥1.25 SD below the mean"): "Child language ability at 4 years more accurately predicted low language at 7 than a range of early child, family, and environmental factors." Said low language abilities at 7 years old were also "associated with a higher prevalence of co-occurring difficulties."

Aside from pointing out that language ability at 4 years old might be quite important to language ability at 7 years old, the question that should be in most people's minds is 'why?' Why are nearly 1 in 5 children presenting with low language ability at 7 years old (and presumably at 4 years old too)? Yes, there are variables such as adverse early life factors (prematurity, birth weight, coming from a non-English speaking background, etc) that will no doubt influence various aspects of language ability, but the authors note that such factors only account for roughly 15% at most of the variation in language scores seen in their cohort (not including "child language scores at ages 2 and 4"). Ergo, there are other factors involved with regards to these findings.

In light of the McKean findings, I'm also going to draw your attention back to another occasion when language ability has been discussed on this blog (see here) and specifically: "At school entry, approximately two children in every class of 30 pupils will experience language disorder severe enough to hinder academic progress." [2] Low language (ability) is not necessarily the same as a diagnosed language disorder, and probably accounts for the variation between the studies (1 in 5 vs. 1 in 15). But in amongst a spectrum of language ability (disorder?) the questions about 'why?' still very much remain (and please, no sweeping generalisations about us 'just being better at diagnosing').

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[1] McKean C. et al. Language Outcomes at 7 Years: Early Predictors and Co-Occurring Difficulties. Pediatrics. 2017 Feb 8. pii: e20161684.

[2] Norbury CF. et al. The impact of nonverbal ability on prevalence and clinical presentation of language disorder: evidence from a population study. Journal of Child Psychology and Psychiatry. 2016. May 16.

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McKean C, Reilly S, Bavin EL, Bretherton L, Cini E, Conway L, Cook F, Eadie P, Prior M, Wake M, & Mensah F (2017). Language Outcomes at 7 Years: Early Predictors and Co-Occurring Difficulties. Pediatrics PMID: 28179482

Say my name

"At 9 months of age, infants developing ASD [autism spectrum disorder] were more likely to fail to orient to their names, persisting through 24 months."

So said the findings reported by Meghan Miller and colleagues [1] investigating an often over-looked but typically informative question relevant to childhood autism screening and assessment: the response to name. Anyone who knows a little about instruments such as the ADOS (Autism Diagnostic Observation Schedule) will already know about the importance of response to name ("a full response is defined as orientating to and making eye contact with the examiner who calls his name") as part of assessment.

Based on the inclusion of some 150 infants, siblings of children with or without a diagnosis of autism, a response to name task was carried out at various intervals in infancy in this prospective study ("6, 9, 12, 15, 18, and 24 months of age"). At 3 years of age, child participants were "classified into 1 of 3 outcome groups: group with ASD (n = 20), high-risk group without ASD (n = 76), or low-risk group without ASD (n = 60)." As per the opening sentence, consistently not responding to their name was a feature of quite a few of those children who subsequently went on to develop autism. Some but not all. Alongside other findings reported in relation to receptive language for example, the authors concluded: "Infants who consistently fail to respond to their names in the second year of life may be at risk not only for ASD but also for greater impairment by age 3 years."

Such work continues a theme from some of the authors on the Miller paper [2] and how relatively simple observations during play interaction [3], could be valuable variables when it comes to ascertaining potential risk of developing autism. Of course one needs to be careful that a lack of response to name does not automatically mean that an autism diagnosis is imminent or indicated as per the typical requirement to check a child's hearing for example and to consider the possibility of other diagnoses being applicable. I might also remind readers of the potential effects of regression when it comes to autism (see here) and how not every child presents with autistic features in early infancy (something that needs to be taken into account when it comes to other recent research too).

To close, say my name...

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[1] Miller M. et al. Response to Name in Infants Developing Autism Spectrum Disorder: A Prospective Study. J Pediatr. 2017 Feb 2. pii: S0022-3476(16)31566-9.

[2] Nadig AS. et al. A prospective study of response to name in infants at risk for autism. Arch Pediatr Adolesc Med. 2007 Apr;161(4):378-83.

[3] Trillingsgaard A. et al. What distinguishes autism spectrum disorders from other developmental disorders before the age of four years? Eur Child Adolesc Psychiatry. 2005 Mar;14(2):65-72.

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Miller M, Iosif AM, Hill M, Young GS, Schwichtenberg AJ, & Ozonoff S (2017). Response to Name in Infants Developing Autism Spectrum Disorder: A Prospective Study. The Journal of pediatrics PMID: 28162768

"Autoimmune epilepsy is an underrecognized condition..."

"Among adult patients with epilepsy of unknown etiology, a significant minority had detectable serum Abs [autoantibodies] suggesting an autoimmune etiology."

So said the findings reported by Divyanshu Dubey and colleagues [1] continuing a research theme previously discussed on this blog (see here) on how epilepsy / seizure-type disorder(s) for some might have more to do with immune function than many people might think.

OK, a brief bit of background: epilepsy is a blanket term covering a wide variety of different presentations that affect the brain and specifically, 'the electrics' of the brain. Seizures are the most common symptom. Treatment typically comes in the form of anti-epileptic medicines (although other options are being considered for some). It's been known for a while that outside of the 'brain' focus of epilepsy, other biological systems might also play a role in the development/maintenance of the condition(s); specifically the immune system and quite often in cases where traditional anti-epileptic medicines don't seem to be able to control seizures effectively. The details are still a little sketchy but studies like the one from Dubey et al are trying to put some scientific flesh on to the bones of what facets of the immune system are potentially involved, specifically under 'autoimmune' conditions where the body fails to recognise 'self' as self and mounts an immune response against the body's own tissue(s).

Dubey and colleagues looked at a group of participants "presenting to neurology services with new-onset epilepsy or established epilepsy of unknown etiology" and tested donated serum samples "for Abs reported to be associated with autoimmune epilepsy (NMDAR-Ab, VGKCc-Ab, leucine-rich glioma-inactivated protein 1 [LGI1] Ab, GAD65-Ab, γ-aminobutyric acid type B receptor [GABAB] Ab, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor [AMPAR] Ab, antineuronal nuclear antibody type 1 [ANNA-1 or anti-Hu] Ab, Purkinje cell cytoplasmic antibody type 2 [PCA-2] Ab, amphiphysin Ab, collapsin-response mediator protein 5 [CRMP-5] Ab, and thyroperoxidase [TPO] Ab)." Quite a lot of those autoantibodies probably sound like gibberish to the lay reader but some of them have been discussed in other contexts on this blog (see here and see here for examples).

Results: some (15) of the 127 participants initially enrolled in the study were "subsequently excluded after identification of an alternative diagnosis." This in itself is interesting, as diagnoses such as "hypoxic or anoxic injury following cardiac arrest" and "ischemic stroke" are mentioned, illustrating how several different roads can lead to epilepsy and/or the presentation of seizures.

Then: "Serum Abs suggesting a potential autoimmune etiology were detected in 39 (34.8%) cases." Over a third of the cohort showed serological evidence of autoantibodies and some presented with more than one type of autoantibody as being present. Breaking down those serologically positive participants, we are told that: "19 patients (48.7%) had new-onset epilepsy and 20 patients (51.3%) had established epilepsy." The authors did also subsequently limit their findings to those cases excluding TPO-Ab and low-titer GAD65-Ab (autoantibodies where a specific role to epilepsy is unclear or not specific) but even then reported that: "23 patients (20.5%) with unexplained epilepsy had positive serologic findings strongly suggestive of an autoimmune cause of epilepsy." There is also a final part to the Dubey paper which also merits mention: "Among the 23 patients who were seropositive, 15 (65.2%) received some sort of immunotherapy. Better seizure outcome was associated with use of immunomodulatory therapy... especially with use of intravenous methylprednisolone... or plasmapheresis."

Alongside other (independent) studies in this area, the peer-reviewed evidence does seem to growing to suggest that within the wide (and heterogeneous) 'spectrum' that is epilepsy, at least some of that epilepsy might have an important immune component to it. To quote again from Dubey: "The data presented here suggest that autoimmune encephalitis may explain at least 20% of adult-onset epilepsies of unknown etiology." Aside from the importance of screening for said autoantibodies when certain cases of epilepsy appear at clinic, there are a few other potentially important points that could be raised about such data. Autism is area that I would be interested to see some further investigations carried out on with the Dubey findings in mind. Epilepsy is an important comorbidity 'over-represented' when it comes to autism (see here) and given the suggestions down the years that immune function (specifically autoimmunity) might be a facet of 'some' autism (see here for example) it's not beyond the realms of possibility that comorbid epilepsy might be a further facet of any autoimmune processes. Birds of an autoimmune feather tend to stick together and all that (see here). Add in the findings specifically talking about 'anti-NMDA-receptor encephalitis "mimicking an autistic regression"' (see here) and how methlyprednisolone might not be an uncommon medicine for some types of (autoimmune-related autistic presentation) and the hypotheses to be tested are laid out in front of you. By saying that, I don't want to take anything away from the more typical forms of epilepsy that can present (either alone or alongside autism) but rather point to the expanding knowledge base suggesting that immune functions may extend much further than just protecting the host from infection et al...

To close, slightly related to some of the content included in this post, the trailer for the film Brain on Fire (from the book of the same name) is out and looking like required viewing.

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[1] Dubey D. et al. Neurological Autoantibody Prevalence in Epilepsy of Unknown Etiology. JAMA Neurol. 2017 Feb 6.

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Dubey D, Alqallaf A, Hays R, Freeman M, Chen K, Ding K, Agostini M, & Vernino S (2017). Neurological Autoantibody Prevalence in Epilepsy of Unknown Etiology. JAMA neurology PMID: 28166327

History of bipolar disorder = elevated risk of dementia: is vitamin D important?

"History of BD [bipolar disorder] is associated with significantly higher risk of dementia in older adults."

So said the systematic review and meta-analysis published by Breno Diniz and colleagues [1] taking in the accumulated peer-reviewed literature on this topic. Including data for some 3000 individuals diagnosed with bipolar disorder and nearly 200,000 controls (without bipolar disorder), authors calculated something of a significantly higher risk of dementia in those with a documented history of bipolar disorder. They note that there is more research to do in this area, specifically on mechanisms and "to evaluate interventions that may reduce the risk of dementia in this population."

Outside of the literature included in the Diniz study, similar findings have been reported in the science literature. The paper by Almeida and colleagues [2] noted that: "Bipolar disorder in later life is associated with increased risk of dementia" based on their analysis of ~38,000 older men (65-85 years old) and their "13-year risk of dementia." Perhaps more worryingly were their findings that: "Bipolar disorder was also associated with increased mortality" in relation to "death by suicide, accidents, pneumonia or influenza, and diseases of the liver and digestive system." Other data looking more generally at clinical depression paints a similar picture [3] suggesting something of a connection between various types of depression and risk of various types of dementia: "depressive symptomatology is associated with pathological mechanisms associated with neurodegeneration."

I've tackled the topic of dementia a couple of times on this blog; most recently in relation to how incidental vitamin D deficiency *could be* something important when it comes to at least some cases of dementia (see here). Minus any sweeping generalisations and accepting that there may be many different roads leading to dementia and/or bipolar disorder, I am intrigued at the possibility that the sunshine vitamin might be something to consider as a 'connector' between elements of the depression and dementia spectrums as per other findings (see here for example). At the very least, it invites lots more targeted investigation, including whether vitamin D might indeed be a nootropic of choice for some (see here)...

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[1] Diniz BS. et al. History of Bipolar Disorder and the Risk of Dementia: A Systematic Review and Meta-Analysis. The American Journal of Geriatric Psychiatry. 2017. Jan 4.

[2] Almeida OP. et al. Risk of dementia and death in community-dwelling older men with bipolar disorder. Br J Psychiatry. 2016 Aug;209(2):121-6.

[3] Cherbuin N. et al. Dementia risk estimates associated with measures of depression: a systematic review and meta-analysis. BMJ Open. 2015 Dec 21;5(12):e008853.

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Diniz BS, Teixeira AL, Cao F, Gildengers A, Soares JC, Butters MA, & Reynolds CF 3rd (2017). History of Bipolar Disorder and the Risk of Dementia: A Systematic Review and Meta-Analysis. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry PMID: 28161155

Neuropsychiatric disorder onset "temporally related to prior vaccinations"?

"Given the modest magnitude of these findings in contrast to the clear public health benefits of the timely administration of vaccines in preventing mortality and morbidity in childhood infectious diseases, we encourage families to maintain vaccination schedules according to CDC guidelines."

The quote opening this post comes from the paper published by Douglas Leslie and colleagues [1] (open-access) and offers not a conclusion from their study looking at the possibility that "the onset of some neuropsychiatric disorders may be temporally related to prior vaccinations in a subset of individuals" but a caution that cause-and-effect were not 'proven' in their study. Anyone with any knowledge about previous occasions where administration of vaccines have been correlated with specific psychiatric or behavioural outcomes (see here and see here for examples) will recognise how important such a caution is, bearing in mind that vaccines are medicines (albeit preventative) and are subject to similar monitoring for safety and the small possibility of adverse effects as other medicines.

Based on the examination of "the MarketScan® Commercial Claims and Encounters database", a US drug and medical insurance claims database, researchers looked at various diagnoses of interest including OCD (obsessive compulsive disorder), AN (anorexia nervosa), anxiety disorder, tic disorder, major depression, bipolar disorder and ADHD (attention-deficit hyperactivity disorder) in children/young adults aged 6-15 years old. This alongside several other classes of diagnosis including broken bones and 'open wounds'. Participants were matched one-to-one with controls without said neuropsychiatric diagnoses and exposure(s) to various vaccinations - "influenza, tetanus and diphtheria (TD), hepatitis A, hepatitis B, meningitis, and varicella" - were 'tracked'. Interestingly, this is not the lead authors' first foray into using the MarketScan database [2], where autism was the previous topic of analysis (specifically healthcare service use and costs).

Results: bearing in mind that samples sizes varied according to those diagnoses under investigation, the authors report: "Receipt of any vaccine in the previous 6 months was highest for children with AN (21.4%), followed by OCD (15.9%) and tic disorder (15.8%), and was lowest for children with open wounds (10.3%)." This information needs to be treated carefully because - again - it tells us nothing about any cause-and-effect relationship, just correlation and trend; trends that could be there for all-manner of different reasons outside of the variables looked at. Further: "HRs [hazard ratio] associated with receipt of any vaccine were highest for children with AN... followed by OCD."

The authors also looked at specific vaccinations in relation to those neuropsychiatric disorders included in their study. They report: "Influenza vaccinations during the prior 3, 6, and 12 months were... associated with incident diagnoses of AN, OCD, and an anxiety disorder." Conversely: "children with major depression were less likely to have received the influenza vaccine in the previous 3 months" and "children with bipolar disorder were also less likely to have received the influenza vaccine in the previous 3 or 6 months."

OK, it is worth reiterating - yet again - that this was a study looking at possible associations and not necessarily cause-and-effect. Indeed, judging by that last paragraph and the table of HRs produced by the authors (see here) one might easily claim that flu vaccination might potentially shield someone from developing major depression as much as 'cause' AN, OCD and/or anxiety disorder. Such is the nature of such studies and the findings being reported. And indeed someone has actually looked at depressive symptoms (symptoms that is, not depression as a clinical diagnosis) before and after an influenza vaccination and found very little...

I note that with specific regard to the influenza vaccine and the findings that "children with AN, OCD, or a tic disorder were more likely to have received the influenza vaccine in the preceding periods" the authors head into the research talking about narcolepsy and the "AS03-adjuvanted H1N1 vaccine" as a possible template for their findings. This despite not covering the diagnosis of narcolepsy in their study (they could have). I've touched upon this area of research before on this blog (see here) (something that continues to appear in media discussions) and whilst not disputing the findings, do for example, wonder why in the work of Szakács and colleagues [3] ADHD was picked up as a comorbidity present in their "post-H1N1 vaccination (PHV) narcolepsy group" but in the Leslie data the HRs showed little evidence of any relationship. Yes, H1N1 vaccination is not necessarily the same as influenza vaccination reported in the Leslie data (we don't actually know what specific influenza vaccines were administered), but surely if discussions turn to an 'autoimmune' element as a possible mechanistic feature potentially linking vaccination and [some] neuropsychiatric disorder(s), one would expect to see the same/similar pattern of conditions being represented and reported? For balance, I should also point out that other independent study has talked about eating disorders potentially having "immune-mediated mechanisms" connected, particularly those associated with autoimmunity [4] although I don't doubt such a connection is likely complicated and probably not universally applicable.

It's not difficult to find issues with the Leslie paper and no doubt these will be emphasised in any further discussions about the data reported even when the authors stress throughout that "findings do not demonstrate a causal role of vaccination in the pathoetiology of any of these conditions." The strengths of the data - e.g. the use of that administrative database for confirming diagnoses and vaccine exposure - are worth mentioning again in light of other debates on data sources from other 'disappearing' manuscripts in this area. I might also add that by focusing in on various diagnoses but not autism (which again, they could have done) and not a certain vaccine, the authors seem well aware of the history in this area - "the association of the measles, mumps, and rubella vaccine with autism spectrum disorder has been convincingly disproven" - and probably either thought nothing more of it or chose to steer well clear of it (or perhaps a combination of both).

Is there a 'where next' when it comes to the Leslie data? To quote again from the paper: "findings require replication in a larger population-based sample, possibly including assessments of various potentially important host factors, e.g., the individual’s genomic and epigenomic background, the individual’s microbiome, their history of antecedent psychosocial stress, infections, as well as other potentially simultaneously administered vaccinations, the differences in vaccine types, and the route of administration (e.g., intramuscular or intranasal administration of influenza vaccine)." The scientific literature also provides some other avenues for further study in this area [5]. But science does not happen in a social vacuum; any further research needs to be done with care and focus. Mindful of both the important reliance on vaccination in protecting both the individual and population at large and mindful that sweeping generalisations (often emanating from scientific study) need to be minimised.

And on the topic of the research of Douglas Leslie, I'll be coming to another recent paper he published on the important issue of depression in parents of children diagnosed with autism [6] quite soon...

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[1] Leslie DL. et al. Temporal Association of Certain Neuropsychiatric Disorders Following Vaccination of Children and Adolescents: A Pilot Case-Control Study. Front Psychiatry. 2017 Jan 19;8:3.

[2] Wang L. et al. Healthcare Service Use and Costs for Autism Spectrum Disorder: A Comparison Between Medicaid and Private Insurance. Journal of autism and developmental disorders. 2013;43(5):1057-1064.

[3] Szakács A. et al. Psychiatric comorbidity and cognitive profile in children with narcolepsy with or without association to the H1N1 influenza vaccination. Sleep. 2015 Apr 1;38(4):615-21.

[4] Raevuori A. et al. The increased risk for autoimmune diseases in patients with eating disorders. PLoS One. 2014 Aug 22;9(8):e104845.

[5] Sadarangani SP. et al. "Let there be light": the role of vitamin D in the immune response to vaccines. Expert Rev Vaccines. 2015;14(11):1427-40.

[6] Cohrs AC. & Leslie DL. Depression in Parents of Children Diagnosed with Autism Spectrum Disorder: A Claims-Based Analysis. J Autism Dev Disord. 2017 Feb 18.

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Leslie DL, Kobre RA, Richmand BJ, Aktan Guloksuz S, & Leckman JF (2017). Temporal Association of Certain Neuropsychiatric Disorders Following Vaccination of Children and Adolescents: A Pilot Case-Control Study. Frontiers in psychiatry, 8 PMID: 28154539

Catatonic symptoms and autism

"Catatonic symptoms are more prevalent in young people with autism than previously thought" said the article recently published by Breen and Hare [1]. Continuing a research theme of at least one of the authors [2], the idea that catatonic symptoms - primarily manifesting as stupor, unresponsiveness to light, noise or touch, mutism, etc - might be over-represented when it comes to autism is not a new one by any means.

Breen & Hare set about looking for "the presence and nature of such attenuated behaviours in children and adolescents with autism" based on something called the Attenuated Behaviour Questionnaire. This was delivered to parents/caregivers online alongside looking at information from other measures based on the presence of repetitive behaviour and depression.

"Attenuated behaviour indicative of catatonia was relatively common in young people with autism with up to 20.2% having an existing diagnosis of catatonia and evidence of a relationship between attenuated behaviours and measures of depression and repetitive and restricted behaviours." Such findings as I said, are by no means novel but once again highlight how a diagnosis of autism or autism spectrum disorder (ASD) is seemingly protective of nothing when it comes to comorbidity. To quote another author on this topic: "an unabashed drumroll for increased recognition and treatment of catatonia in autism spectrum disorders (ASD)" [3] is needed.

Catatonia appearing alongside [some] autism leads into a number of areas in relation to the 'closeness' of any relationship (some people have talked about 'autistic catatonia') and the management strategies that may be subsequently indicated. On the issue of management, guidance is available [4] albeit including a strategy - electroconvulsive therapy (ECT) - that is probably not going to win any awards in terms of popularity given its historical basis. Accepting that still today ECT as an 'intervention' option when it comes to autism still courts heated discussion (see here), there is the requirement for much greater study of catatonic symptoms in relation to autism and whether there may be several presentations ripe for more novel intervention [5] (in light of a growing area of research interest). Said intervention might also take into account the plurality of autism too (see here)...

To close, yet another song for my brood and a very proud father who saw some real talent in the karate competition yesterday (those first place trophies are proof that team kata and team kumite are definitely the way forward)...

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[1] Breen J. & Hare DJ. The nature and prevalence of catatonic symptoms in young people with autism. J Intellect Disabil Res. 2017 Feb 1.

[2] Hare DJ. & Malone C. Catatonia and Autistic Spectrum Disorders. Autism. 2004; 8: 183-195.

[3] Dhossche DM. Decalogue of Catatonia in Autism Spectrum Disorders. Frontiers in Psychiatry. 2014;5:157.

[4] Mazzone L. et al. Catatonia in patients with autism: prevalence and management. CNS Drugs. 2014 Mar;28(3):205-15.

[5] Kiani R. et al. Anti-NMDA-receptor encephalitis presenting with catatonia and neuroleptic malignant syndrome in patients with intellectual disability and autism. BJPsych Bull. 2015 Feb;39(1):32-5.

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Breen J, & Hare DJ (2017). The nature and prevalence of catatonic symptoms in young people with autism. Journal of intellectual disability research : JIDR PMID: 28150394

Social interaction and autism: it takes two to tango

Psychology experiments are not generally fodder for this blog when it comes to autism. The main reason being that quite a few appearing in the peer-reviewed literature tend to look at quite abstract features perhaps somewhat removed from the daily lives of autistic people and their significant others. A few also seem to struggle with the idea that grand over-arching psychological theories (that seem to inevitably follow psychological findings in particular) are not required when it comes to autism in these days of heterogeneity and plurality.

I am making an exception today however with the paper by Noah Sasson and colleagues [1] (open-access) and their findings suggesting advocating "for a broader perspective of social difficulties in ASD [autism spectrum disorder] that considers both the individual’s impairments and the biases of potential social partners." In other words, it takes two to [socially, interactively] tango. I might add that a doctoral thesis by one of the co-authors on the Sasson paper (Daniel Faso) is also available for further inspection too (see here).

Based on the idea that issues with social interaction "quantity and quality" might not be something exclusively under the control of those diagnosed with autism, Sasson et al devised a series of experiments to test their hypothesis: "three studies conceived and conducted independently by three research groups assessing observers’ first impressions of—and intentions to socially engage with— children and adults with ASD based upon “thin slices” of their real-world social behavior." I'm not going to go into too much detail about the experiments because the paper is open-access and you can read about them for yourselves. 'Thin slices' in the context of the experiments carried out referred to media that were rated pertinent to "observers’ first impressions of individuals with ASD engaging in real-world social behavior."

The results make for some important reading as across the different experiments undertaken the key messages were that: "first impressions of individuals with ASD are significantly less favorable than those of matched TD [typically developing] controls, and are associated with greater reluctance on the part of observers to pursue social engagement." Further: "social interaction difficulties in ASD are not solely an individual impairment but also a relational one, and consideration of both of these factors is necessary for a full understanding of social impairment in ASD." I relay all of that bearing in mind that these were experiments carried out under controlled conditions (I don't know about you, but I don't generally rate people at first contact using a "0-3" Likert scale or a "non-graduated slider" on 'how approachable' they were or the likelihood of a friendship developing).

Although important, I don't think anyone should be too surprised by the results reported in the context of how first impressions count and how people are generally quick to judge from "personality and character traits" whether social engagement with a person or group of people is going to be a short or longer-term thing. I say this also bearing in mind that minus any psychobabble, people generally take into account things like context, familiarity and similarity when it comes to their social interaction decisions too [if for example, you happen to be a fan of Star Wars or a Shotokan karateka, I might be more inclined to chat with you than say if you talked about the goings-on on various reality TV shows]. Indeed, the authors note: "these studies present only group-wise comparisons and do not address individual differences among those with ASD, nor whether individual characteristics of the raters (e.g., gender, personality, etc.) affect the results reported here." I'd also forward the idea that they might also include important concepts such as self-monitoring for example when it comes to future studies in this area. Similarly, it would also be handy to see if 'comorbidity counts' when it comes to further investigations on this topic in light of expanding links between different labels and traits (see here).

The question of what to do about the Sasson findings similarly provide some food for thought. The authors suggest that: "intervention and education approaches that target both those with ASD as well as their TD [typically developing] peers may offer a more comprehensive approach for improving social and functional outcomes in autism." In the context of other studies looking at social interaction and autism particularly in the school setting (see here) I can see how this might work in terms of raising awareness of how people are not always the same when it comes to the presentation of their social persona. Intervening with a wider group (i.e. peers) and taking the onus off 'just the person with autism' is a win-win situation and will no doubt have other positive knock-on effects in terms of self-esteem and helping to remove barriers around the 'disability' framing of autism. I might add that in these days of the potential virality of personality traits, it makes sense to include everyone.

In a wider context - outside of school - and in the big, wide [adult] world however, I'm slightly less sure of how such intervention is going to be achieved. Yes, we would all love people to be more understanding and less 'judgemental' in their first (and subsequent) impressions, but when it comes to influencing aspects such as views on "awkwardness, attractiveness, [and] likability" I'm not so sure that this can be universally achieved. Indeed, facets such as attractiveness and likability are probably going to be influenced by lots of variables outside of those just linked to an autism diagnosis and its presentation (frank or not). By saying all that, I'm not suggesting that we shouldn't try to educate and perhaps even move people away from the whole 'first impressions last' [2] thing, but rather am looking at the realistic prospect of achieving such a societal goal, mindful that it takes two to tango...

And on the topic of first impressions, at least get the handshake right (i.e. let go)...

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[1] Sasson NJ. et al. Neurotypical Peers are Less Willing to Interact with Those with Autism based on Thin Slice Judgments. Sci Rep. 2017 Feb 1;7:40700.

[2] Gunaydin G. et al. Impressions Based on a Portrait Predict, 1-Month Later, Impressions Following a Live Interaction. Social Psychological and Personality Science. 2017. 8: 36-44.

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Sasson NJ, Faso DJ, Nugent J, Lovell S, Kennedy DP, & Grossman RB (2017). Neurotypical Peers are Less Willing to Interact with Those with Autism based on Thin Slice Judgments. Scientific reports, 7 PMID: 28145411

Vitamin D halting colds and flu?

"Overall, the study said one person would be spared infection for every 33 taking vitamin D supplements. That is more effective than flu vaccination, which needs to treat 40 to prevent one case, although flu is far more serious than the common cold."

That was some of the media interpretation of the paper - "systematic review and meta-analysis of individual participant data" - published by Adrian Martineau and colleagues [1] looking at the collected data on vitamin D supplementation "on risk of acute respiratory tract infection." Including data on approximately 11,000 'randomised' participants reported in 25 studies, authors assessed whether the quite messy data on vitamin d supplementation potentially decreasing the risk of acute respiratory tract infection showed any semi-definitive trends.

Results: "Vitamin D supplementation resulted in a statistically significant reduction in the proportion of participants experiencing at least one acute respiratory tract infection." Further: "Use of vitamin D did not influence risk of serious adverse events of any cause... or death due to any cause. Instances of potential adverse reactions to vitamin D were rare." And finally: "Subgroup analysis revealed that daily or weekly vitamin D supplementation without additional bolus doses protected against acute respiratory tract infection, whereas regimens containing large bolus doses did not."

I note that in the BBC news report on the Martineau paper we are told: "Public Health England (PHE) says the infections data is not conclusive, although it does recommend supplements." This slightly counter-intuitive position follows more general advice from the powers-that-be that perhaps we should all be taking a little more vitamin D (see here) given what is emerging when it comes to the varied functions of the sunshine vitamin/hormone. But bear in mind that supplementation comes with potential risks too (see here) particularly when people forget to treat their vitamins and minerals as what they are: biologically active pharmaceutics. Neither is everyone completely sold on the idea that vitamin D 'could stop colds or flu' as an accompanying editorial to the Martineau paper makes clear [2]: "The results are heterogeneous and not sufficiently applicable to the general population."

What such research does advance however, is that vitamin D is a potentially important nutrient (more so for some groups) and one that we should be [cautiously] dedicating a lot more investigation to for all-manner of possible reasons (see here and see here) outside of just bone health and the English disease. And within that scheme of research, don't forget a few things: (a) there's more to vitamin D metabolism than just 'getting enough' and (b) even today, science is still finding out new things about the chemistry of vitamin D [3]. In short, the scheme of science around vitamin D needs to be broad...

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[1] Martineau AR. et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ 2017; 356: i6583.

[2] Bolland MJ. & Avenell A. Do vitamin D supplements help prevent respiratory tract infections? BMJ 2017; 356: j456.

[3] Pauwels S. et al. 1β,25-Dihydroxyvitamin D3: A new vitamin D metabolite in human serum. J Steroid Biochem Mol Biol. 2017 Feb 10. pii: S0960-0760(17)30040-7.

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Adrian R Martineau, David A Jolliffe, Richard L Hooper, Lauren Greenberg, John F Aloia, Peter Bergman, Gal Dubnov-Raz, Susanna Esposito, & et al (2017). Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data BMJ : 10.1136/bmj.i6583

"early medical events are associated with clinical ASD phenotypes"

The paper by Charlotte Willfors and colleagues [1] (open-access) provides some food for thought today and the observation that various individual and cumulative medical events - "early medical events likely to be caused by environmental factors" - may be important to at least some autism.

Researchers "scrutinized the early medical histories of a rare and informative sample of 13 MZ [monozygotic] twin pairs discordant for clinical ASD [autism spectrum disorder]" also including "13 MZ typically developing (TD) control pairs (n=52) matched for sex" as an 'exploratory step. Discordant for autism means that one twin had autism and the other did not.

This research first step looked at medical events (likely to be caused by environmental factors!) included things like delivery and neonatal variables (e.g. foetal distress, hypoxia), minor and frequent infections (e.g. ear infections), allergy and epilepsy to name a few. Data was acquired from a few sources including medical records and medical history "assessed from a parent reported questionnaire." They examined exposure to the medical events "in relation to either quantitative or qualitative discordance for ASD." Qualitative discordance referred to when "only one twin within a pair meeting the diagnostic criteria of ASD." A 'confirmatory' study was also carried out whereby a larger, independent cohort of 100 twin pairs "quantitatively discordant for autistic traits" were also quizzed and findings cross-validated.

Results: a few non-shared environmental (NSE) events seemed to be important based on their analysis. So: "Single early medical factors, likely to be caused by NSE, that discriminated between twins in qualitative ASD discordant pairs were dysregulation during the first year of life (comprising feeding and sleeping problems, excessive crying and worrying) and birth weight." Authors also reported that cumulatively, the appearance of early medical events were significantly different in MZ twins with autism compared with their non-ASD co-twin. It's worth mentioning that some of those 'dysregulation' events have been talked about in the earliest descriptions of autism (see here). Birth weight too has something of a long-standing connection to [some] autism (see here). When it came to analysis based on autistic traits (the confirmatory study) it seemed that "early dysregulation and the cumulative load of a variety of early adverse medical events" continued to be important variables (although birth weight linked to ASD traits lost its significance).

These are important findings. The focus on MZ twins (who share a common structural genetic blueprint) means that the genetics side of things is to a large extent 'controlled for' and the results are more likely to reflect some environmental or, more accurately, non-genetic influence. There is a caveat to this though, as per the authors recognition: "with the exception of putative post-twinning de novo mutations." I might also add that MZ twins are also not necessarily epigenetically the same too so gene expression can (and does) differ. What causes these epigenetic differences is still the source of some debate but I might chime in with one idea (see here) out of many possibilities.

"Our data indicate that taking into account the cumulative load of early medical factors might strengthen or discourage a suspicion of ASD, at least in a minority of cases." This is an interesting thought provided by the authors based on their findings. It ties in well with the idea that although behavioural presentation is core to autism presentation and diagnosis, behaviour might not be the only important feature present in relation to autism. I do have to express a degree of caution however with such an approach based on the idea that various types of regression have been noted in the peer-reviewed literature to accompany some autism (see here) and with it, the concept of 'acquired autism' should really be properly recognised (see here for example) in these days of the plural 'autisms'. Indeed, there's a research study idea for anyone out there: looking at MZ twins discordant for autism with onset of said autism tied into a regression of skills?

Scientific replication is the name of the [future] game in this area of study, drawing on larger cohorts and perhaps based in other geographical areas outside of Sweden. We also need to find out what mechanisms might be potentially associating something like 'early dysregulation' with the onset of autism, taking into account how factors such as early feeding practices/issues for example, might provide at least one avenue for future study (see here).

To close, in light of some recent media headlines about the 'myth' that autism rates are on the up (and quite significantly so over past two decades), I offer some past posts suggesting that the word 'myth' should be reserved for other [non-peer-reviewed] matters (see here and see here and see here) and not this particular branch of epidemiological science. As to what may be 'causing' the upswing in numbers of diagnosed cases, well, it's likely to be very, very, very complicated (and without any need for sweeping generalisations please)...

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[1] Willfors C. et al. Medical history of discordant twins and environmental etiologies of autism. Transl Psychiatry. 2017 Jan 31;7(1):e1014.

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Willfors C, Carlsson T, Anderlid BM, Nordgren A, Kostrzewa E, Berggren S, Ronald A, Kuja-Halkola R, Tammimies K, & Bölte S (2017). Medical history of discordant twins and environmental etiologies of autism. Translational psychiatry, 7 (1) PMID: 28140403

"Androgens were not associated with autistic traits at 12 months of age"

EARLI - the Early Autism Risk Longitudinal Investigation study - has been mentioned on this blog before (see here) with the aim of the initiative to "examine possible environmental risk factors for autism and study whether there is any interplay between environmental factors and genetic susceptibility."

In this post I'm bringing the paper by Bo Park and colleagues [1] (open-access) to your attention and the observation(s) that umbilical cord blood levels of testosterone and other related androgens were seemingly not associated with autistic traits at 12 and 36 months of age in their cohort. Such findings represent yet another biological research blow (see here) to facets of the Extreme Male Brain (EMB) theory of autism and the suggestion that "ASD [autism spectrum disorder] is an extreme presentation of a typical male cognitive profile where the drive to “systemize” is stronger than the drive to empathize."

So, looking at cord blood samples from 137 children recruited on to EARLI - "a high autism-risk cohort following pregnant mothers with an older child diagnosed with an ASD (autistic disorder, Asperger syndrome, or pervasive developmental disorder not otherwise specified)" - researchers looked at whether measures of various androgens might correlate with scores on the Autism Observation Scales for Infants (AOSI) and Social Responsiveness Scale (SRS). Said schedules were administered at 12 months and 36 months respectively and various potentially confounding variables were taken into account when it came to looking at any associations. It's also worth pointing out that the technology of choice when it came to those measures of cord blood levels of androgens was an old favourite of this blog: liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Results: well as per the title of this post, and after adjustment for potentially confounding variables - "maternal age, gestational age, and cesarean delivery" - there wasn't a great deal to see in terms of levels of androgens and the presence of autistic traits. Indeed, the title of this post only tells half the story as testosterone was also found not to be associated with the SRS scores at 36 months too. The authors do note that: "Male infants (n=75) showed significantly higher umbilical cord testosterone levels and greater social deficits at 36 months of age" than females, but after adjustment for confounders this observation was left wanting. They also talk about some interesting observations about when a child had an older female sibling diagnosed with autism - "androgen levels and autistic traits may depend on sex of the older affected sibling" - but I'm not so sure about the strength of such findings and whether other mechanisms might also be at work. I might reiterate that autistic traits were the name of the research game in this study not a diagnosis of autism.

As mentioned, the Park findings represent another setback for the generalisability of the role of androgens (prenatal and beyond) in relation to autism and/or autistic traits. I guess that in these days of the plural 'autisms' (see here) it's perhaps not entirely unexpected that grand theories of autism seem doomed to fail when put up to scientific scrutiny. Indeed someone recently has talked about this [2]. I still however remain interested in the discussions around the EMB theory of autism, and although this and other research has not been entirely kind to the hypothesis, it is still perhaps deserving of further study in order to see who it may be most relevant to in these days of plural autisms and subgroupings...

To close, isn't this why Twitter was invented?

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[1] Park BY. et al. Umbilical cord blood androgen levels and ASD-related phenotypes at 12 and 36 months in an enriched risk cohort study. Molecular Autism. 2017; 8: 3.

[2] Müller R-A. & Amaral DG. Editorial: Time to give up on Autism Spectrum Disorder? Autism Res. 2017. Jan 27.

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Park, B., Lee, B., Burstyn, I., Tabb, L., Keelan, J., Whitehouse, A., Croen, L., Fallin, M., Hertz-Picciotto, I., Montgomery, O., & Newschaffer, C. (2017). Umbilical cord blood androgen levels and ASD-related phenotypes at 12 and 36 months in an enriched risk cohort study Molecular Autism, 8 (1) DOI: 10.1186/s13229-017-0118-z

Relative age and ADHD medication

"Youngest children in class 'more likely to be given ADHD drugs'" went the NHS Choices headline that led me to the short report produced by Martin Whitely and colleagues [1] (open-access).

ADHD - attention-deficit hyperactivity disorder - is something of interest to this blog; not least the idea that relative age (age relative to peers in the same school year group) might be an important variable when it comes to at least some diagnoses of the condition (see here).

The Whitely paper draws on data from a research favourite place - Western Australia (WA) - and focused on "the proportions of WA children born in the early and late months of a recommended school-year intake who received at least one Pharmaceutical Benefits Scheme [PBS] prescription for an ADHD medication in 2013."

The results: from a starting population of some 300,000 children, about 6,000 of them (~2%) were in receipt of a state-recognised prescription of an ADHD medication. The article does not actually mention which ADHD medication was given but methylphenidate (a.k.a Ritalin) is listed in the PBS directory and is the typically indicated medication used for ADHD (see here). Boys, we are told, were more likely to be prescribed ADHD medication than girls (2.9% vs. 0.8% respectively).

Then to the headline: when splitting the children into two age groups - 6-10 year olds and 11-15 year olds - researchers noted that those born in June (the last birth month influencing year of school intake) were more likely to be prescribed ADHD medication than those born in July. This trend was noted in both age groups. The conclusion being that the youngest children in a year group at school were more likely to be in receipt of prescribed medication for ADHD compared to older children in the year group.

Alongside the caveats linked to the Whitely report made by NHS Choices, there is a need for further investigation in this area and in particular, whether the results generalise to places outside of just WA. I've already linked to my previous discussion about relative age and ADHD diagnosis/medication (see here again) and from comparisons with the Taiwanese data [2] on this topic, including the fact that Taiwan have a different cut-off month for school entry (August 31). On that basis, yes the trend appears to generalise across geographies...

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[1] Whitely M. et al. Influence of birth month on the probability of Western Australian children being treated for ADHD. MJA. 2017; 206: Feb 6.

[2] Chen MH. et al. Influence of Relative Age on Diagnosis and Treatment of Attention-Deficit Hyperactivity Disorder in Taiwanese Children. J Pediatr. 2016 May;172:162-167.e1.

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Martin Whitely, Leanne Lester, John Phillimore, & Suzanne Robinson (2017). Influence of birth month on the probability of Western Australian children being treated for ADHD The Medical Journal of Australia